WHEN it comes to health, the news in recent times has been sombre.

It has been another rollercoaster year battling Covid, with the UK emerging from a third lockdown in spring.

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Millions of people have since had their jabs, and boosters are being rolled out as winter looms large.

But Covid is not the only big health story to come out of the past two years.

Behind the scenes, scientists around the world have been working on medical trials in the hope of finding cures for major illnesses.

And there have been dozens of major breakthroughs that could save billions of lives and change the way diseases are treated forever.

Just this month it emerged the vaccine for the human papillomavirus virus (HPV) could eradicate cervical cancer within the next few years.

From asthma to Alzheimers and cancer to infertility, CLARE OREILLY looks at the new treatments, vaccines and medicines that could put an end to some of the most common and deadly conditions.

CERVICAL cancer kills more than two women every day in the UK, claiming around 850 lives every year.

Yet a new study has found the disease could soon be a thing of the past.

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Kings College London scientists found the human papillomavirus (HPV) vaccine cut cases by 90 per cent.

The jab, which was first rolled out to teenage girls in the UK in 2008 then to boys in 2019, prevents HPV, which is responsible for nearly all cases of cervical cancer.

The study, in the Lancet, tracked women who received some of the first doses and found it prevented an estimated 17,200 pre-cancers and 450 cases in women in their twenties.

Cancer Research UKs chief executive Michelle Mitchell said: Its a historic moment to see the first study showing that the HPV vaccine has and will continue to protect women from cervical cancer.

A NEW antibody-based treatment developed by scientists in the UK and Germany could soon yield a vaccine to prevent Alzheimers.

The degenerative condition is thought to be caused by a type of protein that sticks to brain cells.

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The scientists were able to trigger the immune system to make antibodies, which targeted the protein before it was deposited.

Professor Mark Carr, who led a team at the University of Leicester, said: It has the real potential to provide an effective treatment for Alzheimers using a therapeutic antibody and highlights the potential of a simple vaccine.

Meanwhile, a year-long study has started in Norway where Alzheimers patients will receive a transfusion of blood taken from runners.

It is hoped the chemicals released in the blood after running have a rejuvenating effect to slow disease progression.

THREE new drugs are being put through trials in the hope they could end the misery of hot flushes for menopausal women.

Hot flushes are thought to be caused by changes in hormone levels affecting the bodys temperature control.

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But the medicines fezolinetant, elinzanetant and pavinetant can block the receptors which are responsible for the common symptom.

London GP Dr Zoe Watson says it could be years before the treatment is available on the NHS, though.

She says: It looks interesting in theory, but there are question marks over its efficacy, its side-effect profile and its cost.

Certainly if it does this well then it could be extremely useful for women whose most troubling menopausal symptom is hot flushes.

However, menopause is much more than just hot flushes and halting periods."

A BRAND new injection could reverse spinal cord injuries and allow patients to walk again just four weeks after treatment.

Developed by a team at Northwestern University in the US, the jab encourages nerves to regrow.

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It gave paralysed mice the ability to walk and human trials are expected to begin next year.

For decades, this has remained a major challenge for scientists because our bodys central nervous system, which includes the brain and spinal cord, doesnt have any significant capacity to repair itself after injury.

Professor Samuel Stupp said: Our research aims to find a therapy that can prevent individuals from becoming paralysed after major trauma or disease.

We are going straight to the FDA [the US Food and Drug Administration] to get this approved for use in patients.

DEMENTIA affects around 850,000 people in the UK and costs 26.3billion a year, but scientists at Durham University have made a breakthrough.

They are working on a treatment that could boost memory and muscle control in patients with the killer disease.

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Using infrared light to zap the brain improved the memory and thought processing in trials of healthy people.

And the next step is to enlist dementia patients to test the therapy.

Its delivered by a specially equipped helmet, which beams invisible light waves into the brain and forces cells to boost levels, improving blood flow too.

Dr Paul Chazot, who led the study, said: While more research is needed, there are promising signs that therapy involving infrared light might also be beneficial for people living with dementia and this is worth exploring.

ANYONE with asthma knows how debilitating it can be to receive a diagnosis.

Yet more than five million people in the UK are asthmatic. But a brand new drug, already approved for use on the NHS, is set to transform the lives of many with the condition, making attacks less frequent and less severe.

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Dupilumab is prescribed to treat eczema and rhinosinusitis a type of sinusitis where the nasal cavity as well as sinuses become inflamed.

Its from a family of drugs used to treat Covid.

Currently only patients with very serious asthma who have had at least four severe asthma attacks in the last year and are ineligible for other biological treatments will be considered for a prescription.

But the drug is set to change the lives of many asthma sufferers across the country.

HALF of us will get cancer at some point in our lives. But new jab Survivin could change the landscape dramatically, scientists say.

The first clinical trials are already under way, and the injection works to boost the bodys immune system. It supercharges the immune cells, helping them seek out and destroy cancerous cells while leaving healthy cells alone.

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Currently there are 36 terminally ill patients taking part in the trials, which are focused on ovarian, prostate and lung cancers.

Michelle Mitchell, chief executive of Cancer Research UK, said: Just this month we heard the HPV vaccine has likely prevented hundreds of women from developing cervical cancer.

This is a new and exciting frontier in cancer medicine and if this trial and others are successful, we could see thousands more lives saved.

AROUND seven per cent of all men are affected by infertility.

And while treatments currently focus on solutions rather than cures, scientists at the University of Georgia, in the US, are looking to reverse male infertility altogether.

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The researchers have used primate embryonic stem cells the building blocks of all cells in the body to grow sperm cells in the earlier stages of development in a petri dish.

These spermatids, which lack a head and tail for swimming, were capable of fertilising a rhesus macaque egg in vitro.

Lead researcher and associate professor Dr Charles Easley says: This is a major breakthrough towards producing stem cell-based therapies to treat male infertility in cases where the men do not produce any viable sperm cells.

It is the first step that shows this technology is potentially translatable.

GETTING through the blood/brain barrier to target treatments for brain cancer is complex.

But now a team of scientists in Toronto, Canada, have found a way to use ultrasound beams.

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They help open the barrier and can help facilitate drug delivery, which could change the way the disease is treated.

A trial this year saw four women with breast cancer that had spread to their brains treated with magnetic resonance-guided focused ultrasound (MRgFUS).

It allowed the antibody therapy herceptin to pass into their brain tissue, and caused the tumours to shrink without damaging any healthy tissue.

Dr Nir Lipsman, who led the study, said: It has long been theorised that focused ultrasound can be used to enhance drug delivery, but this is the first time we have shown we can get drugs into the brain.

A DRUG taken in pill form is to be trialled to combat the deadliest form of cancer.Auceliciclib is already used to treat brain tumours.

But now scientists hope it can help fight pancreatic cancer, which is often first diagnosed when it is at a late stage.

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Professor Shudong Wang and her team at the University of South Australia are also working on new ways to detect the disease.

She said: Pancreatic cancer is extremely difficult to diagnose at an early stage because there are very few symptoms.

If it is caught early the malignant tumour can be surgically removed, but once it spreads into other organs it is lethal.

Chemotherapy and radiotherapy only buy patients a little extra time.

The team hopes the drug will be more effective and with fewer side-effects than current treatment options.

THE heroic scientists who developed the Covid vaccine did not stop there.

The team at the University of Oxford has also developed a malaria jab that will save billions of lives.

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A trial showed 77 per cent of volunteers who were vaccinated stayed malaria-free over the following 12 months.

More than 100 malaria vaccines have been developed in recent decades, but the Oxford jab is the first to have such a high success rate.

Halidou Tinto, professor of parasitology and the principal investigator on the trial, said: These are very exciting results showing unprecedented efficacy levels from a vaccine that has been well-tolerated in our trial programme.

We look forward to the upcoming phase III trial to demonstrate large-scale safety and efficacy data for a vaccine that is greatly needed.

A DRUG that repairs cancerous cells could revolutionise the way breast cancer is treated.

Patients given olaparib as part of a two-and-a-half year trial were 42 per cent less likely to see their cancer return.

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There was also a 43 per cent dEcrease in the risk of the disease spreading.

Until the breakthrough earlier this year, the drug was mainly used for late-stage cancers, but the new findings suggest it is effective as an early treatment.

Professor Andrew Tutt, professor of oncology at the Institute of Cancer Research who led the study, said: Women with early-stage breast cancer who have inherited BRCA1 or BRCA2 mutations are typically diagnosed at a younger age.

Up to now, there has been no treatment that specifically targets the unique biology of these cancers to reduce the rate of recurrence, beyond initial treatment such as surgery.

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From asthma to cancer to infertility, the new treatments, jabs and meds making us healthier... - The Sun

Spinal Cord Stem Cells Comments Off on From asthma to cancer to infertility, the new treatments, jabs and meds making us healthier… – The Sun | November 22nd, 2021

This article was originally published here

Sci Rep. 2021 Nov 5;11(1):21722. doi: 10.1038/s41598-021-01071-2.

ABSTRACT

Spinal cord regeneration is limited due to various obstacles and complex pathophysiological events after injury. Combination therapy is one approach that recently garnered attention for spinal cord injury (SCI) recovery. A composite of three-dimensional (3D) collagen hydrogel containing epothilone B (EpoB)-loaded polycaprolactone (PCL) microspheres (2.5 ng/mg, 10 ng/mg, and 40 ng/mg EpoB/PCL) were fabricated and optimized to improve motor neuron (MN) differentiation efficacy of human endometrial stem cells (hEnSCs). The microspheres were characterized using liquid chromatography-mass/mass spectrometry (LC-mas/mas) to assess the drug release and scanning electron microscope (SEM) for morphological assessment. hEnSCs were isolated, then characterized by flow cytometry, and seeded on the optimized 3D composite. Based on cell morphology and proliferation, cross-linked collagen hydrogels with and without 2.5 ng/mg EpoB loaded PCL microspheres were selected as the optimized formulations to compare the effect of EpoB release on MN differentiation. After differentiation, the expression of MN markers was estimated by real-time PCR and immunofluorescence (IF). The collagen hydrogel containing the EpoB group had the highest HB9 and ISL-1 expression and the longest neurite elongation. Providing a 3D permissive environment with EpoB, significantly improves MN-like cell differentiation and maturation of hEnSCs and is a promising approach to replace lost neurons after SCI.

PMID:34741076 | DOI:10.1038/s41598-021-01071-2

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Improving motor neuron-like cell differentiation of hEnSCs by the combination of epothilone B loaded PCL microspheres in optimized 3D collagen...

Spinal Cord Stem Cells Comments Off on Improving motor neuron-like cell differentiation of hEnSCs by the combination of epothilone B loaded PCL microspheres in optimized 3D collagen… | November 8th, 2021

The scientists, Christopher Rathnam and colleagues, say they have designed a way of controlling the formation of 3D spheroids made from stem cells, while enhancing the spheroids ability to differentiate into functional neurons.

The technology led to an increase in stem cell survival and differentiation two challenges with existing stem cell therapy systems in a mouse model of spinal cord injury, noted the team in a paper published inScience Advances

We believe that our technology platform is an ideal candidate for improving many other types of cell therapies that require high cell survival and effective control of cell fate, making it useful not only for treating [spinal cord injuries] but also for various other diseases and disorders, said the authors.

Although stem cell therapy holds enormous potential for treating debilitating injuries and diseases of the CNS, the team outlined how low survival and inefficient differentiation have restricted its clinical applications.

Recently, 3D cell culture methods, such as stem cellbased spheroids and organoids, have demonstrated advantages by incorporating tissue-mimetic 3D cell-cell interactions, said the experts.

However, a lack of drug and nutrient diffusion, insufficient cell-matrix interactions, and tedious fabrication procedures have compromised their therapeutic effects in vivo, they added.

To address these issues, the Rathnam led team developed a method in which biodegradable manganese dioxide nanosheets guide the rapid assembly of neural stem cells, derived from human induced pluripotent stem cells (iPSCs), into 3D spheroids.

The technique also enables controlled drug release inside the core of the spheroids, which could help to improve cell survival and differentiation, they said.

To evaluate the efficacy of the structures, which they termed synthetic matrix-assisted and rapidly templated (SMART) spheroids, the researchers implanted them at injury sites in a mouse model of spinal cord injury.

As controls, they injected cell suspensions and conventional neurospheres, formed without the use of their novel nanosheets, at the spinal cord injury sites, with the same total number of cells per animal and at the same concentrations.

They found significantly higher cell survival and improved neuronal differentiation efficiency for the SMART neurospheres compared with the controls both 7 days and 1 month after injection.

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Spinal Cord Stem Cells Comments Off on Team finds way to enhance stem cell therapy for CNS injuries – BioPharma-Reporter.com | October 28th, 2021

Forty years ago,neurologistsand neurobiologistsbelieved that the adult brain became lessplastic and less able to learn and retain new things.Theyhad no idea that non-neuronal cells had anything to do with information processing in the brain, including learning and memory.

Now,afterdecades of researchingand characterizinga particular cell type, called glial cells, in the brain, Akiko Nishiyama, professor of physiology and neurobiology and the new department head,can tell youthatthese cells areessential to enabling humans to learn new tasks well into adulthood, thanks to a very dynamic regulation of the ability of oligodendrocyte precursor cells she had found to generate mature myelin-forming cells. She believes that these cells also play a yet unidentified critical role in the network of brain activity.

We sat down with Nishiyama to talk about her goals for the department and current trends in the growing field of physiology and neurobiology.

What isthephysiology and neurobiology (PNB)majorat UConn?

Physiology is the study of how different parts of the body work, andneurobiology is the study of how the nervous system (brain, spinal cord, and peripheral nerves) works, and this is what I study.ThePNBdepartmentis where faculty andstudentsstudy both disciplines.

In the early- to mid-20th Century, we saw a tremendous expansion of the study of the nervous system, which led to the emergence of a multi-disciplinary field called neurobiology. The name of our department reflects this transition.

How did you get started inneurobiology? Tell us about your research.

I startedmy career in neuropathologyafter finishing six years of medical training.I was curious about how different cells in the nervous system support the function of neurons and how these support cells, known as glial cells, might malfunction in the process of neurodegenerative diseases. Halfway through the residency-doctoral program, I switched to a more basic doctoral program in molecular neurobiology, because I wanted to ask fundamental molecular and cellular questions about how different glial cells in the nervous system interact with neurons.

I sought my postdoctoral training in a lab studying the NG2 protein that seemed to be present in a yet-unidentified subset of glia,andI spent my career characterizing them.

Thirty years later, these cells have become widely known to cellular neurobiologists and have made it into textbooks. My studies established that NG2 cells are precursor cells to oligodendrocytes that make myelin sheaths but are different from stem cells or other known glial cell types.

Now we know these myelin structures are constantly being remodeled as we learn new skills as adults. And if you disrupt the process of the precursor cells, you disrupt the ability to acquire new tasks or learn new motor skills.

Why are these cells important?

We used to think that myelin was formed during the few years after birth and remained stable throughout life.What I found was that oligodendrocyte precursor cells persist in the adult brain and are implicated in some neurological disorders, such as multiple sclerosis.

Thisis an expanding areaof research in a new field called myelin plasticity.Myelin repair is important for the functional repair not only in multiple sclerosis but also after trauma such as spinal cord injury. New genomic studies are emerging that have linked oligodendrocytes to neuropsychiatric and neurodegenerative diseases such as schizophrenia and Parkinsons disease.

What are some of the things you can do with a degree in PNB?

We provide a wide-ranging set of skills, collectively, in the department, because the possibilities grow every day.

Many of our undergraduate students pursue medical, dental, or other health care professions. For instance, we recently developed theInteroperative Neuromonitoring Programwith a masters degree in Surgical Neurophysiology. This program trains specialized medical technologists who monitor the patients muscle and brain activity and other neurophysiologicalindicatorsduring surgery that may be important for surgeons and anesthesiologists to see in real-time.

Some PNB majors go to graduate school to pursue a career in academic or industry research. In addition,students withan advanced degree inphysiology andneurobiology can become teachers or science writers.

Regardless of whether they are pursuing research, we train our undergraduate students to develop a good habit ofidentifying and thinkingthrough a problem. We have faculty with diverse expertise, and our students are introduced to a wide range of questions and approaches to answer them in the classroom as well as in faculty laboratories.

What are some of your goals for the department over the next five years?

Imreally luckyto have astrong andfriendly department. Its a smallenoughdepartment that I can get to knoweach faculty and staff memberquite well.

I would like tobetter connectwith our undergraduate majors early during their time at UConn. Currently, we see them for the first time when they take our gatewayHuman Physiology and Anatomycourse in their sophomore year, and most of our faculty do not see them until they are juniors or seniors. I am interested in exposing freshmen and early sophomores to more experientialtypesof learning, monitoring their progress, and providing feedback and support where needed.

One of the strengths of our department is our facultys research. Many of our faculty, especially the younger faculty, have expanding research programs, have been successful in securing large external grants, and are active in mentoring graduate and undergraduate students in their labs. I would like to provide an environment where the successful faculty can attain an even greater level of excellence and as a department attract a larger number of talented doctoral and postdoctoral trainees to UConn.

I would like to strengthen our graduate program to providemoremultidisciplinary training for the next generation of physiologists andneurobiologiststo gain quantitative and computer skillsas well.

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Two teens developed severe psychiatric symptoms such as paranoia, delusions and suicidal thoughts during mild COVID-19 infections. Now, scientists think they've identified a potential trigger: Rogue antibodies may have mistakenly attacked the teens' brains, rather than the coronavirus.

The researchers spotted these rogue antibodies in two teens who were examined at the University of California, San Francisco (UCSF) Benioff Childrens Hospital after catching COVID-19 in 2020, according to a new report on the cases published Monday (Oct. 25) in the journal JAMA Neurology. The antibodies appeared in the patients' cerebrospinal fluid (CSF), which is a clear liquid that flows in and around the hollow spaces of the brain and spinal cord.

But while such antibodies may attack brain tissue, it's too early to say that these antibodies directly caused the troubling symptoms in the teens, the researchers wrote in the new study. That's because many of the identified antibodies appear to target structures located on the inside of cells, rather than on the outside, co-author Dr. Samuel Pleasure, a physician-scientist and professor of neurology at UCSF, told Live Science in an email.

Related: 20 of the worst epidemics and pandemics in history

"So, we suspect that either the COVID autoantibodies" meaning antibodies that attack the body rather than the virus "are indicative of an out of control autoimmune response that might be driving the symptoms, without the antibodies necessarily causing the symptoms directly," he said. Future studies will be needed to test this hypothesis, and to see whether any other, undiscovered autoantibodies target structures on the surface of cells and thus cause direct damage, he added.

The study's results demonstrate that COVID-19 may trigger the development of brain-targeting autoantibodies, said Dr. Grace Gombolay, a pediatric neurologist at Childrens Healthcare of Atlanta and an assistant professor at Emory University School of Medicine, who wasn't involved in the new study. And they also hint that, in some cases, treatments that "calm down" the immune system may help resolve psychiatric symptoms of COVID-19, she told Live Science in an email.

Both teens in the study received intravenous immunoglobulin, a therapy used to essentially reset the immune response in autoimmune and inflammatory disorders, after which the teens' psychiatric symptoms either partially or completely remitted. But it's possible the patients would have "improved on their own, even without treatment," and this study is too small to rule this out, Gombolay noted.

Other viruses, such as herpes simplex virus, can sometimes drive the development of antibodies that attack brain cells, trigger harmful inflammation and cause neurological symptoms, Gombolay said. "Thus, it is reasonable to suspect that an association could also be seen in COVID-19."

Prior to their research in teens, the study authors published evidence of neural autoantibodies in adult COVID-19 patients. According to a report published May 18 in the journal Cell Reports Medicine, these adult patients experienced seizures, loss of smell and hard-to-treat headaches, and most of them had also been hospitalized due to the respiratory symptoms of COVID-19.

But "in the case of these teens, the patients had quite minimal respiratory symptoms," Pleasure said. This suggests that there's a chance of such symptoms arising during or after cases of mild respiratory COVID-19, Pleasure said.

