DUBLIN--(BUSINESS WIRE)--Horizon Therapeutics plc (Nasdaq: HZNP) today announced that new UPLIZNA analyses will be presented at the 38th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2022, Oct. 26-28. UPLIZNA is the first and only anti-CD19 B-cell-depleting humanized monoclonal antibody approved by the U.S. Food and Drug Administration (FDA) and European Commission (EC) for the treatment of adult patients with anti-aquaporin-4 (AQP4) antibody positive NMOSD.

Presentation Details:

In addition, Horizon will host a symposium Thursday, Oct. 27 from 8:45-9:45 a.m. CEST called Step into the new era of NMOSD, chaired by Hans-Peter Hartung, M.D., Ph.D. and featuring presentations from Jrme de Sze Ph.D., Brian Weinshenker, M.D., and Orhan Aktas, M.D. Topics will include NMOSD diagnosis and care, advantages of CD19 treatments and the clinical relevance of UPLIZNA in NMOSD.

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% 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 some 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 the Full Prescribing Information at http://www.UPLIZNA.com.

About Horizon

Horizon is a global biotechnology company 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, visit http://www.horizontherapeutics.com and follow us on Twitter, LinkedIn, Instagram and Facebook.

References

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Introduction

Within the spinal column lies the spinal cord, a vital aspect of the central nervous system (CNS). The three primary roles of the spinal cord are to send motor commands from the brain to the body, send sensory information from the body to the brain, and coordinate reflexes. The spinal cordis organized segmentally, with thirty-one pairs of spinal nerves emanating from it. A spinal cord injury disrupts this conduit between the body and brain and canlead to deficits in sensation, movement, and autonomic regulation, as well as death.

The spinal cord is composed of gray and white matter, appearing in a cross-section as H-shaped gray matter surrounded by white matter. The gray matter consists of the cell bodies of motor and sensory neurons, interneurons,and neuropils (neuroglia cells and mostly unmyelinated axons). In contrast, the white matter is composed of interconnecting fiber tracts, which are primarily myelinated sensory and motor axons. The supports of the gray matters H make up the right dorsal, right ventral, left dorsal, and left ventral horns. Running longitudinally through the center of the spinal cord is the central canal, which is continuous with the brains ventricles and filled with cerebrospinal fluid (CSF).

The white matteris organized into tracts. Ascending tracts carry information from the sensory receptors to higher levels of the CNS, while descending tracts carry information from theCNS to the periphery. The major tracts and their most defining features are as follows:[1]

Ascending Tracts

Dorsal column: contains the gracile fasciculus and cuneate fasciculus, which togetherform the dorsal funiculus. The dorsal column is responsible for pressure and vibration sensation, two-point discrimination, movement sense, and conscious proprioception. The dorsal column decussates at the superior portion of the medulla oblongata and forms the medial lemniscus.

Lateral spinothalamic: carries pain and temperature information. The lateral spinothalamic tract decussates at the anterior commissure, two segments above the entry to the spinal cord.

Descending Tracts

Lateral and anterior corticospinal: involved in conscious control of the skeletal muscle. The majority of lateral corticospinal tract fibers decussate at the inferior portion of the medulla oblongata, while anterior corticospinal descends ipsilaterally in the spinal cord and decussates at the segmental level. The lateral corticospinal tract, also called the pyramidal tract, innervates primarily contralateralmuscles of the limbs, while the anterior corticospinal tract innervates proximal muscles of the trunk.

Vestibulospinal: carries information from the inner ear to control head positioning and is involved in modifying muscle tone to maintain posture and balance. The vestibulospinal tract does not decussate.

Rubrospinal: involved in the movement of the flexor and extensor muscles.The rubrospinal tract originates from the red nuclei in the midbrain and decussates at the start of its pathway.

There is a laminar distribution of neurons in the gray matter, characterized by density and topography:

Lamina II is composed mainly of islet cells with rostrocaudal axes, which contain GABA and are thought to be inhibitory, and stalked cells with dorsoventral dendritic trees.

Lamina V and VI are composed of medium-sized multipolar neurons that can be fusiform or triangular. These neurons communicate with the reticular formation of the brainstem.

Lamina VII is composed of homogenous medium-sized multipolar neurons and contains, in individual segments, well-defined nuclei, including the intermediolateral nucleus (T1-L1), which has autonomic functions, and the dorsal nucleus of Clarke (T1-L2), which make up the dorsal spinocerebellar tract.

Lamina VIII consists of neurons with dorsoventrally polarized dendritic trees.

Lamina IX has the cell bodies of motor neurons, with dendrites extending dorsally into laminas as far as VI. Lamina IX also has Renshaw cells, inhibitory interneurons, placed at the medial border of motor nuclei.

Neurulation begins in the trilaminar embryo when part of the mesoderm differentiates into the notochord. The formation of the notochord signals the overlying ectoderm to form the neural plate, the first structure that will become the nervous system. The neural plate folds in on itself, creating the neural tube, initially open at both ends and ultimately closed. From the neural tube comes the primitive brain and spinal cord.[9]The development of the nervous system begins seventeen days after gestation, and in the fifth week, myotomes start to form, allowing the development of rudimentary reflex circuitries. Myelination of the motor tracts begins in the first few months of life and continues into adolescence.

An interesting note is that reciprocal excitation changes to inhibition between nine and twelve months of age. Before that age, supraspinal descending fibers activate interneurons, resulting in extension or flexion. During this period of development, glycine and GABA are excitatory.[10]

The spinal cord is the conduit between the brain and the rest of the body. It sends motor commands from the motor cortex to the muscles of the body and sensory information from the afferent fibers to the sensory cortex. Additionally, the spinal cord can act without signals from the brain in certain instances. The spinal cord independently coordinates reflexes using reflex arcs.Reflex arcs allow the body to respond to sensory information without waiting for input from the brain. The reflex arc starts with a signal from a sensory receptor, which is carried to the spinal cord via a sensory nerve fiber, synapsed on an interneuron, carried over to the motor neuron, which stimulates an effector muscle or organ.[11]The spinal cord also has central pattern generators, which are interneurons that form the neural circuits, which control rhythmic movements. Although the existence of central pattern generators in humans is controversial, the lumbar spinal cord produces rhythmic muscle activation without volitional motor control or step-specific sensory feedback, suggesting their role in human movement.[12]

Three connective tissue layers,termed meninges, conceal the spinal cord. Directly lining the spinal cord is the pia mater, which also thickens to form the denticulate ligament, anchoring the spinal cord in the middle of the vertebral canal. The next layer of meninges is the arachnoid mater.Between the pia mater and arachnoid mater is the subarachnoid space, which contains CSF. On top of the arachnoid mater is the last layer of meninges, the dura mater, then the epidural space separating the meninges from the vertebral column.[13]

The spinal cord extends from the medulla oblongata of the brain stem at the level of the foramen magnum. In an adult human, the spinal cord gives rise to thirty-one pairs of spinal nerves, each of which originates from the adjacent spinal cord segment:

Spinal nerves emerge from the spinal cord as rootlets, whichjoin together to form two nerve roots.The anterior nerve roots contain motor fibers extending from the anterior horn to peripheral target organs. The motor neurons are multipolar, with at least two dendrites, a single axon, and one or more collateral branches. They control skeletal muscles and the autonomic nervous system. The posterior nerve roots contain sensory fibers and dorsal root ganglia. They contain sensory fibers transmitting sensory information from the periphery towards the CNS. The sensory neurons located at the dorsal root ganglia are pseudounipolar. The anterior and posterior nerve roots converge into spinal nerves, which split into dorsal and ventral rami.A dermatome is a skin area innervated by a single spinal nerve root (or spinal cord segment).

There are five spinal plexuses, which include sensory and motor nerves from the anterior rami:

Cervical plexus (C1-C5): the deep branches innervate neck muscles, and the superficial branches innervate the skin on the neck, head, and chest. The cranial plexus also has an autonomic function, including controlling the diaphragm and interactions with the vagus nerve.

Brachial (C5-T1): controls movement and sensation of the upper extremity.

Lumbar (L1-L4): controls movement and sensation of the abdominal wall, thigh, and external genitals.

Sacral (L4, L5, S1-S4): controls movement and sensation of the foot, leg, and thigh.

Coccygeal (S4, S5, Co): innervates the skin around the tailbone.

In adults, the spinal cord tapers to an end, termed the conus medullaris, at the second lumbar vertebra level. Past the conus medullaris, a bundle of spinal roots extends termed the cauda equina. The cauda equina and the subarachnoid space continue until S2 and is the target location for a lumbar puncture (spinal tap).

Electrophysiological Testing

Evoked potentials (EPs) measure electrical signals going to the brain and can determine whether there is motor or somatosensory impairment. The signal is detected by electroencephalography (EEG) or electromyography (EMG). Evoked potentialsmay be used to assess spinal cord damage in the setting of spinal cord injury and tumors, and measure functional impairment and predict disease progression in multiple sclerosis.[15]Somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs)are frequentlyused intra-operatively for monitoring and can be used post-operatively as surrogate endpoints to check muscle strength and sensory status.[16]

Nerve conduction studies determine whether there has been an injury to a spinal nerve root, peripheral nerve, neuromuscular junction, muscle, cranial nerve, or spinal nerve. They can also be used to pinpoint spinal cord lesions.Nerve conduction studies work by stimulating nerves close to the skin or using a needle placed near a nerve or nerve root. Neurologists often use them with needle electromyograms.[17]

Lumbar Puncture

A lumbar puncture, or spinal tap, samples the CSF from the subarachnoid space. The needle to obtain the sample should be inserted between lumbar spinal canal levels L3 and L4 to avoid contact with the spinal cord.[18]TheCSF is then sent to a laboratory to establish whether any insult can be determined.For instance, a lumbar puncture can confirm or exclude bacterial meningitis, which will produce a cloudy fluid suggestive of a high leukocyte count. It is also important to know when not to use a lumbar puncture. Contraindications to lumbar puncture include signs of cerebral herniation, focal neurological signs, uncorrected coagulopathies, or cardiorespiratory compromise.[19]

Deep Tendon Testing

One aspect of theneurological exam is a test of the deep tendon reflexes, which are involuntary motor responses to various stimuli that function via reflex arcs within the spinal cord. They can be used to test the function of the motor and sensory nerves at specific spinal cord levels.Reflex grading is on a scale of 0 (absent reflex) to 5+ (sustained clonus).[20]Some commonly tested reflexes are as follows:

Additionally, the Babinski reflex, or the extensor plantar reflex, can be seen in newborns but is an abnormal response aftersix to twelve months of age. If the Babinski reflex is seen after 12 months of age, it may indicate an abnormality in the corticospinal system.[21]

Spinal Cord Injury

Primary spinal cord injury occurs due to local deformation of the spine, such as direct compression. Secondary spinal cord injury occurs following primary damage and involves cascades of biochemical and cellular processes, including electrolyte disturbances, free radical damage, edema, ischemia, and inflammation.[22]Secondary spinal cord injury has several phases: acute, subacute, and chronic. During the acute phase (up to 48 hours after the primary injury), hemorrhage and ischemia lead to ion balance disruption, excitotoxicity, and inflammation. During the subacute phase (up to two weeks following primary injury), there is a phagocytic response and a reactive proliferation of astrocytes, which leads to a glial scar in the chronic phase. The thinking is that scarification is the critical component to permanent disability because it prevents axonal regeneration; axons otherwise could regenerate, but their growth is blocked. However, that notion has been subject to challenge, and there are suggestions that astrocyte scar formation could aid in regeneration.[23]In the chronic phase (over six months after the primary injury), the scarification process is complete.[24]

Developmental

Open neural tube defects occur when there is a failure of the neural tube to close. If it fails to close at the cranial end, the fetusmay develop anencephaly. If the failure is at the caudal end, the fetusmay have myelomeningocele or open spina bifida. Craniorachischisis can also occur if the entire neural tube remains open. Closed neural tube defects are spinal cord development problems that are skin-covered, such as occult spina bifida.Folic acid supplements lower the risk of neural tube defects, although severe folate deficiency in mouse models does not lead to neural tube defects unless there is already a genetic predisposition. Suggestions are that folate can overcome a genetic predispositionfor adverse effects, potentially leading to neural tube defects.[25]

A spinal cord injury can be classified as complete or incomplete. A complete injury, based on the International Standard Neurological Classification of Spinal Cord Injury (ISNCSCI) examination, developed by the American Spinal Cord Injury Association (ASIA), implies that there is no sensation at the inferior segments of the spinal cord (S4-S5); no deep anal pressure (DAP) or voluntary anal contraction (VAC) is present. If no perianal sensation is present and DAP and VAC are absent, the present function below the level of injury is a zone of partial preservation.[26]

An injury in the cervical region often results in quadriplegia if both sides of the spinal cord are affected and hemiplegia if only one side is affected. Nerves from C3, C4, and C5 stimulate the phrenic nerve, which controls the diaphragm, so injury to C4 and above may result in a permanent need for a ventilator. An injury to the thoracic region often limits the function of nerves related to the lower torso and lower extremities. Usually, it does not affect the upper torso and upper extremities, except in rare cases such as subacute posttraumatic ascending myelopathy (SPAM).[27]Injury to thespinal cord often causes loss of bowel and bladder control, loss of sexual function, and blood pressure dysregulation, as the spinal cordrelays autonomic and somatic information.

Syndromes

Several syndromes correlate with spinal cord injury. Central cord syndrome usually occurs in individuals who suffer a hyperextension injury, and it often leads to incomplete injury with weakness predominantly affecting the upper limbs. The reason for this phenomenon is the organization of the fibers in the spinal cord: the fibers running to the lower extremities are longer than those running to the upper extremities; the longer fibers are located more laterally in the spinal cord (L-L rule). As the central portion of the spinal cord is injured, there is a sparing of the fibers running to the lower extremities. Brown-Sequard syndrome is due to a spinal cord hemisection,leading to a complete loss of sensation at the level of the lesion, as well as deficits below the lesion loss of proprioception, vibration, and motor control, ipsilaterally, and a loss of pain and temperature sensation, contralaterally. Anterior cord syndrome is due to a compromised blood supply to the anterior two-thirds of the spinal cord, damaging the corticospinal and spinothalamic tracts.This syndrome is associated with several deficits at and below the lesion, including motor loss and a loss of pain and temperature sensation. However, light touch and joint position sense from the dorsal columns are left intact.[26]Injury to T12-L2 segmentsmay result in conus medullaris syndrome, while injury to L3-L5 segmentscan lead to cauda equina syndrome. Usually, these syndromes present as incomplete injuries and result in neurogenic bladder and/or bowel, loss of sexual function, and perianal loss of sensation.[28]

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BRENTWOOD, Tenn., Sept. 09, 2022 (GLOBE NEWSWIRE) -- IMAC Holdings, Inc. (Nasdaq: BACK) (IMAC or the Company), today announces it has completed the third cohort of its Phase 1 clinical trial for its investigational compound utilizing umbilical cord-derived allogenic mesenchymal stem cells for the treatment of bradykinesia due to Parkinsons disease.

The third cohort consists of five patients with bradykinesia due to Parkinsons disease receiving an intravenous infusion of a high concentration stem cell treatment. The third and final cohort of the Phase 1 clinical trial was completed on Tuesday, September 6, 2022.

About IMACs Phase 1 Clinical Trial

The Phase 1 clinical trial, consisting of a 15-patient dose escalation safety and tolerability study, is being conducted at three of IMACs clinical centers in Chesterfield, Missouri, Paducah, Kentucky, and Brentwood, Tennessee. The trial is divided into three groups: 1) five patients with bradykinesia due to Parkinsons disease received a low concentration dose, intravenous infusion of stem cells, 2) five received a medium concentration intravenous dose, 3) and five received a high concentration intravenous dose. All groups will be subsequently tracked for 12 months. IMACs medical doctors and physical therapists at the clinical sites have been trained to administer the treatment and manage the therapy. Ricardo Knight, M.D., M.B.A., who is medical director of the IMAC Regeneration Center of Chicago, is the trials principal investigator.

The Institute of Regenerative and Cellular Medicine serves as the trials independent investigational review board, while Regenerative Outcomes provides management of the study. Further details of the trial can be found at clinicaltrials.gov.

About Bradykinesia Due to Parkinsons Disease

In addition to unusually slow movements and reflexes, bradykinesia may lead to limited ability to lift arms and legs, reduced facial expressions, rigid muscle tone, a shuffling walk, and difficulty with repetitive motion tasks, self-care, and daily activities. Parkinsons disease is the typical culprit of bradykinesia, and as it progresses through its stages, a persons ability to move and respond declines.

According to Zion Market Research, the global Parkinsons disease therapeutics market was $2.61 billion in 2018 and is expected to grow to $5.28 billion by 2025. The Parkinsons Disease Foundation estimates that nearly 10 million people are suffering from Parkinsons disease, and almost 60,000 new cases are reported annually in the U.S.

About IMAC Holdings, Inc.

IMAC Holdingsowns and manages health and wellness centers that deliver sports medicine, orthopedic care, and restorative joint and tissue therapies for movement restricting pain and neurodegenerative diseases.IMACis comprised of three business segments: outpatient medical centers, The Back Space, and a clinical research division. With treatments to address both young and aging populations,IMAC Holdingsowns or manages outpatient medical clinics that deliver regenerative rehabilitation services as a minimally invasive approach to acute and chronic musculoskeletal and neurological health problems. IMACs The Back Company retail spinal health and wellness treatment centers deliver chiropractic care within Walmart locations. IMACs research division is currently conducting a Phase I clinical trial evaluating a mesenchymal stem cell therapy candidate for bradykinesia due to Parkinsons disease. For more information visitwww.imacholdings.com.

# # #

Safe Harbor Statement

This press release contains forward-looking statements. These forward-looking statements, and terms such as anticipate, expect, believe, may, will, should or other comparable terms, are based largely on IMAC's expectations and are subject to a number of risks and uncertainties, certain of which are beyond IMAC's control. Actual results could differ materially from these forward-looking statements as a result of, among other factors, risks and uncertainties associated with its ability to raise additional funding, its ability to maintain and grow its business, variability of operating results, its ability to maintain and enhance its brand, its development and introduction of new products and services, the successful integration of acquired companies, technologies and assets, marketing and other business development initiatives, competition in the industry, general government regulation, economic conditions, dependence on key personnel, the ability to attract, hire and retain personnel who possess the skills and experience necessary to meet customers requirements, and its ability to protect its intellectual property. IMAC encourages you to review other factors that may affect its future results in its registration statement and in its other filings with the Securities and Exchange Commission. In light of these risks and uncertainties, there can be no assurance that the forward-looking information contained in this press release will in fact occur.