Over the course of five months in 2020, 18 children and teens were hospitalized at UCSF Benioff Children's Hospital with confirmed COVID-19; the patients tested positive for the virus with either a PCR or rapid antigen test. From this group of pediatric patients, the study authors recruited three teens who underwent neurological evaluations and became the focus for the new case study.

One patient had a history of unspecified anxiety and depression, and after catching COVID-19 they developed signs of delusion and paranoia. The second patient had a history of unspecified anxiety and motor tics, and following infection they experienced rapid mood shifts, aggression and suicidal thoughts; they also experienced "foggy brain," impaired concentration and difficulty completing homework. The third patient, who had no known psychiatric history, was admitted after exhibiting repetitive behaviors, disordered eating, agitation and insomnia for several days, when they hadn't shown these behaviors previously.

As part of their neurological examinations, each teen underwent a spinal tap, where a sample of CSF is drawn from the lower back. All three patients had elevated antibody levels in their CSF, but only the CSF of patients 1 and 2 carried antibodies against SARS-CoV-2, the virus that causes COVID-19. In those two teens, it's possible the virus itself infiltrated their brains and spinal cords, the study authors noted. "I would suspect that if there is direct viral invasion it is transient, but there is still a lot of uncertainty here," Pleasure noted.

These same patients also carried neural autoantibodies in their CSF: In mice, the team found that these antibodies latched onto several areas of the brain, including the brain stem; the cerebellum, located at the very back of the brain; the cortex; and the olfactory bulb, which is involved in smell perception.

The team then used lab-dish experiments to identify the targets the neural antibodies grabbed onto. The researchers flagged a number of potential targets and zoomed in on one in particular: a protein called transcription factor 4 (TCF4). Mutations in the gene for TCF4 can cause a rare neurological disorder called Pitt-Hopkins syndrome, and some studies hint that dysfunctional TCF4 may be involved in schizophrenia, according to a 2021 report in the journal Translational Psychiatry.

These findings hint that the autoantibodies might contribute to a runaway immune response that causes psychiatric symptoms in some COVID-19 patients, but again, the small study cannot prove that the antibodies themselves directly cause disease. It may be that other immune-related factors, apart from the antibodies, drive the emergence of these symptoms.

"These autoantibodies may be most clinically meaningful as markers of immune dysregulation, but we havent found evidence that they are actually causing the patients symptoms. Theres certainly more work to be done in this area," co-first author Dr. Christopher Bartley, an adjunct instructor in psychiatry at the UCSF Weill Institute for Neurosciences, said in a statement.

In future studies, "it would be helpful to examine CSF of children with COVID-19 who did not have neuropsychiatric symptoms," as a point of comparison to those who did, Gombolay said. "However, obtaining CSF from those patients is challenging as CSF has to be obtained by a spinal tap, and a spinal tap is not typically done unless a patient has neurological symptoms."

That said, the team is now collaborating with several groups studying long COVID, who are collecting CSF samples from patients with and without neuropsychiatric symptoms, Pleasure said. "In adults, it is not uncommon to have patients be willing to undergo a spinal tap for research purposes with appropriate informed consent and institutional review." Using these samples, as well as some studies in animal models, the team will work to pinpoint the autoimmune mechanisms behind these troubling neuropsychiatric symptoms, and figure out how autoantibodies fit into that picture.

Originally published on Live Science.

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'Rogue' antibodies found in brains of teens with delusions and paranoia after COVID-19 - Livescience.com

Spinal Cord Stem Cells Comments Off on ‘Rogue’ antibodies found in brains of teens with delusions and paranoia after COVID-19 – Livescience.com | October 28th, 2021

Abstract

Traumatic spinal cord injury (SCI) is a life changing neurological condition with substantial socioeconomic implications for patients and their care-givers. Recent advances in medical management of SCI has significantly improved diagnosis, stabilization, survival rate and well-being of SCI patients. However, there has been small progress on treatment options for improving the neurological outcomes of SCI patients. This incremental success mainly reflects the complexity of SCI pathophysiology and the diverse biochemical and physiological changes that occur in the injured spinal cord. Therefore, in the past few decades, considerable efforts have been made by SCI researchers to elucidate the pathophysiology of SCI and unravel the underlying cellular and molecular mechanisms of tissue degeneration and repair in the injured spinal cord. To this end, a number of preclinical animal and injury models have been developed to more closely recapitulate the primary and secondary injury processes of SCI. In this review, we will provide a comprehensive overview of the recent advances in our understanding of the pathophysiology of SCI. We will also discuss the neurological outcomes of human SCI and the available experimental model systems that have been employed to identify SCI mechanisms and develop therapeutic strategies for this condition.

Keywords: spinal cord injury, secondary injury mechanisms, clinical classifications and demography, animal models, glial and immune response, glial scar, chondroitin sulfate proteoglycans (CSPGs), cell death

Spinal cord injury (SCI) is a debilitating neurological condition with tremendous socioeconomic impact on affected individuals and the health care system. According to the National Spinal Cord Injury Statistical Center, there are 12,500 new cases of SCI each year in North America (1). Etiologically, more than 90% of SCI cases are traumatic and caused by incidences such as traffic accidents, violence, sports or falls (2). There is a reported male-to-female ratio of 2:1 for SCI, which happens more frequently in adults compared to children (2). Demographically, men are mostly affected during their early and late adulthood (3rd and 8th decades of life) (2), while women are at higher risk during their adolescence (1519 years) and 7th decade of their lives (2). The age distribution is bimodal, with a first peak involving young adults and a second peak involving adults over the age of 60 (3). Adults older than 60 years of age whom suffer SCI have considerably worse outcomes than younger patients, and their injuries usually result from falls and age-related bony changes (1).

The clinical outcomes of SCI depend on the severity and location of the lesion and may include partial or complete loss of sensory and/or motor function below the level of injury. Lower thoracic lesions can cause paraplegia while lesions at cervical level are associated with quadriplegia (4). SCI typically affects the cervical level of the spinal cord (50%) with the single most common level affected being C5 (1). Other injuries include the thoracic level (35%) and lumbar region (11%). With recent advancements in medical procedures and patient care, SCI patients often survive these traumatic injuries and live for decades after the initial injury (5). Reports on the clinical outcomes of patients who suffered SCI between 1955 and 2006 in Australia demonstrated that survival rates for those suffering from tetraplegia and paraplegia is 91.2 and 95.9%, respectively (5). The 40-year survival rate of these individuals was 47 and 62% for persons with tetraplegia and paraplegia, respectively (5). The life expectancy of SCI patients highly depends on the level of injury and preserved functions. For instance, patients with ASIA Impairment Scale (AIS) grade D who require a wheelchair for daily activities have an estimated 75% of a normal life expectancy, while patients who do not require wheelchair and catheterization can have a higher life expectancy up to 90% of a normal individual (6). Today, the estimated life-time cost of a SCI patient is $2.35 million per patient (1). Therefore, it is critical to unravel the cellular and molecular mechanisms of SCI and develop new effective treatments for this devastating condition. Over the past decades, a wealth of research has been conducted in preclinical and clinical SCI with the hope to find new therapeutic targets for traumatic SCI.

SCI commonly results from a sudden, traumatic impact on the spine that fractures or dislocates vertebrae. The initial mechanical forces delivered to the spinal cord at the time of injury is known as primary injury where displaced bone fragments, disc materials, and/or ligaments bruise or tear into the spinal cord tissue (79). Notably, most injuries do not completely sever the spinal cord (10). Four main characteristic mechanisms of primary injury have been identified that include: (1) Impact plus persistent compression; (2) Impact alone with transient compression; (3) Distraction; (4) Laceration/transection (8, 11). The most common form of primary injury is impact plus persistent compression, which typically occurs through burst fractures with bone fragments compressing the spinal cord or through fracture-dislocation injuries (8, 12, 13). Impact alone with transient compression is observed less frequently but most commonly in hyperextension injuries (8). Distraction injuries occur when two adjacent vertebrae are pulled apart causing the spinal column to stretch and tear in the axial plane (8, 12). Lastly, laceration and transection injuries can occur through missile injuries, severe dislocations, or sharp bone fragment dislocations and can vary greatly from minor injuries to complete transection (8). There are also distinct differences between the outcomes of SCI in military and civilian cases. Compared to civilian SCI, blast injury is the common cause of SCI in battlefield that usually involves multiple segments of the spinal cord (14). Blast SCI also results in higher severity scores and is associated with longer hospital stays (15). A study on American military personnel, who sustained SCI in a combat zone from 2001 to 2009, showed increased severity and poorer neurological recovery compared to civilian SCI (15). Moreover, lower lumbar burst fractures and lumbosacral dissociation happen more frequently in combat injuries (1). Regardless of the form of primary injury, these forces directly damage ascending and descending pathways in the spinal cord and disrupt blood vessels and cell membranes (11, 16) causing spinal shock, systemic hypotension, vasospasm, ischemia, ionic imbalance, and neurotransmitter accumulation (17). To date, the most effective clinical treatment to limit tissue damage following primary injury is the early surgical decompression (< 24 h post-injury) of the injured spinal cord (18, 19). Overall, the extent of the primary injury determines the severity and outcome of SCI (20, 21).

Functional classification of SCI has been developed to establish reproducible scoring systems by which the severity of SCI could be measured, compared, and correlated with the clinical outcomes (20). Generally, SCI can be classified as either complete or incomplete. In complete SCI, neurological assessments show no spared motor or sensory function below the level of injury (4). In the past decades, several scoring systems have been employed for clinical classification of neurological deficits following SCI. The first classification system, Frankel Grade, was developed by Frankel and colleagues in 1969 (22). They assessed the severity and prognosis of SCI using numerical sensory and motor scales (22). This was a 5-grade system in which Grade A was the most severe SCI with complete loss of sensory and motor function below the level of injury. Grade B represented complete motor loss with preserved sensory function and sacral sparing. Patients in Grade C and D had different degrees of motor function preservation and Grade E represented normal sensory and motor function. The Frankel Grade was widely utilized after its publication due to its ease of use. However, lack of clear distinction between Grades C and D and inaccurate categorization of motor improvements in patients over time, led to its replacement by other scoring systems (20).

Other classification methods followed Frankel's system. In 1987, Bracken et al. at Yale University School of Medicine classified motor and sensory functions separately in a 5 and 7-scale systems, respectively (23). However, this scoring system failed to account for sacral function (20). Moreover, integration of motor and sensory classifications was impossible in this system and it was abandoned due to complexity and impracticality in clinical settings (20). Several other scoring systems were developed in 1970' and 1980's by different groups such as Lucas and Ducker at the Maryland Institute for Emergency Medical Services in late 1970's (24), Klose and colleagues at the University of Miami Neuro-spinal Index (UMNI) in early 1980s (25) and Chehrazi and colleagues (Yale Scale) in 1981 (26). These scoring systems also became obsolete due to their disadvantage in evaluation of sacral functions, difficulty of use or discrepancies between their motor and sensory scoring sub-systems (20).

The ASIA scoring system is currently the most widely accepted and employed clinical scoring system for SCI. ASIA was developed in 1984 by the American Spinal Cord Injury Association and has been updated over time to improve its reliability (). In this system, sensory function is scored from 02 and motor function from 0 to 5 (20). The ASIA impairment score (AIS) ranges from complete loss of sensation and movement (AIS = A) to normal neurological function (AIS = E). The first step in ASIA system is to identify the neurological level of injury (NLI). In this assessment, except upper cervical vertebrae that closely overlay the underlying spinal cord segments, the anatomical relationship between the spinal cord segments and their corresponding vertebra is not reciprocally aligned along the adult spinal cord (20). At thoracic and lumbar levels, each vertebra overlays a spinal cord segment one or two levels below and as the result, a T11 vertebral burst fracture results in neurological deficit at and below L1 spinal cord segment. Hence, the neurological level of injury (NLI) is defined as the most caudal neurological level at which all sensory and motor functions are normal (20). Upon identifying the NLI, if the injury is complete (AIS = A), zone of partial preservation (ZPP) is determined (20). ZPP is defined as all the segments below the NLI that have some preserved sensory or motor function. A precise record of ZPP enables the examiners to distinguish spontaneous from treatment-induced functional recovery, thus, essential for evaluating the therapeutic efficacy of treatments (20). Complete loss of motor and preservation of some sensory functions below the neurological level of the injury is categorized as AIS B (20). If motor function is also partially spared below the level of the injury, AIS score can be C or D (20). The AIS is scored D when the majority of the muscle groups below the level of the injury exhibit strength level of 3 or higher (for more details see ). ASIA classification combines the assessments of motor, sensory and sacral functions, thus addressing the shortcomings of previous scoring systems (20). The validity and reproducibility of ASIA system combined with its accuracy in prediction of patients' outcome have made it the most accepted and reliable clinical scoring system utilized for neurological classification of SCI (20).

ASIA scoring for the neurological classification of the SCI. A sample scoring sheet used for ASIA scoring in clinical setting is provided (adopted from: http://asia-spinalinjury.org).

In clinical management of SCI, neurological outcomes are generally determined at 72 h after injury using ASIA scoring system (20, 27). This time-point has shown to provide a more precise assessment of neurological impairments after SCI (28). One important predictor of functional recovery is to determine whether the injury was incomplete or complete. As time passes, SCI patients experience some spontaneous recovery of motor and sensory functions. Most of the functional recovery occurs during the first 3 months and in most cases reaches a plateau by 9 months after injury (20). However, additional recovery may occur up to 1218 months post-injury (20). Long term outcomes of SCI are closely related to the level of the injury, the severity of the primary injury and progression of secondary injury, which will be discussed in this review.

Depending on the level of SCI, patients experience paraplegia or tetraplegia. Paraplegia is defined as the impairment of sensory or motor function in lower extremities (27, 28). Patients with incomplete paraplegia generally have a good prognosis in regaining locomotor ability (~76% of patients) within a year (27). Complete paraplegic patients, however, experience limited recovery of lower limb function if their NLI is above T9 (29). An NLI below T9 is associated with 38% chance of regaining some lower extremity function (29). In patients with complete paraplegia, the chance of recovery to an incomplete status is only 4% with only half of these patients regaining bladder and bowel control (29). Tetraplegia is defined as partial or total loss of sensory or motor function in all four limbs. Patients with incomplete tetraplegia will gain better recovery than complete tetra- and paraplegia (30). Unlike complete SCI, recovery from incomplete tetraplegia usually happens at multiple levels below the NLI (20). Patients generally reach a plateau of recovery within 912 months after injury (20). Regaining some motor function within the first month after the injury is associated with a better neurological outcome (20). Moreover, appearance of muscle flicker (a series of local involuntary muscle contractions) in the lower extremities is highly associated with recovery of function (31). Patients with complete tetraplegia, often (6690%) regain function at one level below the injury (28, 30). Importantly, initial muscle strength is an important predictor of functional recovery in these patients (20). Complete tetraplegic patients with cervical SCI can regain antigravity muscle function in 27% of the cases when their initial muscle strength is 0 on a 5-point scale (32). However, the rate of regaining antigravity muscle strength at one caudal level below the injury increases to 97% when the patients have initial muscle strength of 12 on a 5-point scale (33).

An association between sensory and motor recovery has been demonstrated in SCI where spontaneous sensory recovery usually follows the pattern of motor recovery (20, 34). Maintenance of pinprick sensation at the zone of partial preservation or in sacral segments has been shown as a reliable predictor of motor recovery (35). One proposed reason for this association is that pinprick fibers in lateral spinothalamic tract travel in proximity of motor fibers in the lateral corticospinal tract, and thus, preservation of sensory fibers can be an indicator of the integrity of motor fiber (20). Diagnosis of an incomplete injury is of great importance and failure to detect sensory preservation at sacral segments results in an inaccurate assessment of prognosis (20).

In the past few decades, various animal models have been developed to allow understanding the complex biomedical mechanisms of SCI and to develop therapeutic strategies for this condition. An ideal animal model should have several characteristics including its relevance to the pathophysiology of human SCI, reproducibility, availability, and its potential to generate various severities of injury (36).

Small rodents are the most frequently employed animals in SCI studies due to their availability, ease of use and cost-effectiveness compared to primates and larger non-primate models of SCI (36, 37). Among rodents, rats more closely mimic pathophysiological, electrophysiological, functional, and morphological features of non-primate and human SCI (38). In rat (39), cat (40), monkey (41), and human SCI (17), a cystic cavity forms in the center of the spinal cord, which is a surrounded by a rim of anatomically preserved white matter. A study by Metz and colleagues compared the functional and anatomical outcomes of rat contusive injuries and human chronic SCI (42). High resolution MRI assessments identified that SCI-induced neuroanatomical changes such as spinal cord atrophy and size of the lesion were significantly correlated with the electrophysiological and functional outcomes in both rat and human contusive injuries (42). Histological assessments in rats also showed a close correlation between the spared white matter and functional preservation following injury (42). These studies provide evidence that rat models of contusive SCI could serve as an adequate model to develop and evaluate the structural and functional benefits of therapeutic strategies for SCI (42).

Mice show different histopathology than human SCI in which the lesion site is filled with dense fibrous connective-like tissue (4346). Mouse SCI studies show the presence of fibroblast-like cells expressing fibronectin, collagen, CD11b, CD34, CD13, and CD45 within the lesion core of chronic SCI, while it is absent in the injured spinal cord of rats (47). Another key difference between rat and mice SCI is the time-point of inflammatory cell infiltration. While microglia/macrophage infiltration is relatively consistent between rat and mouse models of SCI (47), there is a temporal difference in infiltration of neutrophils and T cells between the two species (47, 48). In SCI rats, infiltration of neutrophils, the first responders, peaks at 6 h post injury, followed by a significant decline at 2448 h after SCI (48). Similarly, in mouse SCI, neutrophil infiltration occurs within 6 h following injury; however, their numbers continue to rise and do not peak until 314 days post injury (49). T cell infiltration also varies between rat and mouse SCI models (50). In rats, T cell infiltration occurs between 3 and 7 days post injury and declines by 50% in the following 2 weeks (47), whereas in mice, T cell infiltration is not detected until 14 days post injury and their number doubles between 2 and 6 weeks post injury (47). Regardless of their pathophysiological relevance, mice have been used extensively in SCI studies primarily due to the availability of transgenic and mutant mouse models that have allowed uncovering molecular and cellular mechanisms of SCI (38).

In recent years, there has been emerging interest in employment of non-human primates and other larger animals such as pig, dog and cat as intermediate pre-clinical models (5153) to allow more effective translation of promising treatments from rodent models to human clinical trials (50). Although rodents have served as invaluable models for studying SCI mechanisms and therapeutic development, larger mammals, in particular non-human primates, share a closer size, neuroanatomy, and physiology to humans. Importantly, their larger size provides a more relevant platform for drug development, bioengineering inventions, and electrophysiological and rehabilitation studies. Nonetheless, both small and large animal models of SCI have limitations in their ability to predict the outcome in human SCI. One important factor is high degree of variability in the nature of SCI incidence, severity and location of the injury in human SCI, while in laboratory animal models, these variabilities are less (36). Values acquired by clinical scoring systems such as ASIA or Frankel scoring systems lack the consistency of the data acquired from laboratory settings, which makes the translation of therapeutic interventions from experimental to clinical settings challenging (36). A significant effect from an experimental treatment in consistent laboratory settings may not be reproducible in clinical settings due to high variability and heterogeneity in human populations and their injuries (36). To date, several pharmacological and cellular preclinical discoveries have led to human clinical trials based on their efficacy in improving the outcomes of SCI in small animal models. However, the majority of these trials failed to reproduce the same efficacy in human SCI. Thus, in pre-clinical studies, animal models, and study designs should be carefully chosen to reflect the reality of clinical setting as closely as possible (36). Larger animals provide the opportunity to refine promising therapeutic strategies prior to testing in human SCI; however, their higher cost, need for specialized facilities and small subject (sample) size have limited their use in SCI research (50). Thus, rodents are currently the most commonly employed models for preclinical discoveries and therapeutic development, while the use of larger animals is normally pursued for late stage therapies that have shown efficacy and promise in small animal models. provides a summary of available SCI models.