IMAC Press Contact:

Laura Fristoe

lfristoe@imacrc.com

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The green colors are increased synapses resulting from a regeneration in nerve axons SWNS

A revolutionary treatment that could repair spinal cord injuries has been developed by scientists which regrew nerves in paralyzed mice within three months.

The medication triggers cells of long spindly parts of the severed nerves called axons to regenerative themselves.

Currently, spinal cord injury does not have any effective treatments that involves a repairing of what was damaged. Physical rehabilitation can help patients regain some mobility, and a number of electrical stimulation technologies can stimulate nerves and muscles to act as before, but never with the precision of the real thing.

This work shows a drug called TTK21 that is administered systemically once a week after a chronic spinal cord injury in animals can promote neuronal regrowth and an increase in synapses that are needed for neuronal transmission, said lead author Dr. Simone Di Giovanni, of Imperial College London.

This is important because chronic spinal cord injury is a condition without a cure where neuronal regrowth and repair fail.

Damage to the spinal cord interrupts the constant stream of electrical signals from the brain to the body. It can lead to paralysis below an injury.

The study published in the journal PLOS Biology showed TTK21 aided the regrowth of sensory and motor neurons when given to mice 12 weeks after severe injury.

It belongs to a group of therapies known as epigenetic activators which target damaged DNA.

In experiments, lab rodents with severe spinal cord injury lived in an enriched environment with opportunities to be physically activeas is encouraged in human patients.

Treatment lasted for 10 weeks. Several improvements were identified, the most noticeable being the sprouting of more axons in the spinal cord. Retraction of motor axons above the point of injury was also halted, and sensory axon growth increased.

SIMILAR: Movement in Paralyzed Arms is Restored by Zapping Spinal Cords With Electrical Stimulation

The next step will be to boost the effects even more and get regenerating axons to reconnect to the rest of the nervous system so animals can regain their ability to move with ease.

We are now exploring the combination of this drug with strategies that bridge the spinal cord gap such as biomaterials as possible avenues to improve disability in SCI patients, said Di Giovanni.

For decades, this has remained a major challenge. Our bodys central nervous system, which includes the brain and spinal cord, does not have any significant capacity to repair itself.

RELATED: First Time Someone With Cut Spinal Cord is Able to Walk Freely, Thanks to New Swiss Technology

In the U.S., an estimated 300,000 people and another 50,000 in the UK are living with a spinal cord injury.

Last year GNN reported that Yale had used stem cells to repair patients injured spinal cords, which could be another future avenue to repairing nerves and axons.

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Oxytocin is a neurohormone called the love hormone because it promotes social bonds and generates pleasurable feelings.

It also regulates lactation, uterine contractions, the movement of sperm, and testosterone production.

Now, a new study suggests that the hormone might someday help regenerate damaged heart muscles.

The researchers said that previous research has concluded that the epicardium, a membrane found in the layers of the heart, can partially regenerate injured heart cells. In mammals, however, this process doesnt work independently but might if cells are reprogrammed.

Researchers noted that zebrafish produced oxytocin after their hearts were injured by extreme cold, leading to a response that promotes heart regeneration.

The heart possesses a population of cells, called epicardial cells, that reside in its outer layers, said Aitor Aguirre, Ph.D., one of the authors of the study and an assistant professor of biomedical engineering at the Institute for Quantitative Health Science and Engineering at Michigan State University.

After a massive cardiac injury, such as a heart attack, epicardial cells become epicardial stem cells and can then regenerate muscle, blood vessels, and other cardiac tissues, but their numbers are far too small for any long-lasting impact, he told Healthline.

What we have found in this study is that oxytocin induces the formation of these stem cells and promotes their expansion, increasing their efficiency in heart regeneration, Aguirre added. It is interesting because this demonstrates that the brain controls some regeneration, so there could be factors in addition to the oxytocin that promotes regeneration.

He noted that the most common role of oxytocin relates to bonding and pleasure, which suggests that being in a caring and loving environment might promote heart healing. You could say that the love hormone fixes broken hearts.

Zebrafish are known for their ability to regenerate cells throughout their body.

Past research has reported that these fish can regenerate organs, including the retina, spinal cord, parts of the brain, and certain internal organs. Experts say this makes them a good resource for studying this concept.

The researchers conducting the current study reported that within three days of the heart injury, the Zebrafish increased the expression of oxytocin in the brain by about 18-fold.

The oxytocin then traveled to the epicardium, which bound to the oxytocin receptor, triggering cells to develop new cells. These cells migrated to the myocardium and developed into cardiomyocytes, blood vessels, and other heart cells, replacing the injured ones.

Oxytocin had a similar effect on human cells in a laboratory. The scientists tested 15 neurohormones and they said oxytocin had the strongest effect on stimulating the regeneration of human cells.

Oxytocin is currently used during labor and delivery. It is used to begin or speed up contractions during labor and typically takes effect about 30 minutes after injection. It can also help to reduce bleeding after birth.

The risk of using oxytocin during labor is overstimulation of the uterus and causes it to contract too often, according to the American College of Obstetrics and Gynecology. This may lead to changes in the fetal heart rate.

While there are benefits to using oxytocin during labor and delivery, there are also risks. These risks and benefits will need to be considered as researchers look at the hormones potential use for stimulating heart regeneration.

Oxytocin, or a similar analog that stimulates its receptor, could conceivably be utilized to regenerate the heart in humans after acute or chronic injury, said Dr. Rigved Tadwalkar, a cardiologist at Providence Saint Johns Health Center in California.

The current study reveals the beneficial effects of oxytocin in zebrafish in vivo and on human tissue in vitro, Tadwalkar told Healthline. The findings suggest that the pathway involved in stimulating stem-like cells to the myocardium is preserved in humans, at least to a degree.

Unfortunately, oxytocin has a short half-life, meaning that it exists only briefly in human circulation, Tadwalkar added. However, we could take advantage of this beneficial signaling pathway in humans by creating drugs that are higher in potency or with longer half-lives.

Since we already use oxytocin clinically, this is not inconceivable, he noted. Even if the effects are limited, the benefit would be splendid in this population. For example, if oxytocin is shown to only have a preventative role, as opposed to a regenerative one, this would still be welcome, as to avert subsequent damage to the heart.

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Neuron generation trajectories. Credit: BGI Genomics

Because of its distinctive and adorable look, the axolotl Ambystoma mexicanum is a popular pet. Unlike other metamorphosing salamanders, axolotls (pronounced ACK-suh-LAH-tuhl) never outgrow their larval, juvenile stage, a trait known as neoteny. Its also recognized for its ability to regenerate missing limbs and other tissues including the brain, spinal cord, tail, skin, limbs, liver, skeletal muscle, heart, upper and lower jaw, and ocular tissues like the retina, cornea, and lens.

Mammals, including humans, are almost incapable of rebuilding damaged tissue after a brain injury. Some species, such as fish and axolotls, on the other hand, may replenish wounded brain regions with new neurons.

Tissue types the axolotl can regenerate as shown in red. Credit: Debuque and Godwin, 2016

Brain regeneration necessitates the coordination of complex responses in a time and region-specific way. In a paper published on the cover of Science, BGI and its research partners used Stereo-seq technology to recreate the axolotl brain architecture throughout developing and regenerative processes at single-cell resolution. Examining the genes and cell types that enable axolotls to renew their brains might lead to better treatments for severe injuries and unlock human regeneration potential.

Cell regeneration images at seven different time points following an injury; the control image is on the left. Credit: BGI Genomics

The research team collected axolotl samples from six development stages and seven regeneration phases with corresponding spatiotemporal Stereo-seq data. The six developmental stages include:

Through the systematic study of cell types in various developmental stages, researchers found that during the early development stage neural stem cells located in the VZ region are difficult to distinguish between subtypes, and with specialized neural stem cell subtypes with spatial regional characteristics from adolescence, thus suggesting that various subtypes may have different functions during regeneration.

In the third part of the study, the researchers generated a group of spatial transcriptomic data of telencephalon sections that covered seven injury-induced regenerative stages. After 15 days, a new subtype of neural stem cells, reaEGC (reactive ependymoglial cells), appeared in the wound area.

Axolotl brain developmental and regeneration processes. Credit: BGI Genomics

Partial tissue connection appeared at the wound, and after 20 to 30 days, new tissue had been regenerated, but the cell type composition was significantly different from the non-injured tissue. The cell types and distribution in the damaged area did not return to the state of the non-injured tissue until 60 days post-injury.

The key neural stem cell subtype (reaEGC) involved in this process was derived from the activation and transformation of quiescent neural stem cell subtypes (wntEGC and sfrpEGC) near the wound after being stimulated by injury.

What are the similarities and differences between neuron formation during development and regeneration? Researchers discovered a similar pattern between development and regeneration, which is from neural stem cells to progenitor cells, subsequently into immature neurons and finally to mature neurons.

Spatial and temporal distribution of axolotl brain development. Credit: BGI Genomics

By comparing the molecular characteristics of the two processes, the researchers found that the neuron formation process is highly similar during regeneration and development, indicating that injury induces neural stem cells to transform themselves into a rejuvenated state of development to initiate the regeneration process.

Our team analyzed the important cell types in the process of axolotl brain regeneration, and tracked the changes in its spatial cell lineage, said Dr. Xiaoyu Wei, the first author of this paper and BGI-Research senior researcher. The spatiotemporal dynamics of key cell types revealed by Stereo-seq provide us a powerful tool to pave new research directions in life sciences.