Animal models are also classified based on the type of SCI. The following sections will provide an overview on the available SCI models that are developed based on injury mechanisms, their specifications and relevance to human SCI ().

A complete transection model of SCI is relatively easy to reproduce (51). However, this model is less relevant to human SCI as a complete transection of the spinal cord rarely happens (51). While they do not represent clinical reality of SCI, transection models are specifically suitable for studying axonal regeneration or developing biomaterial scaffolds to bridge the gap between proximal and distal stamps of the severed spinal cord (51). Due to complete disconnection from higher motor centers, this model is also suitable for studying the role of propriospinal motor and sensory circuits in recovery of locomotion following SCI (51, 80). Partial transection models including hemi-section, unilateral transection and dorsal column lesions are other variants of transection models (51). Partial transection models are valuable for investigation of nerve grafting, plasticity and where a comparison between injured and non-injured pathways is needed in the same animal (51). However, these models lead to a less severe injury and higher magnitude of spontaneous recovery rendering them less suitable for development and evaluation of new therapies (51).

Contusion is caused by a transient physical impact to the spinal cord and is clinically-relevant. There are currently three types of devices that can produce contusion injury in animal models: weight-drop apparatus, electromagnetic impactor, and a recently introduced air gun device (51). The impactor model was first introduced by Gruner at New York University (NYU) in 1992 (81). The original NYU impactor included a metal rod of specific weight (10 g) that could be dropped on the exposed spinal cord from a specific height to induce SCI (51). This model allowed induction of a defined severity of SCI by adjusting the height, which the rod fell on the spinal cord (81). Parameters such as time, velocity at impact and biomechanical response of the tissue can be recorded for analysis and verification (51). The NYU impactor was later renamed to Multicenter Animal Spinal Cord Injury Study (MASCIS) impactor, and conditions surrounding the study and use of the MASCIS impactor were standardized (51). Since its introduction, the MASCIS impactor has been updated twice. The most recent version, MACIS III, was introduced in 2012 and included both electromagnetic control and digital recording of the impact parameters (51). However, inability to control duration of impact and weight bounce, that could cause multiple impacts, have been known limitations of MASCIS impactors (51).

The Infinite Horizon (IH) impactor is another type of impactor that utilizes a stepping motor to generate force-controlled impact in contrast to free fall in the MASICS impactor (51). This feature allows for better control over the force of impact and prevents weight bounce as the computer-controlled metal impounder can be immediately retracted upon transmitting a desired force to the spinal cord (51). IH impactor can be set to different force levels to provide mild, moderate and severe SCI in rats (ex. 100, 150, and 200 kdyn) (51). A limitation with IH impactors is unreliability of their clamps in holding the spinal column firmly during the impact that can cause inconsistent parenchymal injury and neurological deficits (51).

Ohio State University (OSU) impactor is a computer controlled electromagnetic impactor that was originally invented in 1987 and refined in 1992 to improve reliability (58). As the OSU impactor is electromagnetically controlled, multiple strikes are avoided (51). Subsequently, a modified version of the OSU impactor was developed in 2000 for use in mice (43). However, the OSU impactor is limited by its inability to determine the precise initial contact point with the spinal cord due to displacement of CSF upon loading the device (51). To date, MASCIS, IH and OSU impactor devices have been employed extensively and successfully to induce SCI. These impactor devices are available for small and large animals such as mice, rats, marmosets, cats, and pigs (51, 82).

Compressive models of SCI have been also employed for several decades (61). While contusion injury is achieved by applying a force for a very brief period (milliseconds), the compression injury consists of an initial contusion for milliseconds followed by a prolonged compression through force application for a longer duration (seconds to minutes) (51). Thus, compression injury can be categorized as contusive-compressive models (51). Various models of compressive SCI are available.

Clip compression is the most commonly used compression model of SCI in rat and mice (51, 61, 62, 83). It was first introduced by Rivlin and Tator in 1978 (61). In this model, following laminectomy, a modified aneurism clip with a calibrated closing force is applied to the spinal cord for a specific duration of time (usually 1 min) to induce a contusive-compressive injury (51). The severity of injury can be calibrated and modified by adjusting the force of the clip and the duration of compression (51). For example, applying a 50 g clip for 1 min typically produces a severe SCI, while a 35 g clip creates a moderate to severe injury with the same duration (83). Aneurysm clips were originally designed for use in rat SCI, however, in recent years smaller and larger clips have been developed to accommodate its use in mice (62) and pig models (52). The clip compression model has several advantages compared to contusion models. This method is less expensive and easier to perform (51). Importantly, in contrast to the impactor injury that contusion is only applied dorsally to the spinal cord, the clip compression model provides contusion and compression simultaneously both dorsally and ventrally. Hence, clip compression model more closely mimics the most common form of human SCI, which is primarily caused by dislocation and burst compression fractures (83). Despite its advantages, clip compression model can create variabilities such as the velocity of closing and actual delivered force that cannot be measured precisely at the time of application (51).

Calibrated forceps compression has been also employed to induce SCI in rodents. This simple and inexpensive compressive model was first utilized in 1991 for induction of SCI in guinea pigs (64). In this method, a calibrated forceps with a spacer is used to compress the spinal cord bilaterally (51). This model lacks the initial impact and contusive injury, which is associated with most cases of human traumatic SCI. Accordingly, this model is not a clinically relevant model for reproducing human SCI pathology and therapeutic development (51).

Balloon Compression model has been also utilized extensively in primates and larger animals such as dogs and cats (8486). In this model, a catheter with an inflatable balloon is inserted in the epidural or subdural space. The inflation of the balloon with air or saline for a specific duration of time provides the force for induction of SCI (51). Generally, all compression models (clip, forceps, and balloon) have the same limitation as the velocity and amount of force are unmeasurable (51).

In conclusion, while existing animal models do not recapitulate all clinical aspects of human SCI, the compression and contusion models are considered to be the most relevant and commonly employed methods for understanding the secondary injury mechanisms and therapeutic development for SCI.

Secondary injury begins within minutes following the initial primary injury and continues for weeks or months causing progressive damage of spinal cord tissue surrounding the lesion site (7). The concept of secondary SCI was first introduced by Allen in 1911 (87). While studying SCI in dogs, he observed that removal of the post traumatic hematomyelia improved neurological outcome. He hypothesized that presence of some biochemical factors in the necrotic hemorrhagic lesion causes further damage to the spinal cord (87). The term of secondary injury is still being used in the field and is referred to a series of cellular, molecular and biochemical phenomena that continue to self-destruct spinal cord tissue and impede neurological recovery following SCI () (20).

Summary of secondary injury processes following traumatic spinal cord injury. Diagram shows the key pathophysiological events that occur after primary injury and lead to progressive tissue degeneration. Vascular disruption and ischemia occur immediately after primary injury that initiate glial activation, neuroinflammation, and oxidative stress. These acute changes results in cell death, axonal injury, matrix remodeling, and formation of a glial scar.

Secondary injury can be temporally divided into acute, sub-acute, and chronic phases. The acute phase begins immediately following SCI and includes vascular damage, ionic imbalance, neurotransmitter accumulation (excitotoxicity), free radical formation, calcium influx, lipid peroxidation, inflammation, edema, and necrotic cell death (7, 20, 88). As the injury progresses, the sub-acute phase of injury begins which involves apoptosis, demyelination of surviving axons, Wallerian degeneration, axonal dieback, matrix remodeling, and evolution of a glial scar around the injury site (). Further changes occur in the chronic phase of injury including the formation of a cystic cavity, progressive axonal die-back, and maturation of the glial scar (7, 8992). Here, we will review the key components of acute secondary injury that contribute to the pathophysiology of SCI (, ).

Pathophysiology of traumatic spinal cord injury. This schematic diagram illustrates the composition of normal and injured spinal cord. Of note, while these events are shown in one figure, some of the pathophysiological events may not temporally overlap and can occur at various phases of SCI, which are described here. Immediately after primary injury, activation of resident astrocytes and microglia and subsequent infiltration of blood-borne immune cells results in a robust neuroinflammatory response. This acute neuroinflammatory response plays a key role in orchestrating the secondary injury mechanisms in the sub-acute and chronic phases that lead to cell death and tissue degeneration, as well as formation of the glial scar, axonal degeneration and demyelination. During the acute phase, monocyte-derived macrophages occupy the epicenter of the injury to scavenge tissue debris. T and B lymphocytes also infiltrate the spinal cord during sub-acute phase and produce pro-inflammatory cytokines, chemokines, autoantibodies reactive oxygen and nitrogen species that contribute to tissue degeneration. On the other hand, M2-like macrophages and regulatory T and B cells produce growth factors and pro-regenerative cytokines such as IL-10 that foster tissue repair and wound healing. Loss of oligodendrocytes in acute and sub-acute stages of SCI leads to axonal demyelination followed by spontaneous remyelination in sub-acute and chronic phases. During the acute and sub-acute phases of SCI; astrocytes, OPCs and pericytes, which normally reside in the spinal cord parenchyma, proliferate and migrate to the site of injury and contribute to the formation of the glial scar. The glial scar and its associated matrix surround the injury epicenter and create a cellular and biochemical zone with both beneficial and detrimental roles in the repair process. Acutely, the astrocytic glial scar limits the spread of neuroinflammation from the lesion site to the healthy tissue. However, establishment of a mature longstanding glial scar and upregulation of matrix chondroitin sulfate proteoglycans (CSPGs) are shown to inhibit axonal regeneration/sprouting and cell differentiation in subacute and chronic phases.

Disruption of spinal cord vascular supply and hypo-perfusion is one of the early consequences of primary injury (93). Hypovolemia and hemodynamic shock in SCI patients due to excessive bleeding and neurogenic shock result in compromised spinal cord perfusion and ischemia (93). Larger vessels such as anterior spinal artery usually remain intact (94, 95), while rupture of smaller intramedullary vessels and capillaries that are susceptible to traumatic damage leads to extravasation of leukocytes and red blood cells (93). Increased tissue pressure in edematous injured spinal cord and hemorrhage-induced vasospasm in intact vessels further disrupts blood flow to the spinal cord (93, 95). In rat and monkey models of SCI, there is a progressive reduction in blood flow at the lesion epicenter within the first few hours after injury which remains low for up to 24 h (96). The gray matter is more prone to ischemic damage compared to the white matter as it has a 5-fold higher density of capillary beds and contains neurons with high metabolic demand (95, 97, 98). After injury, white matter blood flow typically returns to normal levels within 15 min post injury, whereas there are multiple hemorrhages in the gray matter and as a result, re-perfusion usually does not occur for the first 24 h (9, 99, 100). Vascular insult, hemorrhage and ischemia ultimately lead to cell death and tissue destruction through multiple mechanisms, including oxygen deprivation, loss of adenosine triphosphate (ATP), excitotoxicity, ionic imbalance, free radical formation, and necrotic cell death. Cellular necrosis and release of cytoplasmic content increase the extracellular level of glutamate causing glutamate excitotoxicity (93, 101). Moreover, re-establishment of blood flow in ischemic tissue leads to further damage through generating free radicals and eliciting an inflammatory response (93, 102) that will be discussed in this review.

Within few minutes after primary SCI, the combination of direct cellular damage and ischemia/hypoxia triggers a significant rise of extracellular glutamate, the main excitatory neurotransmitter in the CNS (7). Glutamate binds to ionotropic (NMDA, AMPA, and Kainate receptors) as well as metabotropic receptors resulting in calcium influx inside the cells (103105) (93). The effect of glutamate is not restricted to neurons as its receptors are vastly expressed on the surface of all glia and endothelial cells (103106). Astrocytes can also release excess glutamate extracellularly upon elevation of their intracellular Ca2+ levels. Reduced ability of activated astrocytes for glutamate re-uptake from the interstitial space due to lipid peroxidation results in further accumulation of glutamate in the SCI milieu (93). Using microdialysis, elevated levels of glutamate have been detected in the white matter in the acute stage of injury (107). Based on a study by Panter and colleagues, glutamate increase is detected during the first 2030 min post SCI and returns to the basal levels after 60 min (108).

Under normal condition, concentration of free Ca2+ can considerably vary in different parts of the cell (109). In the cytosol, Ca2+ ranges from 50100 nM while it approaches 0.51.0 mM in the lumen of endoplasmic reticulum (110112). A long-lasting abnormal increase in Ca2+ concentration in cytosol, mitochondria or endoplasmic reticulum has detrimental consequences for the cell (109113). Mitochondria play a central role in calcium dependent neuronal death (113). In neurons, during glutamate induced excitotoxicity, NMDA receptor over-activity leads to mitochondrial calcium overload, which can cause apoptotic or necrotic cell death (113). Shortly after SCI, Ca2+ enters mitochondria through the mitochondrial calcium uniporter (MCU) (114). While the amount of mitochondrial calcium is limited during the resting state of a neuron, they can store a high amount of Ca2+ following stimulation (113). Calcium overload also activates a host of protein kinases and phospholipases that results in calpain mediated protein degradation and oxidative damage due to mitochondrial failure (93). In the injured white matter, astrocytes, oligodendrocytes and myelin are also damaged by the increased release of glutamate and Ca2+-dependent excitotoxicity (115). Within the first few hours after injury, oligodendrocytes show signs of caspase-3 activation and other apoptotic features, and their density declines (116). Interestingly, while glutamate excitotoxicity is triggered by ionic imbalance in the white matter, in the gray matter, it is largely associated with the activity of neuronal NMDA receptors (117, 118). Altogether, activation of NMDA receptors and consequent Ca2+ overload appears to induce intrinsic apoptotic pathways in neurons and oligodendrocytes and causes cell death in the first week of SCI in the rat (119, 120). Administration of NMDA receptor antagonist (MK-801) shortly following SCI has been associated with improved functional recovery and reduced edema (121).

Mitochondrial calcium overload also impedes mitochondrial respiration and results in ATP depletion disabling Na+/K+ ATPase and increasing intracellular Na+ (119, 122124). This reverses the function of the Na+ dependent glutamate transporter that normally utilizes Na+ gradient to transfer glutamate into the cells (119, 125, 126). Moreover, the excess intracellular Na+ reverses the activity of Na+/Ca2+ exchanger allowing more Ca+ influx (127). Cellular depolarization activates voltage gated Na+ channels that results in entry of Cl and water into the cells along with Na+ causing swelling and edema (128). Increased Na+ concentration over-activates Na+/H+ exchanger causing a rise in intracellular H+ (101, 129). Resultant intracellular acidosis increases membrane permeability to Ca2+ that exacerbates the injury-induced ionic imbalance (101, 129). Axons are more susceptible to the damage caused by ionic imbalance due to their high concentration of voltage gated Na+ channels in the nodes of Ranvier (7). Accumulating evidence shows that administration of Na+ channel blockers such as Riluzole attenuates tissue damage and improves functional recovery in SCI underlining sodium as a key player in secondary injury mechanisms (130133).

SCI results in production of free radicals and nitric oxide (NO) (114). Mitochondrial Ca2+ overload activates NADPH oxidase (NOX) and induces generation of superoxide by electron transport chain (ETC) (114). Reactive oxygen and nitrogen species (ROS and RNS) produced by the activity of NOX and ETC activates cytosolic poly (ADP ribose) polymerase (PARP). PARP consumes and depletes NAD+ causing failure of glycolysis, ATP depletion and cell death (114). Moreover, PAR polymers produced by PARP activity, induce the release of apoptosis inducing factor (AIF) from mitochondria and induce cell death (114). On the other hand, acidosis caused by SCI results in the release of intracellular iron from ferritin and transferrin (93). Spontaneous oxidation of Fe2+ to Fe3+ gives rise to more superoxide radicals (93). Subsequently, the Fenton reaction between Fe3+ and hydrogen peroxide produces highly reactive hydroxyl radicals (134). The resultant ROS and RNS react with numerous targets including lipids in the cell membrane with the most deleterious effects (93, 135). Because free radicals are short-lived and difficult to assess, measurements of their activity and final products, such as Malondialdehyde (MDA), are more reliable following SCI. Current evidence indicates that MDA levels are elevated as early as 1 h and up to 1 week after SCI (136, 137).

Oxidation of lipids and proteins is one of the key mechanisms of secondary injury following SCI (93). Lipid peroxidation starts when ROSs interact with polyunsaturated fatty acids in the cell membrane and generate reactive lipids that will then form lipid peroxyl radicals upon interacting with free superoxide radicals (138, 139). Each lipid peroxyl radical can react with a neighboring fatty acid, turn it into an active lipid and start a chain reaction that continues until no more unsaturated lipids are available or terminates when the reactive lipid quenches with another radical (93). The final products of this termination step of the lipid peroxidation is 4-hydroxynonenal (HNE) and 2-propenal, which are highly toxic to the cells (138140). Lipid peroxidation is also an underlying cause of ionic imbalance through destabilizing cellular membranes such as cytoplasmic membrane and endoplasmic reticulum (93). Moreover, lipid peroxidation leads to Na+/K+ ATPase dysfunction that exacerbates the intracellular Na+ overload (141). In addition to ROS associated lipid peroxidation, amino acids are subject to significant RNS associated oxidative damage following SCI (93). RNSs (containing ONOO) can nitrate the tyrosine residues of amino acids to form 3-nitrotyrosine (3-NT), a marker for peroxynitrite (ONOO) mediated protein damage (139). Lipid and protein oxidation following SCI has a number of detrimental consequences at cellular level including mitochondrial respiratory and metabolic failure as well as DNA alteration that ultimately lead to cell death (141).

Cell death is a major event in the secondary injury mechanisms that affects neurons and glia after SCI (142145). Cell death can happen through various mechanisms in response to various injury-induced mediators. Necrosis and apoptosis were originally identified as two major cell death mechanisms following SCI (146148). However, recent research has uncovered additional forms of cell death. In 2012, the Nomenclature Committee on Cell Death (NCCD) NCCD defined 12 different forms of cell death such as necroptosis, pyroptosis, and netosis (149). Among the identified modes of cell death, to date, necrosis, necroptosis, apoptosis, and autophagy have been studied more extensively in the context of SCI and will be discussed in this review.

Following SCI, neurons and glial cells die through necrosis as the result of mechanical damage at the time of primary injury that also continues to the acute and subacute stages of injury (7, 150). Necrosis occurs due to a multitude of factors including accumulation of toxic blood components (151), glutamate excitotoxicity and ionic imbalance (152), ATP depletion (153), pro-inflammatory cytokine release by neutrophils and lymphocytes (154, 155), and free radical formation (142, 156158). It was originally thought that necrosis is caused by a severe impact on a cell that results in rapid cell swelling and lysis. However, follow up evidence showed that in the case of seizure, ischemia and hypoglycemia, necrotic neurons show signs of shrunken, pyknotic, and condensed nuclei, with swollen, irreversibly damaged mitochondria and plasma membrane that are surrounded by astrocytic processes (159). Moreover, necrosis was conventionally viewed as instantaneous energy-independent non-programmed cell death (142, 156). However, recent research has identified another form of necrosis, termed as necroptosis, that is executed by regulated mechanisms.

Programmed necrosis or necroptosis has been described more recently as a highly regulated, caspase-independent cell death with similar morphological characteristics as necrosis (160). Necroptosis is a receptor-mediated process. It is induced downstream of the TNF receptor 1 (TNFR1) and is dependent on the activity of the receptor interacting protein kinase 1 (RIPK1) and RIPK3. Recent studies has uncovered a key role for RIPK1 as the mediator of necroptosis and a regulator of the innate immune response involved in both inflammation and cell death (161). Evidence from SCI studies show that lysosomal damage can potentiate necroptosis by promoting RIPK1 and RIPK3 accumulation (161). Interestingly, inhibition of necroptosis by necrostatin-1, a RIPK1 inhibitor, improves functional outcomes after SCI (150). These initial findings suggest that modulation of necroptosis pathways seems to be a promising target for neuroprotective strategies after SCI.

Apoptosis is the most studied mechanism of cell death after SCI. Apoptosis represents a programmed, energy dependent mode of cell death that begins within hours of primary injury (7). This process takes place in cells that survive the primary injury but endure enough insult to activate their apoptotic pathways (142). In apoptosis, the cell shrinks and is eventually phagocytosed without induction of an inflammatory response (156). Apoptosis typically occurs in a delayed manner in areas more distant to the injury site and most abundantly affects oligodendrocytes. In rat SCI, apoptosis happens as early as 4 h after the injury and reaches a peak at 7 day (156). At the site of injury majority of oligodendrocytes are lost within 7 days after SCI (162). However, apoptosis can be observed at a diminished rate for weeks after SCI (162, 163). Microglia and astrocytes also undergo apoptosis (156, 164). Interestingly, apoptotic cell death occurs in the chronically injured spinal cord in rat, monkey and human models of SCI, which is thought to be due to loss of trophic support from degenerating axons (146, 165).

Apoptosis is induced through extrinsic and intrinsic pathways based on the triggering mechanism (166). The extrinsic pathway is triggered by activation of death receptors such as FAS and TNFR1, which eventually activates caspase 8 (167). The intrinsic pathway, however, is regulated through a balance between intracellular pro- and anti-apoptotic proteins and is triggered by the release of cytochrome C from mitochondria and activating caspase 9 (167). In SCI lesion, apoptosis primarily happens due to injury induced Ca2+ influx, which activates caspases and calpain; enzymes involved in breakdown of cellular proteins (7). Moreover, it is believed that the death of neurons and oligodendrocytes in remote areas from the lesion epicenter can be mediated through cytokines such as TNF-, free radical damage and excitotoxicity since calcium from damaged cells within the lesion barely reaches these remote areas (8, 168). Fas mediated cell death has been suggested as a key mechanism of apoptosis following SCI (144, 169172). Post-mortem studies on acute and chronic human SCI and animal models revealed that Fas mediated apoptosis plays a role in oligodendrocyte apoptosis and inflammatory response at acute and subacute stages of SCI (173). Fas deficient mice exhibit a significant reduction in apoptosis and inflammatory response evidenced by reduced macrophage infiltration and inflammatory cytokine expression following SCI (173). Interestingly, Fas deficient mice show a significantly improved functional recovery after SCI (173) suggesting the promise of anti-apoptotic strategies for SCI.

SCI also results in a dysregulated autophagy (174). Normally, autophagy plays an important role in maintaining the homeostasis of cells by aiding in the turnover of proteins and organelles. In autophagy, cells degrade harmful, defective or unnecessary cytoplasmic proteins and organelles through a lysosomal dependent mechanism (175, 176). The process of autophagy starts with the formation of an autophagosome around the proteins and organelles that are tagged for autophagy (176). Next, fusion of the phagosome with a lysosome form an autolysosome that begins a recycling process (176). In response to cell injury and endoplasmic reticulum (ER) stress, autophagy is activated and limits cellular loss (177, 178). Current evidence suggests a neuroprotective role for autophagy after SCI (175, 179). Dysregulation of autophagy contributes to neuronal loss (174, 180). Accumulation of autophagosomes in ventral horn motor neurons have been detected acutely following SCI (181). Neurons with dysregulated autophagy exhibit higher expression of caspase 12 and become more prone to apoptosis (174). Moreover, blocking autophagy has been associated with neurodegenerative diseases such as Parkinson's and Alzheimer's disease (182184). Autophagy promotes cell survival through elimination of toxic proteins and damaged mitochondria (185, 186). Interestingly, autophagy is crucial in cytoskeletal remodeling and stabilizes neuronal microtubules by degrading SCG10, a protein involved in microtubule disassembly (179). Pharmacological induction of autophagy in a hemi-section model of SCI in mice has been associated with improved neurite outgrowth and axon regeneration, following SCI (179). Altogether, although further studies are needed, autophagy is currently viewed as a beneficial mechanism in SCI.

Neuroinflammation is a key component of the secondary injury mechanisms with local and systemic consequences. Inflammation was originally thought to be detrimental for the outcome of SCI (187). However, now it is well-recognized that inflammation can be both beneficial and detrimental following SCI, depending on the time point and activation state of immune cells (188). There are multiple cell types involved in the inflammatory response following injury including neutrophils, resident microglia, and astrocytes, dendritic cells (DCs), blood-born macrophages, B- and T-lymphocytes (189) (). The first phase of inflammation (02 days post injury) involves the recruitment of resident microglia and astrocytes and blood-born neutrophils to the injury site (190). The second phase of inflammation begins approximately 3 days post injury and involves the recruitment of blood-born macrophages, B- and T-lymphocytes to the injury site (189, 191193). T lymphocytes become activated in response to antigen presentation by macrophages, microglia and other antigen presenting cells (APCs) (194). CD4+ helper T cells produce cytokines that stimulate B cell antibody production and activate phagocytes (195) (). In SCI, B cells produce autoantibodies against injured spinal cord tissue, which exacerbate neuroinflammation and cause tissue destruction (196). While inflammation is more pronounced in the acute phase of injury, it continues in subacute and chronic phase and may persist for the remainder of a patients' life (193). Interestingly, composition and phenotype of inflammatory cells change based on the injury phase and the signals present in the injury microenvironment. It is established that microglia/macrophages, T cells, B cells are capable of adopting a pro-inflammatory or an anti-inflammatory pro-regenerative phenotype in the injured spinal cord (191, 197199). The role of each immune cell population in the pathophysiology of SCI will be discussed in detail in upcoming sections.

Immune response in spinal cord injury. Under normal circumstances, there is a balance between pro-inflammatory effects of CD4+ effector T cells (Teff) and anti-inflammatory effects of regulatory T and B cells (Treg and Breg). Treg and Breg suppress the activation of antigen specific CD4+ Teff cells through production of IL-10 and TGF-. Injury disrupts this balance and promote a pro-inflammatory environment. Activated microglia/macrophages release pro-inflammatory cytokines and chemokines and present antigens to CD4+ T cells causing activation of antigen specific effector T cells. Teff cells stimulate antigen specific B cells to undergo clonal expansion and produce autoantibodies against spinal cord tissue antigens. These autoantibodies cause neurodegeneration through FcR mediated phagocytosis or complement mediated cytotoxicity. M1 macrophages/microglia release pro-inflammatory cytokines and reactive oxygen species (ROS) that are detrimental to neurons and oligodendrocytes. Breg cells possess the ability to promote Treg development and restrict Teff cell differentiation. Breg cells could also induce apoptosis in Teff cells through Fas mediate mechanisms.

Astrocytes are not considered an immune cell per se; however, they play pivotal roles in the neuroinflammatory processes in CNS injury and disease. Their histo-anatomical localization in the CNS has placed them in a strategic position for participating in physiological and pathophysiological processes in the CNS (200). In normal CNS, astrocytes play major roles in maintaining CNS homeostasis. They contribute to the structure and function of blood-brain-barrier (BBB), provide nutrients and growth factors to neurons (200), and remove excess fluid, ions, and neurotransmitters such as glutamate from synaptic spaces and extracellular microenvironment (200). Astrocytes also play key roles in the pathologic CNS by regulating BBB permeability and reconstruction as well as immune cell activity and trafficking (201). Astrocytes contribute to both innate and adaptive immune responses following SCI by differential activation of their intracellular signaling pathways in response to environmental signals (201).

Astrocytes react acutely to CNS injury by increasing cytokine and chemokine production (202). They mediate chemokine production and recruitment of neutrophils through an IL-1R1-Myd88 pathway (202). Activation of the nuclear factor kappa b (NF-B) pathway, one of the key downstream targets of interleukin (IL)1R-Myd88 axis, increases expression of intracellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), which are necessary for adhesion and extravasation of leukocytes in inflammatory conditions such as SCI (201, 202). Within minutes of injury, production of IL-1 is significantly elevated in astrocytes and microglia (203). Moreover, chemokines such as monocyte chemoattractant protein (MCP)-1, chemokine C-C motif ligand 2 (CCL2), C-X-C motif ligand 1 (CXCL1), and CXCL2 are produced by astrocytes, and enhance the recruitment of neutrophils and pro-inflammatory macrophages following injury (201, 202). Astrocytes also promote pro-inflammatory M1-like phenotype in microglia/macrophages in the injured spinal cord through their production of TNF-, IL-12, and IFN- (204206). Interestingly, astrocytes also produce anti-inflammatory cytokines, such as TGF- and IL-10, which can promote a pro-regenerative M2-like phenotype in microglia/macrophages (201, 207, 208).

Immunomodulatory role of astrocytes is defined by activity of various signaling pathways through a wide variety of surface receptors (200). For example, gp130, a member of IL-6 cytokine family, activates SHP2/Ras/Erk signaling cascade in astrocytes and limits neuroinflammation in autoimmune rodent models (209). TGF- signaling in astrocytes has been implicated in modulation of neuroinflammation through inhibition of NF-B activity and nuclear translocation (201, 210). STAT3 is another key signaling pathway in astrocytes with beneficial properties in neuroinflammation. Increase in STAT3 phosphorylation enhances astrocytic scar formation and restricts the expansion of inflammatory cells in mouse SCI, which is associated with improved functional recovery (211). Detrimental signaling pathways in astrocytes are known to be activated by cytokines, sphingolipids and neurotrophins (200). As an example, IL-17 is a key pro-inflammatory cytokine produced by effector T cells that can bind to IL-17R on the astrocyte surface (200). Activation of IL-17R results in the activation of NF-B, which enhances expression of pro-inflammatory mediators, activation of oxidative pathways and exacerbation of neuroinflammation (200, 212). This evidence shows the significance of astrocytes in the inflammatory processes following SCI and other neuroinflammatory diseases of the CNS.

Neutrophils infiltrate the spinal cord from the bloodstream within the first few hours after injury (213). Their population increases acutely in the injured spinal cord tissue and reaches a peak within 24 h post-injury (214). The presence of neutrophils is mostly limited to the acute phase of SCI as they are rarely found sub-acutely in the injured spinal cord (214). The role of neutrophils in SCI pathophysiology is controversial. Evidence shows that neutrophils contribute to phagocytosis and clearance of tissue debris (48). They release inflammatory cytokines, proteases and free radicals that degrade ECM, activate astrocytes and microglia and initiate neuroinflammation (48). Although neutrophils have been conventionally associated with tissue damage (48, 215), their elimination compromises the healing process and impedes functional recovery (216).

To elucidate the role of neutrophils in SCI, Stirling and colleagues used a specific antibody to reduce circulating LyG6/Gr1+ neutrophils in a mouse model of thoracic contusive SCI (216). This approach significantly reduced neutrophil infiltration in the injured spinal cord by 90% at 24 and 48 h after SCI (216). Surprisingly, neutrophil depletion aggravated the neurological and structural outcomes in the injured animals suggesting a beneficial role for neutrophils in the acute phase of injury (216). It is shown that simulated neutrophils release IL-1 receptor antagonist that can exert neuroprotective effects following SCI (217). Moreover, ablation of neutrophils results in altered expression of cytokines and chemokines and downregulation of growth factors such as fibroblast growth factors (FGFs), vascular endothelial growth factors (VEGFs) and bone morphogenetic proteins (BMPs) in the injured spinal cord that seemingly disrupt the normal healing process (216). Altogether, neutrophils play important roles in regulating neuroinflammation at the early stage of SCI that shapes the immune response and repair processes at later stages. While neutrophils were originally viewed as being detrimental in SCI, emerging evidence shows their critical role in the repair process. Further investigations are required to elucidate the role of neutrophils in SCI pathophysiology.

Following neutrophil invasion, microglia/macrophages populate the injured spinal cord within 23 days post-SCI. Macrophage population is derived from invading blood-borne monocytes or originate from the CNS resident macrophages that reside in the perivascular regions within meninges and subarachnoid space (218, 219). The population of microglia/macrophages reaches its peak at 710 days post-injury in mouse SCI, followed by a decline in the subacute and chronic phases (20, 220). While macrophages and microglia share many functions and immunological markers, they have different origins. Microglia are resident immune cells of the CNS that originate from yolk sac during the embryonic period (221). Macrophages are derived from blood monocytes, which originate from myeloid progeny in the bone marrow (222, 223). Upon injury, acute disruption of brain-spinal cord barrier (BSB) enables monocytes, to infiltrate the spinal cord tissue and transform into macrophages (222). Macrophages populate the injury epicenter, while resident microglia are mainly located in the perilesional area (222). Once activated, macrophages, and microglia are morphologically and immunohistologically indistinguishable (224). Macrophages and microglia play a beneficial role in CNS regeneration. They promote the repair process by expression of growth promoting factors such as nerve growth factor (NGF), neurotrophin-3 (NT-3) and thrombospondin (225, 226). Macrophages and microglia are important for wound healing process following SCI due to their ability for phagocytosis and scavenging damaged cells and myelin debris following SCI (222, 227).

Based on microenvironmental signals, macrophages/microglia can be polarized to either pro-inflammatory (M1-like) or anti-inflammatory pro-regenerative (M2-like) phenotype, and accordingly contribute to injury or repair processes following SCI (191, 224, 228230). Whether both microglia and macrophages possess the ability to polarize or it is mainly the property of monocyte derived macrophages is still a matter of debate and needs further elucidation (231233). Some evidence show that Proinflammatory M1-like microglia/macrophages can be induced by exposure to Th1 specific cytokine, interferon (IFN)- (224, 230). Moreover, the SCI microenvironment appears to drive M1 polarization of activated macrophages (231). SCI studies have revealed that increased level of the proinflammatory cytokine, TNF-, and intracellular accumulation of iron drives an M1-like proinflammatory phenotype in macrophages after injury (231). Importantly, following SCI, activated M1-like microglia/macrophages highly express MHCII and present antigens to T cells and contribute to the activation and regulation of innate and adaptive immune response () (224, 228). Studies on acute and subacute SCI and experimental autoimmune encephalomyelitis (EAE) models have shown that M1-like macrophages are associated with higher expression of chondroitin sulfate proteoglycans (CSPGs) and increased EAE severity and tissue damage (234237). In vitro, addition of activated M1-like macrophages to dorsal root ganglion (DRG) neuron cultures leads to axonal retraction and failure of regeneration as the expression of CSPGs is much higher in M1-like compared to M2-like macrophages (237, 238). M1-like macrophages also produce other repulsive factors such as repulsive guidance molecule A (RGMA) that is shown to induce axonal retraction following SCI (239, 240). Interestingly, recent evidence shows that IFN- and TNF polarized M1 microglia show reduced capacity for phagocytosis (241), a process that is critical for tissue repair after SCI.

Pro-regenerative M2-like microglia/macrophages, are polarized by Th2 cytokines, IL-4 and IL-13 and exhibit a high level of IL-10, TGF-, and arginase-1 with reduced NF-B pathway activity (224). IL-10 is a potent immunoregulatory cytokine with positive roles in repair and regeneration following CNS injury (242244). IL-10 knock-out mice show higher production of pro-inflammatory and oxidative stress mediators after SCI (245). Lack of IL-10 is also correlated with upregulated levels of pro-apoptotic factors such as Bax and reduced expression of anti-apoptotic factors such as Bcl-2 (245). SCI mice that lacked IL-10 exhibited poorer recovery of function compared to wild-type mice (245). Our recent studies show that IL-10 polarized M2 microglia show enhanced capacity for phagocytosis (241). We have also found that M2 polarized microglia enhance the ability of neural precursor cells for oligodendrocyte differentiation through IL-10 mediated mechanisms (241). In addition to immune modulation, M2-like microglia/macrophages promote axonal regeneration (224). However, similar to the detrimental effects of prolonged M1 macrophage response, excessive M2-like activity promotes fibrotic scar formation through the release of factors such as TGF-, PDGF, VEGF, IGF-1, and Galectin-3 (224, 246248). Hence, a balance between proinflammatory M1 and pro-regenerative M2 macrophage/microglia response is beneficial for the repair of SCI (249).

T and B lymphocytes play pivotal role in the adaptive immune response after SCI (194). Lymphocytes infiltrate the injured spinal cord acutely during the first week of injury and remain chronically in mouse and rat SCI (47, 193, 194, 196). In contrast to the innate immune response that can be activated directly by foreign antigens, the adaptive immune response requires a complex signaling process in T cells elicited by antigen presenting cells (250). Similar to other immune cells, T and B lymphocytes adopt different phenotypes and contribute to both injury and repair processes in response to microenvironmental signals (194, 251). SCI elicits a CNS-specific autoimmune response in T and B cells, which remains active chronically (196). Autoreactive T cells can exert direct toxic effects on neurons and glial cells (194, 252). Moreover, T cells can indirectly affect neural cell function and survival through pro-inflammatory cytokine and chemokine production (e.g. IL-1, TNF-, IL-12, CCL2, CCL5, and CXCL10) (194, 252). Genetic elimination of T cells (in athymic nude rats) or pharmacological inhibition of T cells (using cyclosporine A and tacrolimus) leads to improved tissue preservation and functional recovery after SCI (194, 253) signifying the impact of T cells in SCI pathophysiology and repair.

Under normal circumstances, systemic autoreactive effector CD4+ helper T cells (Teff) are suppressed by CD4+FoxP3+ regulatory T cells (Treg) () (194, 254). This inhibition is regulated through various mechanisms such as release of anti-inflammatory cytokines IL-10 and TGF- by the Treg cells () (194). Moreover, it is known that Treg mediated inhibition of antigen presentation by dendritic cells (DCs) prevent Teff cell activation (194). Following SCI, this Treg -Teff regulation is disrupted. Increased activity of autoreactive Teff cells contributes to tissue damage through production of pro-inflammatory cytokines and chemokines, promoting M1-like macrophage phenotype and induction of Fas mediated neuronal and oligodendroglial apoptosis () (173). Moreover, autoreactive Teff cells promote activation and differentiation of antigen specific B cells to autoantibody producing plasma cells that contribute to tissue damage after SCI (255). In SCI and MS patients, myelin specific proteins such as myelin basic protein (MBP) significantly increase the population of circulating T cells (256, 257). Moreover, serological assessment of SCI patients has shown high levels of CNS reactive IgM and IgG isotypes confirming SCI-induced autoimmune activity of T and B cells () (196, 258, 259). In animal models of SCI, serum IgM level increases acutely followed by an elevation in the levels of IgG1 and IgG2a at later time-points (196). In addition to autoantibody production, autoreactive B cells contribute to CNS injury through pro-inflammatory cytokines that stimulate and maintain the activation states of Teff cells (194, 260). B cell knockout mice (BCKO) that have no mature B cell but with normal T cells, show a reduction in lesion volume, lower antibody levels in the cerebrospinal fluid and improved recovery of function following SCI compared to wild-type counterparts (255). Of note, antibody mediated injury is regulated through complement activation as well as macrophages/microglia that express immunoglobulin receptors (193, 255).

The effect of SCI on systemic B cell response is controversial. Evidence shows that SCI can suppress B cell activation and antibody production (261). Studies in murine SCI have shown that B cell function seems to be influenced by the level of injury (262). While injury to upper thoracic spinal cord (T3) suppresses the antibody production, a mid-thoracic (T9) injury has no effect on B cell antibody production (262). An increase in the level of corticosterone in serum together with elevation of splenic norepinephrine found to be responsible for the suppression of B cell function acutely following SCI (261). Elevated corticosterone and norepinephrine leads to upregulation of lymphocyte beta-2 adrenergic receptors eliciting lymphocyte apoptosis (194). This suggests a critical role for sympathetic innervation of peripheral lymphoid tissues in regulating B cell response following CNS injury (261). Despite their negative roles, B cells also contribute to spinal cord repair following injury through their immunomodulatory Breg phenotype () (263). Breg cells control antigen-specific T cell autoimmune response through IL-10 production (264).