Corresponding author Xun Xu, Director of Life Sciences at BGI-Research, noted that In nature, there are many self-regenerating species, and the mechanisms of regeneration are pretty diverse. With multi-omics methods, scientists around the world may work together more systematically.

Reference: Single-cell Stereo-seq reveals induced progenitor cells involved in axolotl brain regeneration by Xiaoyu Wei, Sulei Fu, Hanbo Li, Yang Liu, Shuai Wang, Weimin Feng, Yunzhi Yang, Xiawei Liu, Yan-Yun Zeng, Mengnan Cheng, Yiwei Lai, Xiaojie Qiu, Liang Wu, Nannan Zhang, Yujia Jiang, Jiangshan Xu, Xiaoshan Su, Cheng Peng, Lei Han, Wilson Pak-Kin Lou, Chuanyu Liu, Yue Yuan, Kailong Ma, Tao Yang, Xiangyu Pan, Shang Gao, Ao Chen, Miguel A. Esteban, Huanming Yang, Jian Wang, Guangyi Fan, Longqi Liu, Liang Chen, Xun Xu, Ji-Feng Fei and Ying Gu, 2 September 2022, Science.DOI: 10.1126/science.abp9444

This study has passed ethical reviews and follows the corresponding regulations and ethical guidelines.

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Unlocking the Mysteries of Brain Regeneration Groundbreaking Study Offers New Insight - SciTechDaily

Spinal Cord Stem Cells Comments Off on Unlocking the Mysteries of Brain Regeneration Groundbreaking Study Offers New Insight – SciTechDaily | October 5th, 2022

Chronic pain, a disease process that is so complex that we are only just beginning to understand its triggers, has recently been gaining recognition as a medical condition on its own. But how does living with chronic pain feel? And how do the body and brain deal with it?

Aching, dull, gnawing, burning, sharp, shooting, piercing

These are just some of the words people tend to use to describe their pain.

Now imagine you had to endure a bit of this every waking day until you dont know what its like to go about your day without this baseline of pain slowly depleting your mental and physical energy in the background.

That is the reality for many people who deal with chronic pain.

Some days may be great, some days bad; the signs may not always be visible and it may be an inward battle hidden behind gritted teeth and forced smiles.

But how does chronic pain become, well, chronic?

In the latest installment of our In Conversation podcast dedicated to Pain Awareness Month, Medical News Today dives into the science behind chronic pain with Dr. Hilary Guite and Dr. Tony L. Yaksh, professor of anesthesiology and pharmacology at the University of California, San Diego, as Joel Nelson, longtime psoriatic disease and arthritis patient and advocate, shares his personal journey with pain.

Chronic pain may often be dismissed as purely a symptom of a larger problem or not taken as seriously because it is not life threatening. However, the burden of chronic pain is not only personal but also societal.

Studies show that people with chronic pain may have difficulty in going about their daily lives and doing activities, as well as have poorer overall health. People with chronic pain may also have to deal with job insecurity or unemployment.

It wasnt until 2018 that the International Classification of Diseases (ICD) gave chronic pain its own code, in the preliminary version of the new ICD-11 coding system, paving way for its recognition and diagnosis.

According to the World Health Organization (WHO), chronic pain is now classified into two categories: chronic primary pain and chronic secondary pain.

Primary pain, according to this classification, refers to pain that is not caused by or cannot be explained by another medical condition. Some examples may be fibromyalgia or chronic primary low back pain.

Fibromyalgia [is] a condition that varies from person to person, but is a widespread pain condition affecting at least 4 to 5 regions of the body and lasts at least 3 months but usually longer. No other cause is found for the pain and it is, therefore, a type of primary chronic pain, Dr. Guite explained.

Secondary pain, on the other hand, is secondary to or caused by an underlying medical condition. Arthritis, cancer, or ulcerative colitis-related pain would fall within this umbrella.

[M]y chronic pain started around 10 years old. And [since] then, chronic pain has kind of been an intermittent part of my life right through to the present day, Joel Nelson told MNTs In Conversation.

Joel is now 38 years old, which means hes been living with chronic pain for a good few decades.

[M]y first experience with pain was [when] I got a pain in my hip; it was like a gravelly sort of burning feeling. And it just progressed; the more I used the joint, the [more it got] worse, it got to the point where I [was] sort of losing mobility, he said.

That was the point he decided to reach out for helpas most people do.

Joel said one word to describe his chronic pain is noise.

I always have described it as noise because on the days when that pain is intense, my ability to absorb other information, deal with multiple things at a time, its just gone, he said.

Living with my condition today, I think the most important takeaway about the experience is the fluidity of it. [U]ltimately, [my limits and mobility] can range from anything to where I can do more than walking, and I might be able to do a bit of running and cycling like I am currently, to next week I might be back on crutches. [A] lot of that is dictated by pain. So with arthritis, I get a lot of morning stiffness, but its the pain that limits my ability to do things. Joel Nelson

Likening it to a series of chapters, Joel said its not easy to anticipate what will happen next with his chronic pain.

Behind acute pain becoming chronic, scientists have found that a gateway receptor called Toll-like receptor 4 (TLR4) may be a controlling factor.

We know that under a tissue [or nerve] injury of various sorts that we can activate signaling that normally is associated with what we call innate immunity. And one of the mediators of that is something called the toll-like receptor and it turns out that while those are normally there to recognize the presence of foreign bugs, for example, E. coli, those bugs have in their cell membrane, something called lipopolysaccharide, or LPS. We dont have that normally in our system, but it comes from bacteria, said Dr. Yaksh.

Youre born with it, you dont have to develop it. Its there all the time. What weve come to find out over the last years [t]hat there are many products that your body releases that will [a]ctivate those very same toll-like receptors, he added.

Toll-like receptors may prime the central immune system for heightened states of pain. In response to harmful stimuli, stressors, or tissue injury, especially in the microbiome or the gastrointestinal tract, the body starts to release products from inflammatory cells.

When this happens, these products that are released from our own body can [a]ctivate these toll-like receptors, and theres [one] we call TLR4 [which] is present on inflammatory cells, and its also present on sensory neurons, he explained.

Dr. Yaksh said that activating TLR4 itself doesnt cause as much pain, but that it sets the nervous system up to become more reactive.

Coupled with this priming, if there are other stressors present at the timesuch as a bad diet or psychological distress, pointed out Dr. Guite this can set off a whole cascade that can fuel this transition to chronic pain.

[The activation of TLR4] sets up a whole series, a cascade in which there will be an increased expression of a large number of receptors and channels that are able to drive an enhanced response of the system. When this happens, you get this enhanced response downstream to the initial tissue injury. Its not so much that [it] causes the pain condition, it just sets the system up to be more reactive. Dr. Tony Yaksh

He said Joels situation fits within the notion that a person can transition from one type of pain to another.

[T]hat can be exacerbated by the stresses that are psychological which can exacerbate a pain state to one that may, in fact, have an underlying physiological component that we may not really understand, he added.

In Joels case, for example, Dr. Yaksh suggested it was likely that the stress (and joy) of becoming a father and all the other aspects played a role in what exacerbated Joels condition, and made it harder to keep the pain under control. He stressed that this did not make the pain any less real.

I think that probably there was this very strong, emotive component thats associated what Joels situation was, [] that the pain condition and the events that were associated with the psoriatic diagnosis and other aspects, perhaps, in fact, did establish the transition from one state to another [what] we call a transition or an acute to chronic, or the chronification of the pain state, he elaborated.

Theories so far suggest pain happens at the intersection of where the body meets the brain.

[Y]our comment about pain [being] in the brain is absolutely the correct way to think about it; the output function of anything comes from the higher centers, said Dr. Yaksh.

It all boils down to how the brain registers pain when there is tissue damage.

Pain is a crucial function for our survival; it is essentially a warning system that alerts our bodies that there is damage or illness to deal with. After an illness or injury, the nerves surrounding the area start sending signals up to the brain through the spinal cord, which encourages us to get help and stop further damage.

After the body sustains an injury, the damage to the bodys organs and tissues triggers an acute inflammatory response that involves immune cells, blood vessels, and other mediators. However, sometimes, even after this initial injury phase passes and the body heals, the nervous system may stay in this state of distress or reactivity.

When this happens, the body may become hypersensitive to pain. If this increased sensitivity is to heat or touch around the injured area, this is called peripheral sensitization.

[I]f I were to jam my finger, or if I were to develop, in Joels case, an event that leads to a local autoinflammation of the joint, then, in fact, that inflammation leads to the release of factors, which now sensitize the innervation of that joint, Dr. Yaksh elaborated.

Dr. Yaksh said this is something all people experience, regardless of whether it is chronic pain. He explained that after an injury, however, an innocuous activity such as wiggling ones finger can [become] extraordinarily noxious.

He described this as a sensitization generated by peripheral injury and inflammation, where this information is then relayed to the brain through the spinal cord.

The brain is now seeing what is otherwise an innocuous event, generating a signal that looks as if, as we would say, hell has frozen over, bad news is coming up the pipe. Dr. Tony Yaksh

However, sometimes this prolonged response to the initial injury may cause the lingering pain to be widespread, rather than localized to the injured area. This is called central sensitization.

[I]ts interesting in [Joels case], that you clearly have a peripheral issue, whether its the inflammation of a joint, inflammation of the skin, or changes in peripheral nerve function. And so not only do you get changes in joint morphology and things of that sort, but you actually get changes that lead to changes in the way that the information that goes into the spinal cord, and then to higher centers, Dr. Yaksh explained, and youve activated specific populations of sensory fibers that are normally activated only by severe injury.