Detrimental effects of SCI-induced autoimmunity are not limited to the spinal cord. Autoreactive immune cells contribute to the exacerbation of post-SCI sequelae such as cardiovascular, renal and reproductive dysfunctions (194). For example, presence of an autoantibody against platelet prostacyclin receptor has been associated with a higher incidence of coronary artery disease in SCI patients (265). Collectively, evidence shows the critical role of adaptive immune system in SCI pathophysiology and repair. Thus, treatments that harness the pro-regenerative properties of the adaptive immune system can be utilized to reduce immune mediated tissue damage, improve neural tissue preservation and facilitate repair following SCI.

Traumatic SCI triggers the formation of a glial scar tissue around the injury epicenter (266, 267). The glial scar is a multifactorial phenomenon that is contributed f several populations in the injured spinal cord including activated astrocytes, NG2+ oligodendrocyte precursor cells (OPCs), microglia, fibroblasts, and pericytes (268271). The heterogeneous scar forming cells and associated ECM provides a cellular and biochemical zone within and around the lesion () (272). Resident and infiltrating inflammatory cells contribute to the process of glial activation and scar formation by producing cytokines (e.g., IL-1 and IL-6) chemokines and enzymes that activate glial cells or disrupt BSB (267). Activated microglia/macrophages produce proteolytic enzymes such as matrix metalloproteinases (MMPs) that increase vascular permeability and further disruption of the BSB (273). Inhibition of MMPs improves neural preservation and functional recovery in animal models of SCI (273275). In addition to glial and immune cells, fibroblasts, pericytes and ependymal cells also contribute to the structure of the glial scar (267). In penetrating injuries where meninges are compromised, meningeal fibroblasts infiltrate the lesion epicenter (276). Fibroblasts contribute to the production of fibronectin, collagen, and laminin in the ECM of the inured spinal cord (267) and are a source of axon-repulsing molecules such as semaphorins that influence axonal regeneration following SCI (277). Fibroblasts have also been found in contusive injuries where meninges are intact (268, 270). Studies using genetic fate mapping in these injuries have unraveled that perivascular pericytes and fibroblasts migrate to the injury site and form a fibrotic core in the scar which matures within 2 weeks post-injury (268, 270). SCI also triggers proliferation and migration of the stem/progenitor cell pool of the spinal cord parenchyma and ependyma. These cells can give rise to new scar forming astrocytes and OPCs (278280). In a mature glial scar, activated microglia/macrophages occupy the innermost portion closer to the injury epicenter surrounded by NG2+ OPCs () (267), while reactive astrocytes reside in the injury penumbra and form a cellular barrier (267). Of note, in human SCI, the glial scar begins to form within the first hours after the SCI and remains chronically in the spinal cord tissue (281). The glial scar has been found within the injured human spinal cord up to 42 years after the injury (267).

Activated astrocytes play a leading role in the formation of the glial scar (267). Following injury, astrocytes increase their expression of intermediate filaments, GFAP, nestin and vimentin, and become hypertrophied (282, 283). Reactive astrocytes proliferate and mobilize to the site of injury and form a mesh like structure of intermingled filamentous processes around the injury epicenter (284, 285). The astrocytic glial scar has been shown to serve as a protective barrier that prevents the spread of infiltrating immune cells into the adjacent segments (267, 284, 286). Attenuating astrocyte reactivity and scar formation by blockade of STAT3 activation results in poorer outcomes in SCI (211, 286). Reactive astrogliosis is also essential for reconstruction of the BBB, and blocking this process leads to exacerbated leukocyte infiltration, cell death, myelin damage, and reduced functional recovery (211, 285, 286). Despite the protective role of the astrocytic glial scar in acute SCI, its evolution and persistence in the sub-acute and chronic stages of injury has been considered as a potent inhibitor for spinal cord repair and regeneration (267, 287). A number of inhibitory molecules have been associated with activated astrocytes and their secreted products such as proteoglycans and Tenascin-C (288). Thus, manipulation of the astrocytic scar has been pursued as a promising treatment strategy for SCI (267, 289).

Chondroitin sulfate proteoglycans (CSPGs) are well-known for their contribution to the inhibitory role of the glial scar in axonal regeneration (290295), sprouting (296299), conduction (300302), and remyelination (241, 303307). In normal condition, basal levels of CSPGs are expressed in the CNS that play critical roles in neuronal guidance and synapse stabilization (90, 308). Following injury, CSPGs (neurocan, versican, brevican, and phosphacan) are robustly upregulated and reach their peak of expression at 2 weeks post-SCI and remain upregulated chronically (309, 310). Mechanistically, disruption of BSB and hemorrhage following traumatic SCI triggers upregulation of CSPGs in the glial scar by exposing the scar forming cells to factors in plasma such as fibrinogen (311). Studies in cortical injury have shown that fibrinogen induces CSPG expression in astrocytes through TGF/Smad2 signaling pathway (311). The authors show that intracellular Smad2 translocation is essential for Smad2 signal transduction process and its inhibition reduces scar formation (312). In contrast, another study has identified that TGF induces CSPGs production in astrocytes through a SMAD independent pathway (313). This study showed a significant upregulation of CSPGs in SMAD2 and SMAD4 knockdown astrocytes. Interestingly, CSPG upregulation was found to be mediated by the activation of the phosphoinositide 3-kinase (PI3K)/Akt and mTOR axis (313). Further studies are required to confirm these findings.

Extensive research in the past few decades has demonstrated the inhibitory effect of CSPGs on axon regeneration (314, 315). The first successful attempt on improving axon outgrowth and/or sprouting by enzymatic degradation of CSPGs using chondroitinase ABC (ChABC) in a rat SCI model was published in 2002 by Bradbury and colleagues (291). This study showed significant improvement in recovery of locomotor and proprioceptive functions following intrathecal delivery of ChABC in a rat model of dorsal column injury (291). This observation was followed by several other studies demonstrating the promise of CSPGs degradation in improvement of axon regeneration and sprouting of the serotonergic (295, 297, 299, 303), sensory (293, 298, 316), corticospinal (291, 297, 303, 317), and rubrospinal fibers (318) in animal models of CNS injury. Additionally, ChABC treatment is shown to be neuroprotective by preventing CSPG induced axonal dieback and degeneration (303, 319, 320). Studies by our group also showed that degradation of CSPGs using ChABC attenuates axonal dieback in corticospinal fibers in chronic SCI model in the rat (303). ChABC also blocks macrophage-mediated axonal degeneration in neural cultures and after SCI (238).

The inhibitory effects of astrocytic glial scar on axonal regeneration has been recently challenged after SCI (321). Using various transgenic mouse models, a study by Sofroniew's and colleagues has shown that spontaneous axon regrowth failed to happen following the ablation or prevention of astrocytic scar in acute and chronic SCI. They demonstrated that when the intrinsic ability of dorsal root ganglion (DRG) neurons for growth was enhanced by pre-conditioning injury as well as local delivery of a combination of axon growth promoting factors into the SCI lesion, the axons grew to the wall of the glial scar and CSPGs within the lesion. However, when astrocyte scarring was attenuated, the pre-conditioned/growth factor stimulated DRG neurons showed a reduced ability for axon growth (321). From these observations, the authors suggested a positive role for the astrocytic scar in axonal regeneration following SCI (321). Overall, this study points to the importance of reactive and scar forming astrocytes and their pivotal role in the repair process following SCI (322). This is indeed in agreement with previous studies by the same group that showed a beneficial role for activated astrocytes in functional recovery after SCI by limiting the speared of infiltrated inflammatory cells and tissue damage in SCI (285). It is also noteworthy that the glial scar is contributed by various cell populations and not exclusively by astrocytes (269, 271). Therefore, the outcomes of this study need to be interpreted in the context of astrocytes and astrocytic scar. Moreover, the reduced capacity of the injured spinal cord for regeneration is not solely driven by the glial scar as other factors including inflammation and damaged myelin play important inhibitory role in axon regeneration (323, 324). Taken together, further investigation is needed to delineate the mechanisms of the glial scar including the contribution of astrocyte-derived factors on axon regeneration in SCI.

While CSPGs were originally identified as an inhibitor of axon growth and plasticity within the glial scar, emerging evidence has also identified them as an important regulator of endogenous cell response. Emerging evidence has identified CSPGs as an inhibitor of oligodendrocytes (241, 272, 306). Replacement of oligodendrocytes is an important repair process in SCI and other demyelinating conditions such as MS (90). SCI and MS triggers activation of endogenous OPCs and their mobilization to the site of injury (143, 162, 306, 325). In vitro and in vivo evidence shows that CSPGs limit the recruitment of NPCs and OPCs to the lesion and inhibit oligodendrocyte survival, differentiation and maturation (145, 272, 305, 306, 326). Our group and others have shown that targeting CSPGs by ChABC administration or xyloside, or through inhibition of their signaling receptors enhances the capacity of NPCs and OPCs for proliferation, oligodendrocyte differentiation and remyelination following SCI and MS-like lesions (145, 303, 304, 306).

Mechanistically, the inhibitory effects of CSPGs on axon growth and endogenous cell differentiation is mainly governed by signaling through receptor protein tyrosine phosphatase sigma (RPTP) and leukocyte common antigen-related phosphatase receptor (LAR) (327). RPTP is the main receptor mediating the inhibition of axon growth by CSPGs (327, 328). Improved neuronal regeneration has been demonstrated in RPTP/ mice model of SCI and peripheral nerve injury (328, 329). Blockade of RPTP and LAR by intracellular sigma peptide (ISP) and intracellular LAR peptide (ILP), facilitates axon regeneration following SCI (327, 330). Inhibition of RPTP results in significant improvement in locomotion and bladder function associated with serotonergic re-innervation below the level of injury in rat SCI (327). Our group has also shown that CSPGs induce caspase-3 mediated apoptosis in NPCs and OPCs in vitro and in oligodendrocytes in the injured spinal cord that is mediated by both RPTP and LAR (241). Inhibition of LAR and RPTP sufficiently attenuates CSPG-mediated inhibition of oligodendrocyte maturation and myelination in vitro and attenuated oligodendrocyte cell death after SCI (241).

CSPGs have been implicated in regulating immune response in CNS injury and disease. Interestingly, our recent studies indicated that CSPGs signaling appears to restrict endogenous repair by promoting a pro-inflammatory immune response in SCI (241, 331). Inhibition of LAR and RPTP enhanced an anti-inflammatory environment after SCI by promoting the populations of pro-regenerative M2-like microglia/macrophages and regulatory T cells (241) that are known to promote repair process (224). These findings are also in agreement with recent studies in animal models of MS that unraveled a pro-inflammatory role for CSPGs in autoimmune demyelinating conditions (332). In MS and EAE, studies by Stephenson and colleagues have shown that CSPGs are abundant within the leucocyte-containing perivascular cuff, the entry point of inflammatory cells to the CNS tissue (332). Presence of CSPGs in these perivascular cuffs promotes trafficking of immune cells to induce a pro-inflammatory response in MS condition. In contrast to these new findings, early studies in SCI described that preventing CSPG formation with xyloside treatment at the time of injury results in poor functional outcome, while manipulation of CSPGs at 2 days after SCI was beneficial for functional recovery (333). These differential outcomes were associated with the modulatory role of CSPGs in regulating the response of macrophages/microglia. Disruption in CSPG formation immediately after injury promoted an M1 pro-inflammatory phenotype in macrophages/microglia, whereas delayed manipulation of CSPGs resulted in a pro-regenerative M2 phenotype (333). In EAE, by products of CSPG degradation also improve the outcomes by attenuating T cell infiltration and their expression of pro-inflammatory cytokines IFN- and TNF (334).

These emerging findings suggest an important immunomodulatory role for CSPGs in CNS injury and disease; further investigations are needed to elucidate CSPG mechanisms in regulating neuroinflammation. Altogether, current evidence has identified a multifaceted inhibitory role for CSPGs in regulating endogenous repair mechanisms after SCI, suggesting that targeting CSPGs may present a promising treatment strategy for SCI.

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Traumatic Spinal Cord Injury: An Overview of ...

Spinal Cord Stem Cells Comments Off on Traumatic Spinal Cord Injury: An Overview of … | October 16th, 2021

Abstract

Stem cells or mother or queen of all cells are pleuropotent and have the remarkable potential to develop into many different cell types in the body. Serving as a sort of repair system for the body, they can theoretically divide without limit to replenish other cells as long as the person or animal is alive. When a stem cell divides, each new cell has the potential to either remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell. Stem cells differ from other kinds of cells in the body. All stem cells regardless of their source have three general properties:

They are unspecialized; one of the fundamental properties of a stem cell is that it does not have any tissue-specific structures that allow it to perform specialized functions.

They can give rise to specialized cell types. These unspecialized stem cells can give rise to specialized cells, including heart muscle cells, blood cells, or nerve cells.

They are capable of dividing and renewing themselves for long periods. Unlike muscle cells, blood cells, or nerve cells which do not normally replicate themselves - stem cells may replicate many times. A starting population of stem cells that proliferates for many months in the laboratory can yield millions of cells. Today, donated organs and tissues are often used to replace those that are diseased or destroyed. Unfortunately, the number of people needing a transplant far exceeds the number of organs available for transplantation. Pleuropotent stem cells offer the possibility of a renewable source of replacement cells and tissues to treat a myriad of diseases, conditions, and disabilities including Parkinsons and Alzheimers diseases, spinal cord injury, stroke, Cerebral palsy, Battens disease, Amyotrophic lateral sclerosis, restoration of vision and other neuro degenerative diseases as well.

Stem cells may be the persons own cells (a procedure called autologous transplantation) or those of a donor (a procedure called allogenic transplantation). When the persons own stem cells are used, they are collected before chemotherapy or radiation therapy because these treatments can damage stem cells. They are injected back into the body after the treatment.

The sources of stem cells are varied such as pre-implantation embryos, children, adults, aborted fetuses, embryos, umbilical cord, menstrual blood, amniotic fluid and placenta

New research shows that transplanted stem cells migrate to the damaged areas and assume the function of neurons, holding out the promise of therapies for Alzheimers disease, Parkinsons, spinal cord injury, stroke, Cerebral palsy, Battens disease and other neurodegenerative diseases.

The therapeutic use of stem cells, already promising radical new treatments for cancer, immune-related diseases, and other medical conditions, may someday be extended to repairing and replenishing the brain. In a study published in the February 19, 2002, Proceedings of the National Academy of Sciences, researchers exposed the spinal cord of a rat to injury, paralyzing the animals hind limbs and lower body. Stem cells grown in exponential numbers in the laboratory were then injected into the site of the injury. It was seen that week after the injury, motor function improved dramatically,

The following diseases have been treated by various stem cell practitioners with generally positive results and the spectrum has ever since been increasing.

Cerebral palsy is a disorder caused by damage to the brain during pregnancy, delivery or shortly after birth. It is often accompanied by seizures, hearing loss, difficulty speaking, blindness, lack of co-ordination and/or mental retardation. Studies in animals with experimentally induced strokes or traumatic injuries have indicated that benefit is possible by stem cell therapy. The potential to do these transplants via injection into the vasculature rather than directly into the brain increases the likelihood of timely human studies. As a result, variables appropriate to human experiments with intravascular injection of cells, such as cell type, timing of the transplant and effect on function, need to be systematically performed in animal models Studies in animals with experimentally induced strokes or traumatic injuries have indicated that benefit is possible with injury, with the hope of rapidly translating these experiments to human trials.(1)

Cerebral palsy produces chronic motor disability in children. The causes are quite varied and range from abnormalities of brain development to birth-related injuries to postnatal brain injuries. Due to the increased survival of very premature infants, the incidence of cerebral palsy may be increasing. While premature infants and term infants who have suffered neonatal hypoxic-ischemic (HI) injury represent only a minority of the total cerebral palsy population, this group demonstrates easily identifiable clinical findings, and much of their injury is to oligodendrocytes and the white matter (2)

Alzheimers is a complex, fatal disease involving progressive cell degeneration, beginning with the loss of brain cells that control thought, memory and language. The disease, which currently has no cure, was first described by German physician Dr. Alzheimer, who discovered amyloid plaques and neurofibrillary tangles in the brain of a woman who died of an unusual mental illness. A compound similar to the components of DNA may improve the chances that stem cells transplanted from a patients bone marrow to the brain will take over the functions of damaged cells and help treat Alzheimers disease and other neurological illnesses. A research team led by University of Central Florida professor Kiminobu Sugaya found that treating bone marrow cells in laboratory cultures with bromodeoxyuridine, a compound that becomes part of DNA, made adult human stem cells more likely to develop as brain cells after they were implanted in adult rat brains.

It has long been recognized that Alzheimers disease (AD) patients present an irreversible decline of cognitive functions as consequence of cell deterioration in a structure called nucleus basalis of Meynert The reduction of the number of cholinergic cells causes interference in several aspects of behavioral performance including arousal, attention, learning and emotion. It is also common knowledge that AD is an untreatable degenerative disease with very few temporary and palliative drug therapies. Neural stem cell (NSC) grafts present a potential and innovative strategy for the treatment of many disorders of the central nervous system including AD, with the possibility of providing a more permanent remedy than present drug treatments. After grafting, these cells have the capacity to migrate to lesioned regions of the brain and differentiate into the necessary type of cells that are lacking in the diseased brain, supplying it with the cell population needed to promote recovery. (3)

Malignant multiple sclerosis (MS) is a rare but clinically important subtype of MS characterized by the rapid development of significant disability in the early stages of the disease process. These patients are refractory to conventional immunomodulatory agents and the mainstay of their treatment is plasmapheresis or immunosuppression with mitoxantrone, cyclophosphamide, cladribine or, lately, bone marrow transplantation. A report on the case of a 17-year old patient with malignant MS who was treated with high-dose chemotherapy plus anti-thymocyte globulin followed by autologous stem cell transplantation. This intervention resulted in an impressive and long-lasting clinical and radiological response (4).

In other experiment treatment of 24 patients (14 women, 10 men) with relapsing-remitting Multiple Sclerosis, in the course of 28 years was done For treatment, used were embryonic stem cell suspensions (ESCS) containing stem cells of mesenchymal and ectodermal origin obtained from active growth zones of 48 weeks old embryonic cadavers organs. Suspensions were administered in the amount of 13 ml, cell count being 0,1-100x105/ml. In the course of treatment, applied were 24 different suspensions, mode of administration being intracavitary, intravenous, and subcutaneous. After treatment, syndrome of early post-transplant improvement was observed in 70% of patients, its main manifestations being decreased weakness, improved appetite and mood, decreased depression. In the course of first post-treatment months, positive dynamics was observed in the following aspects: Nystagmus, convergence disturbances, spasticity, and coordination. In such symptoms as dysarthria, dysphagia, and ataxia, positive changes occurred at much slower rate. In general, the treatment resulted in improved range and quality of motions in the extremities, normalized muscle tone, decreased fatigue and general weakness, and improved quality of life. Forth, 87% of patients reported no exacerbations, no aggravation of neurological symptoms, and no further progression of disability. MRI performed in 12 years after the initial treatment, showed considerable subsidence of focal lesions, mean by 31%, subsidence of gadolinium enhanced lesions by 48%; T2-weighted images showed marked decrease of the focis relative density.

Doctors firstly isolated adult stem cells from the patients brain, they were then cultured in vitro and encouraged to turn into dopamine-producing neurons. As soon as tests showed that the cells were producing dopamine they were then re-injected into the mans brain. After the transplant, the mans condition was seen to improve and he experienced a reduction in the trembling and muscle rigidity associated with the disease. Brain scans taken 3-months after the transplant revealed that dopamine production had increased by 58%, however it later dropped but the Parkinsons symptoms did not return. The study is the first human study to show that stem cell transplants can help to treat Parkinsons.

The use of fetal-derived neural stem cells has shown significant promise in rodent models of Parkinsons disease, and the potential for tumorigenicity appears to be minimal. The authors report that undifferentiated human neural stem cells (hNSCs) transplanted into severely Parkinsonian 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates could survive, migrate, and induce behavioral recovery of Parkinsonian symptoms, which were directly related to reduced dopamine levels in the nigrostriatal system(5). Working with these cells, the researchers created dopamine neurons deficient in DJ-1, a gene mutated in an inherited form of Parkinsons. They report that DJ-1-deficient cells -- and especially DJ-1-deficient dopamine neurons -- display heightened sensitivity to oxidative stress, caused by products of oxygen metabolism that react with and damage cellular components like proteins and DNA. In a second paper, they link DJ-1 dysfunction to the aggregation of alpha-synuclein, a hallmark of Parkinsons neuropathology. (6,7)

In summary most of studies using aborted human embryonic tissue indicate that:

Clinical benefit does occur; however, the benefit is not marked and there is a delay of many months before the clinical change.

Postmortem examinations show that tissue grafts do survive and innervate the striatum.

PET scans show that there is an increase in dopamine uptake after transplantation.

Followup studies show that long term benefit does occur with transplantation.(8)

During and after a stroke, certain cellular events take place that lead to the death of brain cells. Compounds that inhibit a group of enzymes called histone deacetylases can modulate gene expression, and in some cases produce cellular proteins that are actually neuroprotective -- they are able to block cell death. Great deal of research has gone into developing histone deacetylase inhibitors as novel therapeutics (9)

One Mesenchymal stem cell (MSC) transplantation improves recovery from ischemic stroke in animals. The Researchers examined the feasibility, efficacy, and safety of cell therapy using culture-expanded autologous MSCs in patients with ischemic stroke. They prospectively and randomly allocated 30 patients with cerebral infarcts within the middle cerebral arterial territory Serial evaluations showed no adverse cell-related, serological, or imaging-defined effects. In patients with severe cerebral infarcts, the intravenous infusion of autologous MSCs appears to be a feasible and safe therapy that may improve functional recovery.(10)

Early intravenous stem cell injection displayed anti-inflammatory functionality that promoted neuroprotection, mainly by interrupting splenic inflammatory responses after intra cranial Haemorrage.

In summary, early intravenous NSC injection displayed anti-inflammatory functionality that neural stem cell (NSC) transplantation has been investigated as a means to reconstitute the damaged brain after stroke. In this study, however, was investigated the effect on acute cerebral and peripheral inflammation after intracerebral haemorrhage (ICH). STEM CELLS from fetal human brain were injected intravenously (NSCs-iv, 5 million cells) or intracerebrally (NSCs-ic, 1 million cells) at 2 or 24 h after collagenase-induced ICH in a rat model. Only NSCs-iv-2 h resulted in fewer initial neurologic deteriorations and reduced brain edema formation, inflammatory infiltrations and apoptosis. (11)

Emerging cell therapies for the restoration of sight have focused on two areas of the eye that are critical for visual function, the cornea and the retina. The relatively easy access of the cornea, the homogeneity of the cells forming the different layers of the corneal epithelium and the improvement of cell culture protocols are leading to considerable success in corneal epithelium restoration. Rebuilding the entire cornea is however still far from reality. The restoration of the retina has recently been achieved in different animal models of retinal degeneration using immature photoreceptors (12)

Bone marrow contains stem cells, which have the extraordinary abilities to home in on injuries and possibly regenerate other cell types in the body. In this case, the cells were transplanted to confirm that bone marrow does regenerate the injured RPE. Damage to RPE is present in many diseases of the retina, including age-related macular degeneration, which affects more than 1.75 million people in the United States. (13)

Neural stem cells (NSCs) offer the potential to replace lost tissue after nervous system injury. Thus, stem cells can promote host neural repair in part by secreting growth factors, and their regeneration-promoting activities can be modified by gene delivery.

Attempted repair of human spinal cord injury by transplantation of stem cells depends on complex biological interactions between the host and graft

Extrapolating results from experimental therapy in animals to humans with spinal cord injury requires great caution.

There is great pressure on surgeons to transplant stem cells into humans with spinal cord injury. However, as the efficacy of and exact indications for this therapy are still uncertain, and morbidity (such as rejection or late tumour development) may result, only carefully designed studies based on sound experimental work which attempts to eliminate placebo effects should proceed.

Premature application of stem cell transplantation in humans with spinal cord injury should be discouraged. 14, 15, 16)

Attempted repair of human spinal cord injury by transplantation of stem cells depends on complex biological interactions between the host and graft

Extrapolating results from experimental therapy in animals to humans with spinal cord injury requires great caution.

There is great pressure on surgeons to transplant stem cells into humans with spinal cord injury. However, as the efficacy of and exact indications for this therapy are still uncertain, and morbidity (such as rejection or late tumour development) may result, only carefully designed studies based on sound experimental work which attempts to eliminate placebo effects should proceed.

Premature application of stem cell transplantation in humans with spinal cord injury should be discouraged.

Mesenchymal stem cells have also been identified and are currently being developed for bone, cartilage, muscle, tendon, and ligament repair and regeneration. These MSCs are typically harvested, isolated, and expanded from bone marrow or adipose tissue, and they have been isolated from rodents, dogs, and humans. Interestingly, these cells can undergo extensive sub cultivation in vitro without differentiation, magnifying their potential clinical use.(17) Human MSCs can be directed toward osteoblastic differentiation by adding dexamethasone, ascorbic acid, and -glycerophosphate to the tissue culture media. This osteoblastic commitment and differentiation can be clearly documented by analyzing alkaline phosphatase activity, the expression of bone matrix proteins, and the mineralization of the extracellular matrix.(18)

Children with Battens disease suffer seizures, motor control disturbances, blindness and communication problems. As many as 600 children in the US are currently diagnosed with the condition.(19)

Death can occur in children as young as 8 years old. The children lack an enzyme for breaking down complex fat and protein compounds in the brain, explains Robert Steiner, vice chair of paediatric research at the hospital. The material accumulates and interferes with tissue function, ultimately causing brain cells to die. Tests on animals demonstrated that stem cells injected into the brain secreted the missing enzyme. And the stem cells were found to survive well in the rodent brain. Once injected, the purified neural cells may develop into neurons or other nervous system tissue, including oligodendrocytes, or glial cells, which support the neurons(20).

In a study that demonstrates the promise of cell-based therapies for diseases that have proved intractable to modern medicine, a team of scientists from the University of Wisconsin-Madison has shown it is possible to rescue the dying neurons characteristic of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disorder also known as Lou Gehrigs disease. Previously there was no effective treatments for ALS, which afflicts roughly 40,000 people in the United States and which is almost always fatal within three to five years of diagnosis. Patients gradually experience progressive muscle weakness and paralysis as the motor neurons that control muscles are destroyed by the disease

In the new Wisconsin study, nascent brain cells known as neural progenitor cells derived from human fetal tissue were engineered to secrete a chemical known as glial cell line derived neurotrophic factor (GDNF), an agent that has been shown to protect neurons but that is very difficult to deliver to specific regions of the brain. The engineered cells were then implanted in the spinal cords of rats afflicted with a form of ALS. The implanted cells, in fact, demonstrated an affinity for the areas of the spinal cord where motor neurons were dying. The cells after being injected to the area of damage where they just sit and release GDNF. At the early stages of disease, almost 100 percent protection of motor neurons was seen. (21)

In other study MSCs were isolated from bone marrow of 9 patients with definite ALS. Growth kinetics, immunophenotype, telomere length and karyotype were evaluated during in vitro expansion. No significant differences between donors or patients were observed. The patients received intraspinal injections of autologous MSCs at the thoracic level and monitored for 4 years. No significant acute or late side effects were evidenced. No modification of the spinal cord volume or other signs of abnormal cell proliferation were observed. The results seem to demonstrate that MSCs represent a good chance for stem cell cell-based therapy in ALS and that intraspinal injection of MSCs is safe also in the long term. A new phase 1 study is carried out to verify these data in a larger number of patients. (22)

Stem-cell-based technology offers amazing possibilities for the future. These include the ability to reproduce human tissues and potentially repair damaged organs (such as the brain, spinal cord, vertebral column the eye), where, at present, we mainly provide supportive care to prevent the situation from becoming worse. This potential almost silences the sternest critics of such technology, but the fact remains that the ethical challenges are daunting. It is encouraging that, in tackling these challenges, we stand to reflect a great deal about the ethics of our profession and our relationships with patients, industry, and each other. The experimental basis of stem-cell or OEC transplantation should be sound before these techniques are applied to humans with neurological disorders.

1. Stem cell therapy for cerebral palsy. Bartley J, Carroll JE. Department of Pediatrics of the Medical College of Georgia, Augusta, Georgia, USA

8. Department of Neurology, Mt. Sinai School of Medicine, New York, NY, Medscape journal. Stem Cell Transplantation for Parkinsons Disease

9. Journal of Medicinal Chemistry. Future Therapies For Stroke May Block Cell Death 16 Jun 2007

10. Neurosurg Focus. 2005;19(6) 2005 American Association of Neurological Surgeons

11. Brain Advance Access originally published online on December 20, 2007 Brain 2008 Anti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke.

13. University of Florida(2006, June 8). Bone Marrow May Restore Cells Lost In Vision Diseases. ScienceDaily.

18. Autologous mesenchymal stem cell transplantation in stroke patients Oh Young Bang, MD, PhD 1, Jin Soo Lee, MD Department of Neurology, School of Medicine, Ajou University, Suwon, South Korea Brain Disease Research Center, School of Medicine, Ajou University, Suwon, South Korea.

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Role of Stem Cells in Treatment of Neurological Disorder

Spinal Cord Stem Cells Comments Off on Role of Stem Cells in Treatment of Neurological Disorder | October 16th, 2021

Stem cell research holds great promise for biomedical sciencefrom helping us better understand how diseases develop and spread, to serving as accurate screens for new drugs, to developing cell-based therapies for diabetes, heart failure, Parkinsons disease, and many other conditions that affect millions of Americans. There are 2 basic types of human stem cells: embryonic stem (ES) cells and non-embryonic, or adult stem cells. Just a few years ago, scientists discovered how to make a third type, by reprogramming ordinary skin cells that have already grown up into those that look and act like cells from an embryo. These cells have been named induced pluripotent stem cells, or iPS cells.

NIH research is progressing on multiple fronts to learn more about the differences between the 3 stem cell types and to create patient-specific cells for in-depth study of many diseases. The ability to create iPS cells is a significant breakthrough, since the reprogramming technique is relatively simple to perform with standard laboratory methods, and because skin cells are easy to gather and grow. The most exciting aspect of this research is its potential to speed progress toward achieving personalized therapies. With refinements, this method could yield an unlimited supply of customized cells.

Regenerative medicine is moving toward a day when we can repair and replace damaged tissues. In time, we will be able to make insulin-secreting pancreatic cells, bone cells to heal breaks and defects, and eye and ear cells to restore vision and hearing. NIH researchers are hard at work using stem cells as a powerful tool to study neurological disorders like Parkinsons, Huntingtons disease, amyotrophic lateral sclerosis (ALS), and spinal cord injury, to name a few.

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Stem Cells | National Institutes of Health (NIH)

Spinal Cord Stem Cells Comments Off on Stem Cells | National Institutes of Health (NIH) | October 16th, 2021

Tests to determine how blood pressure changes during certain maneuvers

During the physical examination, doctors can check for signs of autonomic disorders, such as orthostatic hypotension. For example, they measure blood pressure and heart rate while a person is lying down or sitting and after the person stands to check how blood pressure changes when position is changed. When a person stands up, gravity makes it harder for blood from the legs to get back to the heart. Thus, blood pressure decreases. To compensate, the heart pumps harder, and the heart rate increases. However, the changes in heart rate and blood pressure are slight and brief. If the changes are larger or last longer, the person may have orthostatic hypotension.

The tilt table test and the Valsalva maneuver, done together, can help doctors determine whether a decrease in blood pressure is due to an autonomic nervous system disorder.

Doctors examine the pupils for abnormal responses or lack of response to changes in light.

Sweat testing is also done. For one sweat test, the sweat glands are stimulated by electrodes that are filled with acetylcholine and placed on the legs and forearm. Then, the volume of sweat is measured to determine whether sweat production is normal. A slight burning sensation may be felt during the test.

In the thermoregulatory sweat test, a dye is applied to the skin, and a person is placed in a closed, heated compartment to stimulate sweating. Sweat causes the dye to change color. Doctors can then evaluate the pattern of sweat loss, which may help them determine the cause of the autonomic nervous system disorder.

Other tests may be done to check for disorders that can cause the autonomic disorder.

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Overview of the Autonomic Nervous System - Brain, Spinal ...

Spinal Cord Stem Cells Comments Off on Overview of the Autonomic Nervous System – Brain, Spinal … | October 16th, 2021

DUBLIN - Horizon Therapeutics plc (Nasdaq: HZNP) announced the publication of a post-hoc analysis from the N-MOmentum phase 2/3 pivotal trial of UPLIZNA, which highlights a sustained effect on attack risk with no new safety signals in people with NMOSD who received the treatment for four or more years. These data are published in the Multiple Sclerosis Journal.

NMOSD is a rare, severe autoimmune disease that attacks the optic nerve, spinal cord and brain stem. The attacks are often recurrent and can cause irreversible damage to the nerves, leading to cumulative visual and motor disabilities over time. UPLIZNA is the first and only FDA-approved anti-CD19 B-cell-depleting humanized monoclonal antibody for the treatment of adult patients with anti-aquaporin-4 (AQP4) antibody positive NMOSD.

'This long-term study is important because NMOSD is a chronic disease that requires lifelong management. Physicians need to understand the implications of prolonged treatment,' said Bruce Cree, M.D., Ph.D., MAS, professor of clinical neurology at the University of California San Francisco Weill Institute for Neurosciences and primary study investigator. 'It is highly encouraging to see that most patients in this study were attack-free after the first year of UPLIZNA treatment and that new safety concerns were not observed. The data demonstrate that long-term UPLIZNA use is associated with a reduced risk of NMOSD attacks - possibly due to the depth and extent of B-cell depletion with repeated doses.'

The post-hoc analysis represents the experience of 75 people with AQP4 antibody positive NMOSD who were treated with UPLIZNA for four or more years during the open-label extension period of the N-MOmentum trial.

Key study findings include the following:

A total of 18 attacks occurred in 13 people, with an annualized attack rate of 0.052 attacks per person year.

The small number of total attacks decreased significantly after the first year of treatment with UPLIZNA.

67% of attacks occurred within the first year (12 attacks).

92% of patients were attack-free in subsequent years (two attacks each during years two to four).

The infection rate did not increase over time on treatment with UPLIZNA.

UPLIZNA was generally well tolerated, with few treatment-related dose interruptions and no treatment discontinuations.

'NMOSD is a complex and often unpredictable B-cell-mediated disease that presents significant challenges to both patients and physicians,' said Kristina Patterson, M.D., Ph.D., medical director, neuroimmunology, Horizon. 'With recent treatment advancements, the NMOSD community now has more options than ever before - including UPLIZNA, which is engineered for broad, deep and durable B-cell depletion. We are fully committed to increasing our understanding of this disease so we can continue to improve patient care.'

About Neuromyelitis Optica Spectrum Disorder (NMOSD)

NMOSD is a unifying term for neuromyelitis optica (NMO) and related syndromes. NMOSD is a rare, severe, relapsing, neuroinflammatory autoimmune disease that attacks the optic nerve, spinal cord, brain and brain stem.1,2 Approximately 80 percent of all patients with NMOSD test positive for anti-AQP4 antibodies.3 AQP4-IgG binds primarily to astrocytes in the central nervous system and triggers an escalating immune response that results in lesion formation and astrocyte death.4

Anti-AQP4 autoantibodies are produced by plasmablasts and plasma cells. These B-cell populations are central to NMOSD disease pathogenesis, and a large proportion of these cells express CD19.5 Depletion of these CD19+ B cells is thought to remove an important contributor to inflammation, lesion formation and astrocyte damage. Clinically, this damage presents as an NMOSD attack, which can involve the optic nerve, spinal cord and brain.4,6 Loss of vision, paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain and respiratory failure can all be manifestations of the disease.7 Each NMOSD attack can lead to further cumulative damage and disability.8,9 NMOSD occurs more commonly in women and may be more common in individuals of African and Asian descent.10,11

About UPLIZNA

INDICATION

UPLIZNA is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

IMPORTANT SAFETY INFORMATION

UPLIZNA is contraindicated in patients with:

A history of life-threatening infusion reaction to UPLIZNA

Active hepatitis B infection

Active or untreated latent tuberculosis

WARNINGS AND PRECAUTIONS

Infusion Reactions: UPLIZNA can cause infusion reactions, which can include headache, nausea, somnolence, dyspnea, fever, myalgia, rash or other symptoms. Infusion reactions were most common with the first infusion but were also observed during subsequent infusions. Administer pre-medication with a corticosteroid, an antihistamine and an anti-pyretic.

Infections: The most common infections reported by UPLIZNA-treated patients in the randomized and open-label periods included urinary tract infection (20%), nasopharyngitis (13%), upper respiratory tract infection (8%) and influenza (7%). Delay UPLIZNA administration in patients with an active infection until the infection is resolved.

Increased immunosuppressive effects are possible if combining UPLIZNA with another immunosuppressive therapy.

The risk of hepatitis B virus (HBV) reactivation has been observed with other B-cell-depleting antibodies. Perform HBV screening in all patients before initiation of treatment with UPLIZNA. Do not administer to patients with active hepatitis.

Although no confirmed cases of Progressive Multifocal Leukoencephalopathy (PML) were identified in UPLIZNA clinical trials, JC virus infection resulting in PML has been observed in patients treated with other B-cell-depleting antibodies and other therapies that affect immune competence. At the first sign or symptom suggestive of PML, withhold UPLIZNA and perform an appropriate diagnostic evaluation. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating UPLIZNA.

Vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation, until B-cell repletion.

Reduction in Immunoglobulins: There may be a progressive and prolonged hypogammaglobulinemia or decline in the levels of total and individual immunoglobulins such as immunoglobulins G and M (IgG and IgM) with continued UPLIZNA treatment. Monitor the level of immunoglobulins at the beginning, during, and after discontinuation of treatment with UPLIZNA until B-cell repletion especially in patients with opportunistic or recurrent infections.

Fetal Risk: May cause fetal harm based on animal data. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during treatment and for 6 months after stopping UPLIZNA.

Adverse Reactions: The most common adverse reactions (at least 10% of patients treated with UPLIZNA and greater than placebo) were urinary tract infection and arthralgia.

For additional information on UPLIZNA, please see Prescribing Information at http://www.UPLIZNA.com.

About Horizon

Horizon is focused on the discovery, development and commercialization of medicines that address critical needs for people impacted by rare, autoimmune and severe inflammatory diseases. Our pipeline is purposeful: we apply scientific expertise and courage to bring clinically meaningful therapies to patients. We believe science and compassion must work together to transform lives. For more information on how we go to incredible lengths to impact lives, please visit http://www.horizontherapeutics.com and follow us on Twitter, LinkedIn, Instagram and Facebook.

Forward-Looking Statements

This press release contains forward-looking statements, including statements regarding the potential benefits of UPLIZNA and Horizon's research and development plans. These forward-looking statements are based on management's expectations and assumptions as of the date of this press release and actual results may differ materially from those in these forward-looking statements as a result of various factors. These factors include, but are not limited to, risks regarding whether future results of clinical trials will be consistent with preliminary results or results of prior trials or other data or Horizon's expectations, the risks associated with clinical development and adoption of novel medicines and risks related to competition or other factors that may change physician treatment strategies. For a further description of these and other risks facing Horizon, please see the risk factors described in Horizon's filings with the United States Securities and Exchange Commission, including those factors discussed under the caption 'Risk Factors' in those filings. Forward-looking statements speak only as of the date of this press release and Horizon undertakes no obligation to update or revise these statements, except as may be required by law.

Contact:

Rachel Vann

Director

Product Communications

E: media@horizontherapeutics.com

Original post:
Horizon Therapeutics Public : plc - New Analysis Published in Multiple Sclerosis Journal Assesses Long-Term Use of UPLIZNA (inebilizumab-cdon) for the...