[I]ts possible for that spinal cord, which is now, in a sense, organizing the input-output function from the periphery to the brain can become reorganized very much like if I were to take a radio and turn the volume upthe signal to the radio hasnt changed, but the volume gets louder. So, think of the spinal cord as a volume regulator. Dr. Tony Yaksh

And it says, bad news has happened. But we now know actually, that some of that input that comes up the same pathway [g]oes to areas of the brain that has nothing to do with where that pain [comes] fromonly that it is intense, he said.

These outputs that travel up the spinal cord inform the brain of where and how intense the pain is. One area these are processed in is the limbic system, or the old smell brain, said Dr. Yaksh.

These are areas of the brain that are, in fact, associated in humans with the input associated with emotionality, he added.

This stress can also modulate how pain is perceived by the body; it can cause muscles to tense or spasm, as well as lead to a rise in the levels of the hormone cortisol. This may cause inflammation and pain over time.

This can, in turn, can lead to sleeping problems, irritability, fatigue, and depression over time, creating a vicious cycle that adds to an already stressed nervous system, worsening the pain.

Although treatments for acute pain often involve taking various medications such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), or opioids, treatment and management strategies for chronic pain are quite limited.

[W]e started out this conversation by saying pain is in the brain. And your perceptions of what the world is about impact you very directly, and in a way that is actually experimentally definable, changes the way your brain reacts. So when I say pain is in the brain, I am not saying its, its any less real in any way, shape, or form. Its a real thing, said Dr. Yaksh.

We now teach medical students that, you know, just because you dont see the primary diagnosis as being a swollen joint doesnt mean the patient doesnt have something, he pointed out.

Dr. Yaksh said mindfulness is often used in therapy to treat or manage fibromyalgia. He said that this doesnt mean there is no physiological component of fibromyalgia and indeed, recent research has shown that it is very likely to be an autoimmune condition just as real as the presence of antibodies that define the presence of an arthritic joint, he said.

Mindfulness, in a way, can help the individual respond to the nature of the afferent traffic thats coming up the spinal cord; its not something you could become mindful enough to say have surgery done. But it might [t]ake the edge off of some of the things that are, in fact, driving this exaggerated response. Fibromyalgia is a perfect example. Dr. Tony Yaksh

[Mindfulness] doesnt make the pain state any less real [but it] demonstrates that changing the way you think about your pain condition [can] help you deal with that pain condition, he said.

Joel added that, from the perspective of someone with chronic pain, it is a journey to see how the brain and the body work together to maintain pain:

.[I]t is a really delicate conversation when you talk about pain and it residing in the brain and, as somebody whos gone full circle through that journey of being horrified when that was first suggested to going through pain management, and then understanding it so that I could process it better. It changed everything for me.

What the future holds for treating chronic pain currently remains unclear. However, hope is that drugs might be developed to impact receptors such as TLR4 in a way that might not result in the pain going from acute to chronic, and that our understanding of how psychological processes interact with the neuro-immune interface increases over time.

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In Conversation: How to understand chronic pain - Medical News Today

Spinal Cord Stem Cells Comments Off on In Conversation: How to understand chronic pain – Medical News Today | October 5th, 2022

ONE of the most aggressive types of cancer is looking more beatable thanks to an exciting breakthrough.

Patients with glioblastoma - a fast-growing type of cancer that affects the brain and spinal cord - tend to survive just 15 months from the moment of diagnosis.

1

And currently, few successful long-term treatments are available.

But scientists at the Keck School of Medicine of USC have made a discovery that may offer real hope.

The team found that circadian clock proteins - which control our natural rhythms, like when we wake up and when we fall asleep - could be involved in the growth of glioblastoma tumours.

These proteins may also explain why people often do not remain in remission after cancer treatment, and see their glioblastoma come back.

Keck researchers identified a small molecule drug, called SHP656, that could be used to target those clock proteins and treat the devastating disease.

In the vast majority of patients, the cancer returns. And when it returns, its resistant to chemotherapy and radiation, said Professor Steve Kay at Keck.

Kay and his team believe the disease often returns because of cancer stem cells that spread fast by hijacking the bodys circadian clock mechanisms.

But SHP656 could be used to put a stop to that.

This is a potent molecule thats very exciting to us in terms of its potential for deployment against glioblastoma, said Kay.

Clinical trials are now in motion and the team hopes to begin the next phase in glioblastoma patients within two to three years.

Glioblastomas are grade 4brain tumoursand are a type of glioma, one of the most common types of primary brain tumours.

The cancer begins in the brain and almost never spreads to other parts of the body.

However, its complexity makes it difficult to treat.

There are no known causes of glioblastoma making treatment even trickier.

The first line of treatment is surgery to try and cut the tumour out.

However, it's very difficult to remove the tumour without harming healthy parts of the brain.

Chemotherapy and radiation therapy can be helpful to stop the tumour cells growing and spreading.

But despite the high intensity of the treatment, the cancer usually recurs.

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New drug could cure aggressive brain cancer stopping tumours in their tracks... - The US Sun

Spinal Cord Stem Cells Comments Off on New drug could cure aggressive brain cancer stopping tumours in their tracks… – The US Sun | September 27th, 2022

Sep 17, 2022(Nanowerk News) Few human injuries are as catastrophic as those to the spine. An accident, disease or act of violence affecting the spine can result in poor function even paralysis almost anywhere in the body.The spinal column is enormously complex, with limited capacity for regeneration and any health implications are usually long-term and chronic.While there is no known way to repair a spinal cord injury (SCI), scientists may be on the cusp of some important breakthroughs. New approaches are being taken to reverse the nerve damage, with some researchers attempting to reshape the architecture of the spinal cord using materials engineered in the laboratory.Prof Paula Marques, material scientist at the University of Aveiro in Portugal and her colleagues, are seeking to mould a particular biomaterial into a scaffold that can replace damaged spinal tissue. This will create a working bridge over an injured area giving the brain an alternative pathway to communicate with the body.The hope is that, within the next decade, these biomaterials will result in radical new treatments for the 250-500 000 people who suffer a spinal cord injury around the world every year.Even a small improvement in treatment can lead to a big change to quality of life, said Prof Marques.The spinal column is enormously complex. (Image: CHUTTERSNAP via Unsplash)Nerve regenerationIn addition, the scaffold implant would support the regeneration of natural nerve cells, enabling the body eventually to resume its natural function unassisted.Prof Marques is the principal researcher of the NeuroStimSpinal project, an EIC Pathfinder project under Horizon 2020 focusing on graphene-based material combined with a protein-rich material derived from humans known as a 'decellularised extracellular matrix'. In the human body, an extracellular matrix provides the structure and support to living cells.This blend of matrix and graphene-based material creates a 3D structure that skilfully mimics the morphology of the native spinal cord. It will form the backbone as it were of the projects implant.Graphene shows excellent electrical properties, meaning a current can run along it a prerequisite for any material that might be employed to send electrical impulses along the spinal cord.Importantly, the scaffold is porous, meaning cells and spinal fluids can pass through it. Its also biocompatible, preventing rejection by the body, and biodegradable, allowing it to be programmed to degrade over time.Restoring functionProf Marques describes her work as disruptive and says the potential prize of restoring function to people with paralysis is huge.I see real hope, she said. My only frustration is that we cant move forward faster with this research spinal cord injury has such a big impact on human life.There are two main types of cells in nerve tissue: neurons, which transmit electrical impulses, and glial cells, which are non-conductive and provide a support system for the neurons.In lab experiments, the NeuroStimSpinal team which includes experts in material science, electronic engineering, physics and biology have found that when their scaffold is seeded with embryonic neural progenitor cells (cells that renew themselves and have the potential to develop into either neuronal or glial cells) and an electrical stimulus is applied, the blank stem cells successfully differentiate into a mixture of the two cell types.This is very encouraging, said Prof Marques. It shows that the scaffold can provide a good environment for nerve cell regrowth.Her group is one of just a handful around the world that has managed to make neural stem cells develop into new cell lineages in lab conditions.However, to date, no such success has been achieved in live animals. Prof Marques wants her next round of experiments to set SCI research on a new course.In the months ahead, her team will transplant miniature versions of their scaffold into rats. An electric current will be applied to the implant through a control unit inserted under the animals skin to accelerate tissue regrowth. If these experiments show regeneration of the animals spinal cord is possible with the scaffold in place, Prof Marques will apply for fresh funding to take her work to the next level.I hope we can contribute with our scientific knowledge to take a step forward towards SCI repair, she said.Catastrophic strokeA stroke is another catastrophic life event that can result in damage to the nervous system. Strokes, besides being the number two cause of death worldwide, are the third-leading cause of disability-adjusted life years (DALY), a metric used to assess the burden of death and disease.Scientists have yet to find a way to replace the dead brain cells that result from a clot blocking the flow of blood and oxygen to the brain, but they are starting to exploit the latest technology such as advances in virtual reality (VR) to help patients recover from some of the long-term consequences.After a stroke, hands can become stiff due to disrupted connections between the brain and the hand muscles. This spasticity can make it hard, almost impossible, to straighten fingers or grasp an item.These hand impairments can severely impact daily life, said Dr Joseph Galea, a researcher in motor neuroscience at the University of Birmingham in the UK.Though theres been a lot of focus on improving large, reaching-arm movements after a stroke, theres been little work on improving hand functionality.Dr Galea wants to improve hand-movement recovery through the ImpHandRehab project. With funding from the European Research Council, this project asks stroke patients to perform tasks involving increasingly complex hand movements a form of rehabilitation that will ultimately improve dexterity and quality of life. Users perform their tasks wearing a VR headset paired with affordable, off-the-shelf motion-capture gloves.Demonstration of VR training for stroke treatments. (Video: Joseph Galea)What motivates users to stick to their tasks?Immersive VRGaming, explained Dr Galea. Weve developed two really immersive VR games that reward people for doing better and better at something like popping a balloon or controlling a submarine. Weve noticed that the more points or coins are at stake, the harder a person will try and the better theyll perform.Best of all, he and his colleagues have found that after a game has been played for a prolonged period of time, the improved hand performance persists even when the VR headset is removed.We envisage our solution being used by patients at home, said Dr Galea. It would be complementary to traditional rehab techniques.