Spinal Cord Stem Cells Comments Off on Horizon Therapeutics Public : plc – New Analysis Published in Multiple Sclerosis Journal Assesses Long-Term Use of UPLIZNA (inebilizumab-cdon) for the… | October 5th, 2021

DUBLIN--(BUSINESS WIRE)--Horizon Therapeutics plc (Nasdaq: HZNP) today announced the publication of a post-hoc analysis from the N-MOmentum phase 2/3 pivotal trial of UPLIZNA, which highlights a sustained effect on attack risk with no new safety signals in people with NMOSD who received the treatment for four or more years. These data are published in the Multiple Sclerosis Journal.

NMOSD is a rare, severe autoimmune disease that attacks the optic nerve, spinal cord and brain stem. The attacks are often recurrent and can cause irreversible damage to the nerves, leading to cumulative visual and motor disabilities over time. UPLIZNA is the first and only FDA-approved anti-CD19 B-cell-depleting humanized monoclonal antibody for the treatment of adult patients with anti-aquaporin-4 (AQP4) antibody positive NMOSD.

This long-term study is important because NMOSD is a chronic disease that requires lifelong management. Physicians need to understand the implications of prolonged treatment, said Bruce Cree, M.D., Ph.D., MAS, professor of clinical neurology at the University of California San Francisco Weill Institute for Neurosciences and primary study investigator. It is highly encouraging to see that most patients in this study were attack-free after the first year of UPLIZNA treatment and that new safety concerns were not observed. The data demonstrate that long-term UPLIZNA use is associated with a reduced risk of NMOSD attacks possibly due to the depth and extent of B-cell depletion with repeated doses.

The post-hoc analysis represents the experience of 75 people with AQP4 antibody positive NMOSD who were treated with UPLIZNA for four or more years during the open-label extension period of the N-MOmentum trial.

Key study findings include the following:

NMOSD is a complex and often unpredictable B-cell-mediated disease that presents significant challenges to both patients and physicians, said Kristina Patterson, M.D., Ph.D., medical director, neuroimmunology, Horizon. With recent treatment advancements, the NMOSD community now has more options than ever before including UPLIZNA, which is engineered for broad, deep and durable B-cell depletion. We are fully committed to increasing our understanding of this disease so we can continue to improve patient care.

About Neuromyelitis Optica Spectrum Disorder (NMOSD)

NMOSD is a unifying term for neuromyelitis optica (NMO) and related syndromes. NMOSD is a rare, severe, relapsing, neuroinflammatory autoimmune disease that attacks the optic nerve, spinal cord, brain and brain stem.1,2 Approximately 80 percent of all patients with NMOSD test positive for anti-AQP4 antibodies.3 AQP4-IgG binds primarily to astrocytes in the central nervous system and triggers an escalating immune response that results in lesion formation and astrocyte death.4

Anti-AQP4 autoantibodies are produced by plasmablasts and plasma cells. These B-cell populations are central to NMOSD disease pathogenesis, and a large proportion of these cells express CD19.5 Depletion of these CD19+ B cells is thought to remove an important contributor to inflammation, lesion formation and astrocyte damage. Clinically, this damage presents as an NMOSD attack, which can involve the optic nerve, spinal cord and brain.4,6 Loss of vision, paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain and respiratory failure can all be manifestations of the disease.7 Each NMOSD attack can lead to further cumulative damage and disability.8,9 NMOSD occurs more commonly in women and may be more common in individuals of African and Asian descent.10,11

About UPLIZNA

INDICATION

UPLIZNA is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

IMPORTANT SAFETY INFORMATION

UPLIZNA is contraindicated in patients with:

WARNINGS AND PRECAUTIONS

Infusion Reactions: UPLIZNA can cause infusion reactions, which can include headache, nausea, somnolence, dyspnea, fever, myalgia, rash or other symptoms. Infusion reactions were most common with the first infusion but were also observed during subsequent infusions. Administer pre-medication with a corticosteroid, an antihistamine and an anti-pyretic.

Infections: The most common infections reported by UPLIZNA-treated patients in the randomized and open-label periods included urinary tract infection (20%), nasopharyngitis (13%), upper respiratory tract infection (8%) and influenza (7%). Delay UPLIZNA administration in patients with an active infection until the infection is resolved.

Increased immunosuppressive effects are possible if combining UPLIZNA with another immunosuppressive therapy.

The risk of hepatitis B virus (HBV) reactivation has been observed with other B-cell-depleting antibodies. Perform HBV screening in all patients before initiation of treatment with UPLIZNA. Do not administer to patients with active hepatitis.

Although no confirmed cases of Progressive Multifocal Leukoencephalopathy (PML) were identified in UPLIZNA clinical trials, JC virus infection resulting in PML has been observed in patients treated with other B-cell-depleting antibodies and other therapies that affect immune competence. At the first sign or symptom suggestive of PML, withhold UPLIZNA and perform an appropriate diagnostic evaluation. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating UPLIZNA.

Vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation, until B-cell repletion.

Reduction in Immunoglobulins: There may be a progressive and prolonged hypogammaglobulinemia or decline in the levels of total and individual immunoglobulins such as immunoglobulins G and M (IgG and IgM) with continued UPLIZNA treatment. Monitor the level of immunoglobulins at the beginning, during, and after discontinuation of treatment with UPLIZNA until B-cell repletion especially in patients with opportunistic or recurrent infections.

Fetal Risk: May cause fetal harm based on animal data. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during treatment and for 6 months after stopping UPLIZNA.

Adverse Reactions: The most common adverse reactions (at least 10% of patients treated with UPLIZNA and greater than placebo) were urinary tract infection and arthralgia.

For additional information on UPLIZNA, please see Prescribing Information at http://www.UPLIZNA.com.

About Horizon

Horizon is focused on the discovery, development and commercialization of medicines that address critical needs for people impacted by rare, autoimmune and severe inflammatory diseases. Our pipeline is purposeful: we apply scientific expertise and courage to bring clinically meaningful therapies to patients. We believe science and compassion must work together to transform lives. For more information on how we go to incredible lengths to impact lives, please visit http://www.horizontherapeutics.com and follow us on Twitter, LinkedIn, Instagram and Facebook.

Forward-Looking Statements

This press release contains forward-looking statements, including statements regarding the potential benefits of UPLIZNA and Horizons research and development plans. These forward-looking statements are based on management's expectations and assumptions as of the date of this press release and actual results may differ materially from those in these forward-looking statements as a result of various factors. These factors include, but are not limited to, risks regarding whether future results of clinical trials will be consistent with preliminary results or results of prior trials or other data or Horizons expectations, the risks associated with clinical development and adoption of novel medicines and risks related to competition or other factors that may change physician treatment strategies. For a further description of these and other risks facing Horizon, please see the risk factors described in Horizons filings with the United States Securities and Exchange Commission, including those factors discussed under the caption Risk Factors in those filings. Forward-looking statements speak only as of the date of this press release and Horizon undertakes no obligation to update or revise these statements, except as may be required by law.

References

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New Analysis Published in Multiple Sclerosis Journal Assesses Long-Term Use of UPLIZNA (inebilizumab-cdon) for the Treatment of Neuromyelitis Optica...

Spinal Cord Stem Cells Comments Off on New Analysis Published in Multiple Sclerosis Journal Assesses Long-Term Use of UPLIZNA (inebilizumab-cdon) for the Treatment of Neuromyelitis Optica… | October 5th, 2021

Stem cell characterization kitst Market size is done based on a triangulation methodology that is primarily based on experimental modelling approaches such as patient-level data or disease epidemiology for any key indications , number of procedures and install base analysis for any equipment to obtain precise market estimations for the base year as well as in historic data analysis.

Bottom-up approach is always used to obtain Stem cell characterization kits insightful data for the specific country/regions. The country specific data is again analyzed to derive data at a global level.

Market Overview:-

Stem cells are biological cells that can be converted into specific type of cells as per the bodys requirement. Stem cells are of two types, i.e., adult stem cells and embryonic stem cells. Stem cells can be used to treat various diseases such as cancer, neurodegenerative disorder, cardiovascular disorder and tissue regeneration. Stem cell characterization is the initial step for stem cell research.

Stem cell characterization kit is required to understand the utility of the stem cells in downstream experiments and to confirm the pluripotency of the stem cell.The growth of the stem cell characterization kits market is expected to be being fuelled by government funding for stem cell research.

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Fact.MR, a leading authority on market research brings original, in-depth, and insightful reports to investors On Stem Cell Characterization Kits Market Sales & Demand. Fact.MRs report will highlight various growth forecasts, key trends, and notable segments ripe for upcoming investments.

Key Parameters analyzed while estimating the Stem Cell Characterization Kits market include:

Overall Population by age group/Prevalence or Incidence of any disease/Treatment Seeking Rate/Dosage pattern/Average duration of treatment/Overall treatment cost and Reimbursement are considered.

Overall Population/Prevalence or Incidence of disease/treatment seeking rate/ average duration of the treatment/average number of devices used per patient / average number of procedure per device/ average selling price per device/reimbursement are considered.

Number of Healthcare facilities (Hospitals/Ambulatory Surgical Centers/Clinics etc.)

Average number of devices installed per facilities/ lifespan of the devices/replacement rate of the equipment/new sales of the equipment per year/average selling price per equipment are considered.

Extensive rounds of primary and a comprehensive secondary research have been leveraged by the analysts to arrive at various estimations and projections for Sales & Demand of Stem Cell Characterization Kits, its market share, production footprint, current launches, agreements, ongoing R&D projects, and market strategies.

SWOT analysis has been performed in the Sales study to investigate the strengths, weaknesses, opportunities and threats of each player, both at global and regional levels

Company share analysis is used to derive the size of the global Stem Cell Characterization Kits market. As well as a study of the revenues of companies for the last several years also provides the base for forecasting the market size and its Sales growth rate.

This study offers an overview of the existing market trends, metrics, drivers, and restrictions and also offers a point of view for important segments. The report also tracks product and services demand growth forecasts for the market.

Based on type of stem cell, the stem cell characterization kits market is segmented into:

Based on application, the stem cell characterization kits market is segmented into:

Based on end user, the stem cell characterization kits market is segmented into:

North America and Europe are expected to witness significant growth in the global stem cell characterization kit market over the forecast period. This is owing to presence of key manufacturers and researchers of stem cell based therapies in these regions. Moreover, manufacturers such as ThermoFisher Scientific, and Becton Dickinson providing stem cell assays are present in North America region.

Asia Pacific is expected to show significant growth in the stem cell characterization kit market over the forecast period, as researchers from China and Japan are working on stem cell based therapies. For instance, in 2017, clinical trials of embryonic stem cells were launched in China for Parkinsons disease.

The Stem Cell Characterization Kits Sales study analyzes crucial trends that are currently determining the growth of Stem Cell Characterization Kits Market.

There is also to the study approach a detailed segmental review. The report mentions growth parameters in the regional markets along with major players dominating the regional growth.

The Key trends Analysis of Stem Cell Characterization Kits also provides dynamics that are responsible for influencing thefuture Sales and Demand of Stem Cell Characterization Kits marketover the forecast period.

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The report covers following Stem Cell Characterization Kits Market insights and assessment that are helpful for all participants involved in the Stem Cell Characterization Kits market:

NOTE:Our team are studying Covid19 and its impact on the Sales growth of Stem Cell Characterization Kits market and where necessary we will consider the Covid-19 footmark for better analysis of the market Demand and industries outlook. Contact us cogently for more detailed information.

Further, the Stem Cell Characterization Kits market Survey report emphasizes the adoption pattern And Demand of Stem Cell Characterization Kits Market across various industries.

The Stem Cell Characterization Kits Sales study offers a comprehensive analysis on diverse features including production capacities, Stem Cell Characterization Kits demand, product developments, Stem Cell Characterization Kits revenue generation and Stem Cell Characterization Kits Market Outlook across the globe.

Competitive Landscape Analysis On Stem Cell Characterization KitsMarket:

In this report, leading market participants involved in the manufacturing of Stem Cell Characterization Kits are covered. Analysis regarding their product portfolio, key financials such as market shares and sales, SWOT analysis and key strategies are included in this report. To provide decision-makers with credible insights on their competitive landscape, the Stem Cell Characterization Kits industry research report includes detailed market competitive landscape analysis.

Some of the key participants in the global Stem Cell Characterization Kits Market include :

Examples of some of the key participants in the stem cell characterization kits market identified across the value chain include Merck KGaA, Celprogen, Inc., Creative Bioarray, Thermo Fisher Scientific Inc., BD Biosciences, R&D Systems, Inc., System Biosciences, Cosmo Bio USA, BioCat GmbH, and DS Pharma Biomedical Co., Ltd.

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After glancing through the report on globalStem Cell Characterization Kits market Demand, readers will get valuable insight into the following:

The Survey report highlights the growth factors and entry barriers for the key players and talks about the new trends emerging in the globalStem Cell Characterization Kitsmarket.

In addition to this, the study sheds light on changing market size, revenue growth, and share of important product segments. Analysts at Fact.MR give prominent data on recent technological developments and product developments in the Stem Cell Characterization Kits Demand during the assessment period.

A comprehensive estimate on Demand of Stem Cell Characterization Kits market has been provided through an optimistic scenario as well as a conservative scenario, taking into account the sales of Stem Cell Characterization Kits market during the forecast period. Price point comparison by region with global average price is also considered in the study.

Market Snapshot

The rising prevalence of cancer, cardiovascular disorders and neurodegenerative diseases and the role of stem cell therapy in treating these diseases is projected to drive the growth of stem cell characterization kit market.

As per the American Cancer Society, in 2017 cancer accounted around 1 out of 4 deaths in the U.S. and was the second most common cause of deaths in the U.S.

Stem cell therapy and stem cell transplant has huge potential to treat such chronic diseases, which is expected to have a positive impact on the growth of the stem cell characterization kits market.

Stem cell transplant is useful for the treatment of spinal cord injury, stroke, and Alzheimers disease, which is expected to fuel the adoption of stem cell characterization kits over the forecast period.

The Stem Cell Agency, California, is working on the development of new stem cell-based therapies for chronic diseases such as cancer and rare diseases, where stem cell characterization kits are primarily required.

Stem cell characterization kit is also required to identify the appropriate stem cells for the treatment of -Thalassemia. Due to the increasing research and study on stem cells, the stem cell characterization kit market is expected to witness significant growth over the forecast period.

The role of stem cell characterization kit is very important because if the stem cells are not characterized properly into required adult cell type, transplanted stem cells may revert back to teratomas and there is a possibility of transplant rejection. This is expected to influence the growth of the stem cell characterization kit market.

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Chronic Diseases Is Expected To Have Positive Impact On Stem Cell Characterization Kits Market Deman - PharmiWeb.com

Spinal Cord Stem Cells Comments Off on Chronic Diseases Is Expected To Have Positive Impact On Stem Cell Characterization Kits Market Deman – PharmiWeb.com | September 1st, 2021

The Stem Cell Therapy Market report provides a quick description about market status, size, companies share, growth, opportunities and upcoming trends. This report includes the corporate profile, values that the challenges and drivers & restraints that have a serious impact on the industry analysis. The information within the report that help form the longer term projections during the forecast year. The up so far analysis to assists in understanding of the changing competitive analysis. Additionally, the market strategies including moderate growth during the years.

The research on Stem Cell Therapy market scenario which will affect the overview the forecast period, including as opportunities, prime challenges, and current/future trends. To supply an in-depth analysis of all Stem Cell Therapy regions included within the report into sections to supply a comprehensive competitive analysis.

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Some of the leading manufacturers and suppliers of the Stem Cell Therapy market are Magellan, Medipost Co., Ltd, Osiris Therapeutics, Inc., Kolon TissueGene, Inc., JCR Pharmaceuticals Co., Ltd., Anterogen Co. Ltd., Pharmicell Co., Inc., and Stemedica Cell Technologies, Inc.

Stem cells are divided into two major classes; pluripotent and multipotent. Pluripotent stem cells are replicating cells, which are derived from the embryo or fetal tissues. The pluripotent stem cells facilitate the development of cells and tissues in three primary germ layers such as mesoderm, ectoderm, and endoderm.

Market Dynamics

Increasing expansion of facilities by market players for stem cell therapies is expected to propel growth of the stem cell therapy market over the forecast period. For instance, in January 2018, the University of Florida, U.S. launched the Center for Regenerative Medicine that is focused on development of stem cell therapies for the treatment of damaged tissue and organ. The Centre for Regenerative Medicines is divided into two segments such as focus groups and shared services. Focus groups such as research and development activities for stem cell therapies; and the shared services segment offers technical resources related to stem cell therapies.

Furthermore, rising collaboration activities by key players are expected to drive growth of the global stem cell therapy market. For instance, in May 2018, Procella Therapeutics and Smartwise, a medtech company entered into a collaboration with AstraZeneca Pharmaceuticals. Under this collaboration, AstraZeneca utilized Procella Therapeutics stem cell technology for the development of stem cell therapies in cardiovascular diseases. Moreover, in April, 2019, CelluGen Biotech and FamiCord Group collaborated to develop new stem cell-based drugs and advanced medical therapies (ATMP)

What Stem Cell Therapy Market Research Report Covers?

This report covers definition, development, market status, geographical analysis of Stem Cell Therapy market.

Competitor analysis including all the key parameters of Stem Cell Therapy market

Market estimates for at least 7 years

Market Trends (Drivers, Constraints, Opportunities, Threats, Challenges, Investment Opportunities, and proposals)

Strategic proposals in key business portions dependent available estimations

Company profiling with point by point systems, financials, and ongoing improvements

Mapping of the most recent innovative headways and Supply chain patterns

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Increasing application of stem cells for the treatment of patients with blood-related cancers, spinal cord injury and other diseases are the leading factors that are expected to drive growth of stem cell therapy market over the forecast period. According to the National Spinal Cord Injury Statistical Center, 2016, the annual incidence of spinal cord injury (SCI) is approximately 54 cases per million population in the U.S. or approximately 17,000 new SCI cases each year.

Moreover, according to the Leukemia and Lymphoma Society, 2017, around 172,910 people in the U.S. were diagnosed with leukemia, lymphoma or myeloma in 2017, thus leading to increasing adoption of stem cells for its efficient treatment. Increasing product launches by key players such as medium for developing embryonic stem cells is expected to propel the market growth over the forecast period.

For instance, in January 2019, STEMCELL Technologies launched mTeSR Plus, a feeder-free human pluripotent stem cell (hPSC) maintenance medium for avoiding conditions associated with DNA damage, genomic instability, and growth arrest in hPSCs. With the launch of mTeSR, the company has expanded its portfolio of mediums for maintenance of human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells. Increasing research and development of induced pluripotent stem cells coupled with clinical trials is expected to boost growth of the stem cell therapy market over the forecast period.

For instance, in April 2019, Fate Therapeutics in collaboration with UC San Diego researchers launched Off-the-shelf immunotherapy (FT500) developed from human induced pluripotent stem cells. The therapy is currently undergoing clinical trials for the treatment of advanced solid tumors.

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Main points in Stem Cell Therapy Market Report Table of Content

Chapter 1 Industry Overview

1.1 Definition

1.2 Assumptions

1.3 Research Scope

1.4 Market Analysis by Regions

1.5 Global Stem Cell Therapy Market Size Analysis from 2021 to 2027

11.6 COVID-19 Outbreak: Stem Cell Therapy Industry Impact

Chapter 2 Global Stem Cell Therapy Competition by Types, Applications, and Top Regions and Countries

2.1 Global Stem Cell Therapy (Volume and Value) by Type

2.3 Global Stem Cell Therapy (Volume and Value) by Regions

Chapter 3 Production Market Analysis

3.1 Global Production Market Analysis

3.2 Regional Production Market Analysis

Chapter 4 Global Stem Cell Therapy Sales, Consumption, Export, Import by Regions (2016-2021)

Chapter 5 North America Stem Cell Therapy Market Analysis

Chapter 6 East Asia Stem Cell Therapy Market Analysis

Chapter 7 Europe Stem Cell Therapy Market Analysis

Chapter 8 South Asia Stem Cell Therapy Market Analysis

Chapter 9 Southeast Asia Stem Cell Therapy Market Analysis

Chapter 10 Middle East Stem Cell Therapy Market Analysis

Chapter 11 Africa Stem Cell Therapy Market Analysis

Chapter 12 Oceania Stem Cell Therapy Market Analysis

Chapter 13 South America Stem Cell Therapy Market Analysis

Chapter 14 Company Profiles and Key Figures in Stem Cell Therapy Business

Chapter 15 Global Stem Cell Therapy Market Forecast (2021-2027)

Chapter 16 Conclusions

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Stem Cell Therapy Market worth $40.3 billion by 2027 Exclusive Report by CoherentMarketInsights - PharmiWeb.com

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The prevalence of inorganic mercury in human cells increases during aging but decreases in the very old | Scientific Reports - Nature.com

Spinal Cord Stem Cells Comments Off on The prevalence of inorganic mercury in human cells increases during aging but decreases in the very old | Scientific Reports – Nature.com | August 19th, 2021

SAN FRANCISCO, Aug. 12, 2021 /PRNewswire/ --The global regenerative medicine marketsize is expectedto reach USD 57.08 billion by 2027, growing at a CAGR of 11.27% over the forecast period, according to a new report by Grand View Research, Inc. Recent advancements in biological therapies have resulted in a gradual shift in preference toward personalized medicinal strategies over the conventional treatment approach. This has resulted in rising R&D activities in the regenerative medicine arena for the development of novel regenerative therapies.

Key Insights & Findings:

Read 273 page research report, "Regenerative Medicine Market Size, Share & Trends Analysis Report By Product (Cell-based Immunotherapies, Gene Therapies), By Therapeutic Category (Cardiovascular, Oncology), And Segment Forecasts, 2021 - 2027", by Grand View Research

Furthermore,advancements in cell biology, genomics research, and gene-editing technology are anticipated to fuel the growth of the industry. Stem cell-based regenerative therapies are in clinical trials, which may help restore damaged specialized cells in many serious and fatal diseases, such as cancer, Alzheimer's, neurodegenerative diseases, and spinal cord injuries. For instance, various research institutes have adopted Human Embryonic Stem Cells (hESCs) to develop a treatment for Age-related Macular Degeneration (AMD).

Constant advancements in molecular medicines have led to the development of gene-based therapy, which utilizes targeted delivery of DNA as a medicine to fight against various disorders. Gene therapy developments are high in oncology due to the rising prevalence and genetically driven pathophysiology of cancer. The steady commercial success of gene therapies is expected to accelerate the growth of the global market over the forecast period.

Grand View Research has segmented the global regenerative medicine market on the basis of product, therapeutic category, and region:

List of Key Players of Regenerative Medicine Market

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Regenerative Medicine Market Size Worth $57.08 Billion By 2027: Grand View Research, Inc. - PRNewswire

Spinal Cord Stem Cells Comments Off on Regenerative Medicine Market Size Worth $57.08 Billion By 2027: Grand View Research, Inc. – PRNewswire | August 19th, 2021

This article was originally published here

Syst Rev. 2021 Jul 31;10(1):213. doi: 10.1186/s13643-021-01771-w.

ABSTRACT

BACKGROUND: Considerable disparities exist on the use of adipose tissue-derived stem cells (ADSCs) for treatment of spinal cord injury (SCI). Hence, the current systematic review aimed to investigate the efficacy of ADSCs in locomotion recovery following SCI in animal models.

METHODS: A search was conducted in electronic databases of MEDLINE, Embase, Scopus, and Web of Science until the end of July 2019. Reference and citation tracking and searching Google and Google Scholar search engines were performed to achieve more studies. Animal studies conducted on rats having SCI which were treated with ADSCs were included in the study. Exclusion criteria were lacking a non-treated control group, not evaluating locomotion, non-rat studies, not reporting the number of transplanted cells, not reporting isolation and preparation methods of stem cells, review articles, combination therapy, use of genetically modified ADSCs, use of induced pluripotent ADSCs, and human trials. Risk of bias was assessed using Hasannejad et al.s proposed method for quality control of SCI-animal studies. Data were analyzed in STATA 14.0 software, and based on a random effect model, pooled standardized mean difference with a 95% confidence interval was presented.

RESULTS: Of 588 non-duplicated papers, data from 18 articles were included. Overall risk of bias was high risk in 8 studies, some concern in 9 studies and low risk in 1 study. Current evidence demonstrated that ADSCs transplantation could improve locomotion following SCI (standardized mean difference = 1.71; 95%CI 1.29-2.13; p < 0.0001). A considerable heterogeneity was observed between the studies (I2 = 72.0%; p < 0.0001). Subgroup analysis and meta-regression revealed that most of the factors like injury model, the severity of SCI, treatment phase, injury location, and number of transplanted cells did not have a significant effect on the efficacy of ADSCs in improving locomotion following SCI (pfor odds ratios > 0.05).

CONCLUSION: We conclude that any number of ADSCs by any prescription routes can improve locomotion recovery in an SCI animal model, at any phase of SCI, with any severity. Given the remarkable bias about blinding, clinical translation of the present results is tough, because in addition to the complexity of the nervous system and the involvement of far more complex motor circuits in the human, blinding compliance and motor outcome assessment tests in animal studies and clinical trials are significantly different.

PMID:34330329 | DOI:10.1186/s13643-021-01771-w

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Efficacy of adipose tissue-derived stem cells in locomotion recovery after spinal cord injury: a systematic review and meta-analysis on animal studies...

Spinal Cord Stem Cells Comments Off on Efficacy of adipose tissue-derived stem cells in locomotion recovery after spinal cord injury: a systematic review and meta-analysis on animal studies… | August 6th, 2021

Q: Im considering having my own stem cells injected into me to improve physical and mental problems that I am having post-COVID-19 infection. What do you think?

James D., Huntington, N.Y.

A: Theres been a lot of talk about using what are called autologous stem cells (your own) to fight off COVID-19 long-haul symptoms, as well as to treat everything from torn ligaments to Alzheimers disease. None is approved by the Food and Drug Administration. The only stem-cell-based products that are FDA-approved come from blood-forming stem cells (hematopoietic progenitor cells) derived from cord blood and theyre for treating disorders involving production of blood (the hematopoietic system). A list is at fda.gov; search for Approved Cellular and Gene Therapy Products.

In fact, stem cell/regenerative medicine treatment scams are so prevalent that this spring the FDA finally told manufacturers and marketers that they had to comply with regulations on human cell and tissue products. Unfortunately, a June report from Pew Trust found compliance by the companies and enforcement from the FDA to be anemic.

What the report did find was that more than 700 clinics in the U.S. offer unapproved stem-cell and regenerative medicine interventions for conditions such as Alzheimers, muscular dystrophy, autism, spinal cord injuries and, most recently, COVID-19. They also found post-injection infection happens frequently and is likely because of sloppily manufactured products and failure to properly screen for diseases such as HIV and hepatitis B and C.

If youre considering stem-cell treatment, the FDA urges you to ask the clinic for the following info before getting it even if the stem cells are your own:

Proof the FDA has reviewed and approved the treatment. Have your primary care doc confirm the information.

If the clinic is claiming it has an FDA-issued Investigational New Drug application number, ask for it and ask to review the FDA communication acknowledging the IND.

Stem-cell treatment has great potential, but when used for unapproved therapies outside a clinical trial, its risky (and expensive). To search for a trial, go to clinicaltrials.gov.

Q: My doctor says my high blood pressure puts me at increased risk for dementia. I think hes just trying to get me on one more med. Is there really a connection?

Lacie R., Sacramento, Calif.

A: Dementia means that you have cognition problems that cause trouble with memory, thought and everyday tasks. That could result from mini- or regular strokes, and we know that high blood pressure increases your stroke risk. In fact, one Harvard study found that high blood pressure increases a mans risk of stroke by 220 percent; another found that each 10 mmHg rise in systolic pressure (the top number) boosts your risk of ischemic stroke by 28 percent and of hemorrhagic stroke by 38 percent.

Even if your high blood pressure doesnt trigger a stroke, it can lead to impaired cognition and dementia. The 2018 SPRINT-MIND trial found that intensive control of high blood pressure (getting the top number below 120) lowered the risk of mild cognitive impairment by 19 percent compared with standard blood pressure control. Now, a new study in the journal Hypertension indicates that certain antihypertensive medications ACE inhibitors and ARBs (and angiotensin II receptor blockers) can cross the blood-brain barrier and lower dementia risk. Tracking almost 13,000 people for three years, the researchers found that folks taking those meds showed less memory loss than folks taking other sorts of antihypertensive medications.

You dont indicate how high your blood pressure is, but if it is only slightly elevated you may be able to bring it down through changing your diet, losing weight if you need to and exercising for 30 to 60 minutes five days a week. If it is above 125 (top number) or above 85 (bottom number), a combo of those self-care techniques and medication may be the safest choice. But either way, bringing your blood pressure to around 115/75 will protect your brain, as well as your heart, kidneys and eyes.

Contact Drs. Oz and Roizen at sharecare.com.

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Stemming the tide of stem-cell treatment scams - Houston Chronicle

Spinal Cord Stem Cells Comments Off on Stemming the tide of stem-cell treatment scams – Houston Chronicle | July 22nd, 2021

Wei Wu and Xiao-Ming Xu (Credit: IU School of Medicine)

Researchers at Indiana University School of Medicine (Indianapolis, USA) have announced the successful reprogramming of a glial cell type in the central nervous system into new neurons in order to promote recovery after spinal cord injuryrevealing an untapped potential to leverage the cell for regenerative medicine.

This is the first time that scientists have reported modifying a NG2 gliaa type of supporting cell in the central nervous systeminto functional neurons after spinal cord injury, saidWei Wu, research associate in neurological surgery at IU School of Medicine and co-first author of the paper, which was published in the Cell Stem Cell journal.

Wu andXiao-Ming Xu, the Mari Hulman George professor of Neuroscience Research at IU School of Medicine, worked on the study with a team of scientists from the University of Texas Southwestern Medical Center.

Spinal cord injuries affect hundreds of thousands of people in the United States, with thousands more diagnosed each year. Neurons in the spinal cord dont regenerate after injury, which typically causes a person to experience permanent physical and neurological ailments.

Unfortunately, effective treatments for significant recovery remain to be developed, Xu said. We hope that this new discovery will be translated to a clinically relevant repair strategy that benefits those who suffer from a spinal cord injury.

When the spinal cord is injured, glial cells, of which there are three typesastrocyte, ependymal and NG2respond to form glial scar tissue.

Wu added: Only NG2 glial cells were found to exhibit neurogenic potential in the spinal cord following injury in adult mice, but they failed to generate mature neurons. Interestingly, by elevating the critical transcription factor SOX2, the glia-to-neuron conversion is successfully achieved and accompanied with a reduced glial scar formation and increased functional recovery following spinal cord injury.

The researchers reprogrammed the NG2 cells from the mouse model using elevated levels of SOX2a transcription factor found inside the cell thats essential for neurogenesisto neurons. This conversion has two purposes, Xu said: to generate neurons to replace those lost due to a spinal cord injury and reduce the size of the glial scars in the lesion area of the damaged tissue.

This discovery, serves as an important target in the future for potential therapeutic treatments of spinal cord injury, adds Wu, who goes on to note that such a collaboration will be continued between the two laboratories to address neuronal remodelling and functional recovery after successful conversion of glial cells into functional neurons in future.

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IU School of Medicine researchers discover new potential for functional recovery after spinal cord injury - Spinal News International

Spinal Cord Stem Cells Comments Off on IU School of Medicine researchers discover new potential for functional recovery after spinal cord injury – Spinal News International | July 22nd, 2021

Researchers at the Chinese Academy of Sciences and University of Science and Technology of China have devised a novel bioprinting-based method of curing previously untreatable spinal cord injuries.

Using a custom bio-ink, the Chinese team have managed to 3D bioprint neural stem cell-loaded tissues capable of carrying instructions via impulses from the brain, much like those seen in living organisms. Once implanted into disabled rats, the scaffolds have shown the ability to restore movement in paralyzed limbs, and the scientists now believe their approach could find human applications in future.

There is no known effective cure for spinal cord injury, Zhijun Zhang, a nanobiomedical engineer at the Chinese Academy of Sciences told the Scientist. The 3D bioprinting strategy weve developed, may represent a general and versatile strategy for rapid and precise engineering of the central nervous system (CNS), and other neuronal tissues for regenerative medicine.

The SCI injury conundrum

A Spinal Cord Injury or SCI is a blanket term used to describe any damage caused to the bundle of cells and nerves that send signals to and from the brain along the human spinal cord. While the damage itself can be caused either by direct injury, or from bruising to the surrounding vertebrae, the result is often the same: a partial or complete loss of sensory and locomotor function below the affected area.

While theres no current known cure for SCI, a number of promising cell-based therapies are now being developed, with the regeneration of functional neurons seen as central to their future success. In effect, such approaches involve re-establishing links between neurons throughout the injured area in order to restore nerve functionality, but repairing damaged cells continues to be problematic.

Where neural stem cells have previously been implanted into SCI sites, theyve also shown poor viability and uncontrolled differentiation, leading to low therapeutic efficacy. More recent efforts have seen scientists bioprint cell-loaded scaffolds, capable of creating a suitable microenvironment in which neurons can flourish, yet this has raised further issues around printability and initiating cellular interaction.

To get around these problems, the Chinese researchers have now developed a novel bio-ink that gels together at body temperature to prevent neurons from differentiating into cells that dont produce electrical impulses, and can be 3D bioprinted into scaffolds that not only mimic the white matter appearance of the spine, but encourage cell-to-cell interactions.

A paralysis cure in-action

To begin with, Zhang and his team formulated their bio-ink from natural chitosan sugars, as well as a mixture of hyaluronic acids and matrigel, before combining them with rat neural stem cells. The scientists then used a BioScaffolder 3D bioprinter to deposit the resulting concoction into cell-laden scaffolds, which were later stored in culture plates for further testing.

Prior to their implantation, the teams different samples were incubated for three, five and seven days respectively, during which they proliferated and formed connections. Interestingly though, the researchers found that the higher the concentration of hyaluronic acid, the lower levels of interaction they observed, showing that their bio-ink can be tweaked to achieve desired tissue characteristics.

When injected into paraplegic lab rats, the scaffolds exhibited a cell viability of 95% while promoting neuron regeneration to the point that they enabled the rats to regain control over their hind legs. Over a 12-week observation period, the treated animals also showed a revived ability to move their hips, knees and ankles without support, and kick pressure sensors with markedly enhanced muscle strength.

As a result, the scientists have concluded that their approach offers a versatile and powerful platform for building precisely-controlled complex neural tissues with potential human applications, although they concede that more precise regulation of cell differentiation will be needed to achieve this, in addition to further testing on more clinically-relevant injury models.

Overall, this study clearly demonstrated for the first time the feasibility of the 3D bioprinted neural stem cell-laden scaffolds for SCI repair in-vivo, concluded the team in their paper, which, we expect, may move toward clinical applications in the neural tissue engineering, such as SCI and other regenerative medicine fields in the near future.

3D bioprinting in CNS treatments

Thanks to constant advances in flexible electronics and 3D bioprinting technologies, its now becoming increasingly possible to produce neural implants, with the potential to treat complex CNS injuries. Last year, a project started at TU Dresden led to the creation of 3D printed neural implants, capable of linking the human brain to computers as a means of treating neurological conditions such as paralysis.

In a similar study, engineering firm Renishaw has worked with pharmaceuticals expert Herantis Pharma to assess the performance of its 3D printed neuroinfuse drug delivery device. Designed to deliver intermittent infusions into the parenchyma, an organs functional tissue, the platform could be used as a future treatment for Parkinsons disease.

With regards to treating spinal injuries specifically, researchers at the University of California San Diego have also managed to repair spinal cord injuries in rats. By implanting 3D printed two-millimeter-wide grafts into test subjects, the team have been able to facilitate neural stem cell growth, restore nerve connections and ultimately help recover limb functionality in rodent test subjects.

The researchers findings are detailed in their paper titled 3D bioprinted neural tissue constructs for spinal cord injury repair. The study was co-authored by Xiaoyun Liu, Mingming Hao, Zhongjin Chen, Ting Zhang, Jie Huang, Jianwu Dai and Zhijun Zhang.

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Featured image shows the researchers 3D bioprinted scaffolds after 7 and 21 days culturing. Images via the Biomaterials journal.

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Introducing the 3D bioprinted neural tissues with the potential to 'cure' human paralysis - 3D Printing Industry

Spinal Cord Stem Cells Comments Off on Introducing the 3D bioprinted neural tissues with the potential to ‘cure’ human paralysis – 3D Printing Industry | July 22nd, 2021

In the last few years, many researchers have discovered that mesenchymal stem cells (MSCs) hold the key to treating many serious diseases such as diabetes, Parkinsons disease, and multiple sclerosis. According to the study, Prevalence of Parkinsons disease (PD) across North America, published in July 2018 in the journal Nature, the number of people suffering from PD is expected to reach 930,000 in 2020 and 1,238,000 in 2030. Thus, high prevalence of such diseases is also expected to aid in growth of the mesenchymal stem cells market.

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While no one yet knows exactly how the cells work, scientists are excited about the potential benefits of using MSCs as treatment modalities. In particular, the discovery that stem cells can differentiate into other cell types has implications for the field of regenerative medicine. The potential of MSCs to provide treatments for age-related diseases is exciting. Thus, increasing geriatric population is also expected to aid in growth of the mesenchymal stem cells market.

While stem cells from adults hold the most promise for use in treating human illnesses, the discovery that adult stem cells can be directed to treat specific diseases has provided doctors with a new approach to the treatment of patients with life-threatening diseases, which in turn is expected to aid in growth of the mesenchymal stem cells market. Mesenchymal stem cells are found in the bone marrow in rich supply. Because the cells are continually being used to make blood, tissue, and organs, they are not only rich in blood, they are also rich in antigens. This allows adult stem cells to directly apply their healing properties to a host of diseases.

Adult MSCs have the potential to replace diseased or otherwise damaged adult stem cells in a variety of tissues throughout the body, including muscle, bones, and organs. Various researches have revealed exciting potential in using these cells to treat a range of debilitating diseases. For example, since MSCs can be directed to the myeloid tissues of the bone marrow, they can help to repair and regenerate tissue and organs that are injured or became infected. These studies are currently underway and have the potential to provide a major breakthrough in the treatment of many serious diseases, boosting growth of the mesenchymal stem cells market.

MSCs are also being tested to directly apply to a patients spinal cord to promote regrowth of bones and other skeletal tissues. This is done through the introduction of specialized cells into the spinal cord. Since the specialized cells that are made in the laboratory from MSCs can be directed to a number of myeloid tissues, they can provide a direct means of repairing and regenerating spinal cord injury, spinal stenosis, cervical spondylosis, spinal arthritis, etc. The long term effects of mesenchymal stem cells transplantation on the spinal cord are not yet known but the studies so far are very promising and the technology could very soon be available for clinical trials.

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Major Key Players Are: Pluristem Therapeutics, LonzaThermo, Fisher, ATCC, Bio-Techne, MilliporeSigma, Genlantis, Celprogen, Cell Applications, PromoCell GmbH, Cyagen Biosciences, Human Longevity Inc., Axol Bioscience, Cytori Therapeutics, Eutilex Co.Ltd., ID Pharma Co. Ltd., BrainStrom Cell Therapeutics, Cytori Therapeutics Inc., Neovii Biotech, Angel Biotechnology, California Stem Cell Inc., Stemcelltechnologies Inc., and Celgene Corporation Inc.

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Mesenchymal Stem Cells Market Witnesses Upward Trend with High Prevalence of Parkinson's Disease The Manomet Current - The Manomet Current

Spinal Cord Stem Cells Comments Off on Mesenchymal Stem Cells Market Witnesses Upward Trend with High Prevalence of Parkinson’s Disease The Manomet Current – The Manomet Current | July 22nd, 2021