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Rehabilitating spinal cord injury and stroke with graphene and gaming - Nanowerk

Spinal Cord Stem Cells Comments Off on Rehabilitating spinal cord injury and stroke with graphene and gaming – Nanowerk | September 19th, 2022

The induced pluripotent stem cells production market has been estimated to reach a CAGR of 8.0% in the foreseeable years from 2021to 2031.

The revenue generation opportunities in the induced pluripotent stem cells production market are attributed to an increased number of R & D activities by numerous organizations and companies to explore iPSCs potential in cell therapeutics that are targeted to treat various diseases.

Induced pluripotent stem cells come with various advantages compared to ESCs (Embryonic Stem Cells), for instance, maximum flexibility in research applications that are based on cells and avoiding the ethical implication associated to stem cells. These advantages of the industry services are likely to contribute to expansion opportunities in the induced pluripotent stem cell production market in the following years.

Increasing uses of iPSCs and robust pipelines for the cell therapeutics that are derived from iPSC have also been projected to serve as revenue generators in the induced pluripotent stem cells production market in the coming years.

In recent years, regenerative medicines are gaining popularity across the globe. In addition to this, iPSCs have been used at an increased rate to regenerate tissue-specific cells to transplant to patients who are experiencing various injuries. The researchers have also been taking an interest to use iPSCs for ex-vivo expansion of different blood components. These factors are likely to contribute to growth opportunities in the induced pluripotent stem cells production market.

Global Induced Pluripotent Stem Cells Market: Overview

Induced pluripotent stem cells (iPSCs) hold profound potential in replacing the use of embryonic stem cells (ESCs) as important tool for drug discovery and development, disease modeling, and transplantation medicine. Advent of new approaches in reprogramming of somatic cells to produce iPSCs have considerably advanced stem cell research, and hence the induced pluripotent stem cells market. The iPSC technology has shown potential for disease modeling and gene therapy in various areas of regenerative medicine. Notable candidates are Parkinsons disease, spinal cord trauma, myocardial infarction, diabetes, leukemia, and heart ailments.

Over the past few years, researchers have come out with several clinically important changes in reprogramming process; a case in point is silencing retroviruses in the human genome. Molecular mechanisms that underlie reprogramming have gained better understanding. However, the tools based on this growing understanding are still in nascent stage. Several factors affect the efficiency of reprogramming, most notably chromosomal instability and tumor expression. These have hindered researchers to utilize the full therapeutic potential of iPSCs, reflecting an unmet need, and hence, a vast potential in the induced pluripotent stemcellsmarket.

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Global Induced Pluripotent Stem Cells Market: Growth Dynamics

The growing application of induced pluripotent stem cells in generating patient-specific stem cells for drug development and human disease models is a key dynamic shaping their demands. Growing focus on personalized regenerative cell therapies among medical researchers and healthcare proponents in various countries have catalyzed their scope of induced pluripotent stem cells market. Advent of new methods to induce safe reprogramming of cells have helped biotechnology companies improve the clinical safety and efficacy of the prevailing stem cells therapies. The relentless pursuit of alternative source of cell types for regenerative therapies has led industry players and the research fraternity to pin hopes on iPSCs to generate potentially a wide range of human cell types with therapeutic potential.

Advances pertaining to better utilizing of retrovirus and lentivirus as reprogramming transcription factors in recent years have expanded the avenue for players in the induced pluripotent stem cells market. Increasing focus on decreasing the clinical difference between ESCs and iPSCs in all its entirety has shaped current research in iPSC technologies, thus unlocking new, exciting potential for biotechnology and pharmaceutical industries.

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Global Induced Pluripotent Stem Cells Market: Notable Development

Over the past few years, fast emerging markets in the global induced pluripotent stem cells are seeing the advent of patents that unveil new techniques for reprogramming of adult cells to reach embryonic stage. Particularly, the idea that these pluripotent stem cells can be made to form any cells in the body has galvanized companies to test their potential in human cell lines. Also, a few biotech companies have intensified their research efforts to improve the safety of and reduce the risk of genetic aberrations in their approved human cell lines. Recently, this has seen the form of collaborative efforts among them.

Lineage Cell Therapeutics and AgeX Therapeutics have in December 2019 announced that they have applied for a patent for a new method for generating iPSCs. These are based on NIH-approved human cell lines, and have been undergoing clinical-stage programs in the treatment of dry macular degeneration and spinal cord injuries. The companies claim to include multiple techniques for reprogramming of animal somatic cells.

Such initiatives by biotech companies are expected to impart a solid push to the evolution of the induced pluripotent stem cells.

Global Induced Pluripotent Stem Cells Market: Regional Assessment

North America is one of the regions attracting colossal research funding and industry investments in induced pluripotent stem cells technologies. Continuous efforts of players to generate immune-matched supply of pluripotent cells to be used in disease modelling has been a key accelerator for growth. Meanwhile, Asia Pacific has also been showing a promising potential in the expansion of the prospects of the market. The rising number of programs for expanding stem cell-based therapy is opening new avenues in the market.

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Induced Pluripotent Stem Cells Market Reaches at a CAGR of 8.0% in the Forecast Periods [2021-2031] - BioSpace

Spinal Cord Stem Cells Comments Off on Induced Pluripotent Stem Cells Market Reaches at a CAGR of 8.0% in the Forecast Periods [2021-2031] – BioSpace | September 19th, 2022

Theaxolotl(Ambystoma mexicanum) is an aquatic salamander renowned for its ability toregenerate its spinal cord, heart and limbs. These amphibians alsoreadily make new neuronsthroughout their lives. In 1964, researchers observed that adult axolotls couldregenerate parts of their brains, even if a large section was completely removed. But one study found that axolotlbrain regenerationhas a limited ability to rebuild original tissue structure.

So how perfectly can axolotls regenerate their brains after injury?

As aresearcher studying regeneration at the cellular level, I and my colleagues in theTreutlein Labat ETH Zurich and theTanaka Labat the Institute of Molecular Pathology in Vienna wondered whether axolotls are able to regenerate all the different cell types in their brain, including the connections linking one brain region to another. In ourrecently published study, we created an atlas of the cells that make up a part of the axolotl brain, shedding light on both the way it regenerates and brain evolution across species.

Differentcell typeshave different functions. They are able to specialize in certain roles because they each express different genes. Understanding what types of cells are in the brain and what they do helps clarify the overall picture of how the brain works. It also allows researchers to make comparisons across evolution and try to find biological trends across species.

One way to understand which cells are expressing which genes is by using a technique calledsingle-cell RNA sequencing (scRNA-seq). This tool allows researchers to count the number of active genes within each cell of a particular sample. This provides a snapshot of the activities each cell was doing when it was collected.

This tool has been instrumental in understanding the types of cells that exist in the brains of animals. Scientists have used scRNA-seq infish,reptiles,miceand evenhumans. But one major piece of the brain evolution puzzle has been missing: amphibians.

Our team decided to focus on thetelencephalonof the axolotl. In humans, the telencephalon is the largest division of the brain and contains a region called theneocortex, which plays a key role in animal behavior and cognition. Throughout recent evolution, the neocortex hasmassively grown in sizecompared with other brain regions. Similarly, the types of cells that make up the telencephalon overall havehighly diversifiedand grown in complexity over time, making this region an intriguing area to study.

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We used scRNA-seq to identify the different types of cells that make up the axolotl telencephalon, including different types ofneuronsandprogenitor cells, or cells that can divide into more of themselves or turn into other cell types. We identified what genes are active whenprogenitor cells become neurons, and found that many pass through an intermediate cell type called neuroblasts previously unknown to exist in axolotls before becoming mature neurons.

We then put axolotl regeneration to the test by removing one section of their telencephalon. Using aspecialized method of scRNA-seq, we were able to capture and sequence all the new cells at different stages of regeneration, from one to 12 weeks after injury. Ultimately, we found that all cell types that were removed had been completely restored.

We observed that brain regeneration happens in three main phases. The first phase starts with a rapid increase in the number of progenitor cells, and a small fraction of these cells activate a wound-healing process. In phase two, progenitor cells begin to differentiate into neuroblasts. Finally, in phase three, the neuroblasts differentiate into the same types of neurons that were originally lost.

Astonishingly, we also observed that the severedneuronal connectionsbetween the removed area and other areas of the brain had been reconnected. This rewiring indicates that the regenerated area had also regained its original function.

Adding amphibians to the evolutionary puzzle allows researchers to infer how the brain and its cell types has changed over time, as well as the mechanisms behind regeneration.

When we compared our axolotl data with other species, we found that cells in their telencephalon show strong similarity to the mammalianhippocampus, the region of the brain involved in memory formation, and theolfactory cortex, the region of the brain involved in the sense of smell. We even found some similarities in one axolotl cell type to the neocortex, the area of the brain known for perception, thought and spatial reasoning in humans. These similarities indicate that these areas of the brain may be evolutionarily conserved, or stayed comparable over the course of evolution, and that the neocortex of mammals may have an ancestor cell type in the telencephalon of amphibians.

While our study sheds light on the process of brain regeneration, including which genes are involved and how cells ultimately become neurons, we still dont know whatexternal signalsinitiate this process. Moreover, we dont know if the processes we identified are still accessible to animals that evolved later in time, such as mice or humans.

But were not solving the brain evolution puzzle alone. TheTosches Labat Columbia University explored the diversity of cell types inanother species of salamander, Pleurodeles waltl, while the Fei lab at the Guangdong Academy of Medical Sciences in China and collaborators at life sciences companyBGIexplored how cell types arespatially arranged in the axolotl forebrain.

Identifying all the cell types in the axolotl brain also helps pave the way for innovative research in regenerative medicine. The brains of mice and humans havelargely lost their capacityto repair or regenerate themselves.Medical interventionsfor severe brain injury currently focus on drug and stem cell therapies to boost or promote repair. Examining the genes and cell types that allow axolotls to accomplish nearly perfect regeneration may be the key to improve treatments for severe injuries and unlock regeneration potential in humans.

This article is republished fromThe Conversationunder a Creative Commons license. Read theoriginalarticle.

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Axolotls can regenerate their brains - Big Think

Spinal Cord Stem Cells Comments Off on Axolotls can regenerate their brains – Big Think | September 19th, 2022

IMAC Holdings, Inc.

BRENTWOOD, Tenn., Sept. 09, 2022 (GLOBE NEWSWIRE) -- IMAC Holdings, Inc. (Nasdaq: BACK) (IMAC or the Company), today announces it has completed the third cohort of its Phase 1 clinical trial for its investigational compound utilizing umbilical cord-derived allogenic mesenchymal stem cells for the treatment of bradykinesia due to Parkinsons disease.

The third cohort consists of five patients with bradykinesia due to Parkinsons disease receiving an intravenous infusion of a high concentration stem cell treatment. The third and final cohort of the Phase 1 clinical trial was completed on Tuesday, September 6, 2022.

About IMACs Phase 1 Clinical Trial

The Phase 1 clinical trial, consisting of a 15-patient dose escalation safety and tolerability study, is being conducted at three of IMACs clinical centers in Chesterfield, Missouri, Paducah, Kentucky, and Brentwood, Tennessee. The trial is divided into three groups: 1) five patients with bradykinesia due to Parkinsons disease received a low concentration dose, intravenous infusion of stem cells, 2) five received a medium concentration intravenous dose, 3) and five received a high concentration intravenous dose. All groups will be subsequently tracked for 12 months. IMACs medical doctors and physical therapists at the clinical sites have been trained to administer the treatment and manage the therapy. Ricardo Knight, M.D., M.B.A., who is medical director of the IMAC Regeneration Center of Chicago, is the trials principal investigator.

The Institute of Regenerative and Cellular Medicine serves as the trials independent investigational review board, while Regenerative Outcomes provides management of the study. Further details of the trial can be found at clinicaltrials.gov.

About Bradykinesia Due to Parkinsons Disease

In addition to unusually slow movements and reflexes, bradykinesia may lead to limited ability to lift arms and legs, reduced facial expressions, rigid muscle tone, a shuffling walk, and difficulty with repetitive motion tasks, self-care, and daily activities. Parkinsons disease is the typical culprit of bradykinesia, and as it progresses through its stages, a persons ability to move and respond declines.

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According to Zion Market Research, the global Parkinsons disease therapeutics market was $2.61 billion in 2018 and is expected to grow to $5.28 billion by 2025. The Parkinsons Disease Foundation estimates that nearly 10 million people are suffering from Parkinsons disease, and almost 60,000 new cases are reported annually in the U.S.

About IMAC Holdings, Inc.

IMAC Holdingsowns and manages health and wellness centers that deliver sports medicine, orthopedic care, and restorative joint and tissue therapies for movement restricting pain and neurodegenerative diseases.IMACis comprised of three business segments: outpatient medical centers, The Back Space, and a clinical research division. With treatments to address both young and aging populations,IMAC Holdingsowns or manages outpatient medical clinics that deliver regenerative rehabilitation services as a minimally invasive approach to acute and chronic musculoskeletal and neurological health problems. IMACs The Back Company retail spinal health and wellness treatment centers deliver chiropractic care within Walmart locations. IMACs research division is currently conducting a Phase I clinical trial evaluating a mesenchymal stem cell therapy candidate for bradykinesia due to Parkinsons disease. For more information visitwww.imacholdings.com.

# # #

Safe Harbor Statement

This press release contains forward-looking statements. These forward-looking statements, and terms such as anticipate, expect, believe, may, will, should or other comparable terms, are based largely on IMAC's expectations and are subject to a number of risks and uncertainties, certain of which are beyond IMAC's control. Actual results could differ materially from these forward-looking statements as a result of, among other factors, risks and uncertainties associated with its ability to raise additional funding, its ability to maintain and grow its business, variability of operating results, its ability to maintain and enhance its brand, its development and introduction of new products and services, the successful integration of acquired companies, technologies and assets, marketing and other business development initiatives, competition in the industry, general government regulation, economic conditions, dependence on key personnel, the ability to attract, hire and retain personnel who possess the skills and experience necessary to meet customers requirements, and its ability to protect its intellectual property. IMAC encourages you to review other factors that may affect its future results in its registration statement and in its other filings with the Securities and Exchange Commission. In light of these risks and uncertainties, there can be no assurance that the forward-looking information contained in this press release will in fact occur.

IMAC Press Contact:

Laura Fristoe

lfristoe@imacrc.com

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IMAC Holdings, Inc. Announces Completion of Third Cohort of its Phase 1 Clinical Study of Umbilical Cord-Derived Mesenchymal Stem Cells for the...

Spinal Cord Stem Cells Comments Off on IMAC Holdings, Inc. Announces Completion of Third Cohort of its Phase 1 Clinical Study of Umbilical Cord-Derived Mesenchymal Stem Cells for the… | September 11th, 2022

A person with SMA may find it challenging to stand up, walk, control their head movements, and in some cases, even breathe and swallow

Spine. Image courtesy Pearson Scott Foresman/Wikimedia Commons

Spinal muscular atrophy (SMA) is a severe genetic condition that targets motor neurons in the central nervous system (CNS), resulting in progressive muscle atrophy, weakness, and paralysis. It is a group of genetic disorders in which a person cannot control the movement of their muscles due to a loss of nerve cells in the spinal cord and brain stem. A person with SMA may find it challenging to stand up, walk, control their head movements, and in some cases, even breathe and swallow. Some forms of SMA are present at birth, while others develop over time. Some have an impact on life expectancy.

SMA can be clinically divided into five subtypes. The most severe type is SMA type 0, appearbefore birth, can be fatal before or after birth within the first year of life. Type 1 SMA also called infantile-onset, is the most common type of SMA, accounting for 60% cases, which appears in infants and causes them to die or become dependent on a ventilator by the age of two. Children with SMA type 2 are sitters, while those with type 3 can walk on their own for a while before becoming wheelchair-bound. SMA type 4 develops in adults and causes later-life progressive weakness.

SMA is the most frequent cause of death in the infantile age group, occurring in one in 10,000 live births. However, the SMA carrier frequency was 1 in 38 in a recent Indian study. Children with SMA can currently receive supportive care in India that includes assisted ventilation, feeding, physiotherapy, orthotics, and spine stabilization.

What causes SMA?

SMA is caused by a very specific genetic mutation in a gene called theSMN1 gene. SMN is that protein that play a critical role in the survival of the nerve cells that control muscles. (SMN) protein keeps motor neurons healthy and functioning normally. The loss of motor neurons in the spinal cord caused by SMA patients, and insufficient levels of the SMN protein results in skeletal muscle weakness and wasting.

SMA patients gradually lose their ability to control their muscles movement and strength. The muscles closest to the torso and neck are frequently severely affected by the disease. Some SMA patients never sit, stand, or walk. Other signs of SMA include tongue fasciculation, a bell-shaped chest (caused by muscle weakness), weak cough, difficulty breathing , choking or trouble swallowing, weak sucking and labored breathing during feeding.

How is SMA diagnosed?

The diagnosis of spinal muscular atrophy depends on the type of SMA a person has and age of onset. The path to diagnosis for infants and children with more severe forms of SMA frequently starts when a parent or medical professional notices unusual muscle weakness (hypotonia). People with adult-onset SMA types, such as type 4, might begin the diagnosis process after observing minor symptoms like hand tremors.

Physical exam

A physical examination is required to identify the presence of symptoms like muscle weakness or a lack of reflexes in cases where a new-born is not screened for SMA at birth. A primary care physician or a neurologist could perform this.

Family medical history

As part of your or your childs physical examination, a thorough review of the patients family history is necessary to determine whether there have ever been any instances of neuromuscular disease in the family. If the physical examination and family history raise suspicion of SMA, genetic testing will likely be the next step.

Genetic testing

Through molecular genetic testing, which requires a blood sample, SMA is identified. A single gene is examined for mutations linked to a genetic disease in molecular genetic testing.

Importance of early diagnosis

A patient with SMA must first undergo a higher level of cognitive evaluation. The clinician should assess the patient for weakness before concentrating solely on SMA. A muscle biopsy could be the next step in the evaluation to more precisely distinguish between muscle weakness and nerve weakness. Finally, the clinician would probably identify this patients SMA based on the results of the combined muscle biopsy and electrode diagnostics.

If a diagnosis is made early, the individual has access to the tools and the resources that medical science has developed over the last number of years to assist optimal functioning.

The standard method for diagnosing SMA is molecular genetic testing. SMA should be given early consideration in any infant with weakness or hypotonia due to the effectiveness of molecular testing and high frequency of SMA in the hypotonic infant. All other infant causes of hypotonic weakness are included in the differential diagnosis of severe forms of SMA.

SMA is inherited in an autosomal recessive manner. Each pregnancy of a couple who have had a child with SMA has an approximately 25 per cent chance of producing an affected child. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the diagnosis of SMA has been confirmed by molecular genetic testing in an affected family member.

Currently, there are several SMA treatments that have received FDA approval including Risdiplam (Evrysdi), Onasemnogene abeparvovec-xioi (Zolgensma) and Nusinersen (Spinraza). These targeted treatments may prevent the development or slow the progression of some features of SMA.

The severity of the disease varies depending on the type of SMA, with more severe subtypes needing more aggressive treatment. Proactive care and treatment decision-making by the multidisciplinary team and family are of paramount importance.

The author is MBBS, DCH, MRCPCH, Fellowship Pediatric Genetics, Consultant Clinical Geneticist, Salem Genetics Centre. Views are personal.

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Spinal Muscular Atrophy: Causes and importance of early diagnosis for proactive management - Firstpost

Spinal Cord Stem Cells Comments Off on Spinal Muscular Atrophy: Causes and importance of early diagnosis for proactive management – Firstpost | September 11th, 2022

FACT.MR

Over the coming years, the orthopedic navigation systems market is expected to experience significant growth due to rapid technological innovations, introduction of new orthopedic navigation products, rising cases of cardiovascular diseases, increased funding in R&D activities to improve orthopedic navigation product effectiveness, and rise in the prevalence of osteoarthritis.

United States, Rockville MD, Sept. 02, 2022 (GLOBE NEWSWIRE) -- Expanding at a high-value CAGR of 17%, the global demand for orthopedic navigation systems is projected to increase to a valuation of US$ 433.8 million by 2027, predicts Fact.MR, a market research and competitive intelligence provider.

By expressing three-dimensional computer images in comparative patient analysis, which is a feature of image-guided surgical systems, the orthopedic navigation system integrates information from pre-operative planning and intra-operative execution. These computer workstations for image-guided surgery include a surgical planning and display monitor, image-processing software, and a digitizing system.

As a result of bone spine damage to the spinal nerves, spinal cord, or neurological injury weakening, spinal injuries are the primary cause of mortality and morbidity. To reduce long-term functional disability, prompt medical and surgical care is essential, thereby driving the need for orthopedic navigation systems.

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Effective Results of Computer-assisted Navigation Systems

Other elements anticipated to influence the industry's revenue include associated benefits of computer-assisted surgeries (CAS), including low blood loss, shorter hospital stays, and simpler recovery.

Accurate implant alignment is made possible by CAS, which also enhances functioning, and quality-adjusted life years, and causes reduced discomfort, tissue damage, and problems.The aforementioned reasons are behind therising demand for minimally-invasive surgeries.

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Another factor that is anticipated to increase orthopedic navigation system demand is the development of technology in orthopedic surgical navigation procedures, as well as the rising prevalence of osteoarthritis, and increased investments in R&D.

Key Takeaways from Market Study

Demand for orthopedic navigation systems is expected to surge at a CAGR of 17% from 2022 to 2027.

Global orthopedic navigation system sales areanticipated to be driven by an increase in the use of minimally-invasive procedures and navigation software by doctors and surgeons due to the availability of affordable orthopedic navigationsolutions and greater awareness.

In terms of technology, optical navigation systems are superior to electromagnetic (EM) systems because they expose users to less radiation and provide greater accuracy during difficult operations, allowing surgeons to move accurately through the anatomy of a patient.

Sales of optical navigation systems are expected to balloon at a CAGR of 19% from 2022 to 2027.

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Winning Strategy

Top manufacturers of orthopedic navigation systems are concentrating on raising knowledge about these systems as well astheiruse and advantages among patients and medical professionals alike. By providing Continual Medical Education (CME) sessions, manufacturers of surgical navigation solutionsin developed nations have started to reach out to local communities.

As a result, more doctors and specialists are aware of the existence and application of orthopedic navigation systems. Furthermore, the 6- to 7-year warranty on commercially available orthopedic navigation devicesmakes the entire product sales cycle 7 years.

The market for orthopedic navigation systems is anticipated to expand rapidly over the forecast period due to increasing demand for technological assistance in orthopedic therapies.

Robotic-assisted surgical navigation robot NaoTrac was given CE mark clearance by Taiwan-based firm Brain Navi Biotechnology in November 2021. The company specialises in cutting-edge navigation robots.

Acuson Freestyle Elite ultrasound system, which can be used in conjunction with Artis angiography devices to provide quick and simple ultrasound guidance during interventional procedures, was introduced by Siemens Healthineers in March 2017.

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Segmentation of Orthopedic Navigation Systems Industry Research

By Technology :

Electromagnetic

Optical

Radiography

Others

By Application :

Knee

Spine

Hip

Joint Replacement

Others

By End User :

By Region :

North America

Latin America

Europe

East Asia

South Asia & Oceania

MEA

More Valuable Insights on Offer

Fact.MR, in its new offering, presents an unbiased analysis of the global orthopedic navigation systems market, presenting historical demand data (2017-2021) and forecast statistics for the period of 2022-2027.

The study divulges essential insights on the market on the basis of technology (electromagnetic, optical, radiography, others), application (knee, spine, hip, joint replacement, others), and end user (hospitals, clinics, ambulatory surgical centers, others), across five major regions of the world (North America, Europe, Asia Pacific, Latin America, and MEA).

Check out more related studies published by Fact.MR Research:

Orthopedic Braces and Support System Market:The global orthopedic braces and support system market was valued at aroundUS$ 3 Bnin 2020, which amounts to around11%share of the overall orthopedic devices market. Sales of orthopedic braces and support systems are slated to accelerate at a CAGR of6%to topUS$ 5.5 Bnby 2031. Demand for knee braces and supports is set to increase at a CAGR of5%across the assessment period of 2021 to 2031.

Orthopedic Power Tools Market:The global orthopedic power tools market is estimated atUSD 2.2 Billionin 2022 and is forecast to surpassUSD 3.5 Billionby 2032, growing at a CAGR of4.8%from 2022 to 2032.North America orthopedic power tools market accounts for the largest market share of24.8%.The escalating online presence of players with a strong distribution network coupled with well-established healthcare infrastructure is one of the key factors fueling the market growth.

Orthopedic Footwear Market:The global orthopedic footwear market is majorly driven by rise in the number of accidents, which is the major cause of orthopedic injury. In addition to this, increase in the availability as well as variability of orthopedic footwear in various applications also promotes the market growth. In context of this, about 6% of the U.S. population has foot injuries, bunions and flat feet or fallen arches each year. About 60% of U.S. population older than 17 are suffering from foot and ankle related injuries, sprains and strains of the ankle.

Bone Biopsy Systems Market:The global bone biopsy systems market is set to enjoy a valuation ofUS$ 227.6 millionin 2022 and expand at aCAGR of 6%to reachUS$ 408.9 millionby the end of 2032.Sales of bone biopsy systems accounted for more than30%of the global bone biopsy market at the end of 2021.Bone biopsy and bone marrow biopsy sampling have been one of the most painful experiences for patients. Efforts towards reducing this pain has led to the development of powered bone biopsy systems with increased efficiency.

Bone Marrow Processing Systems Market:A bone marrow processing system is a functionally closed, sterile system designed for automatically isolating and concentrating stem cells derived from donated bone marrow aspirate. Rising applications of bone marrow transplant procedures and bone marrow donation procedures used in the treatment of bone marrow cancers, such as acute leukemia, multiple myeloma, immune deficiency disorders, aplastic anemia, spinal fusions, lymphomas, non-union fractures, osteonecrosis and other rare genetic diseases of the bone marrow, is the primary driver in the market.

Bone Growth Stimulator Market:Bone growth stimulator market was nearly worthUS$ 1.8Bn in 2020 and is anticipated to expand1.6xover the forecast period, anticipated to reach a valuation ofUS$ 3Bn by 2031. In the short-run, bone growth stimulators revenue is likely to topUS$ 1.9Bn by 2022.The market for bone growth stimulators is dominated by North America. This is mostly due to the region's expanding elderly population and the growing burden of orthopedic illnesses. As of 2031, the U.S is expected to register a CAGR worth 5%.

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Increasing Road Accidents and Fall Injuries among Aged Population Primarily Driving Need for Orthopedic Navigation Systems: Fact.MR Analysis - Yahoo...

Spinal Cord Stem Cells Comments Off on Increasing Road Accidents and Fall Injuries among Aged Population Primarily Driving Need for Orthopedic Navigation Systems: Fact.MR Analysis – Yahoo… | September 3rd, 2022

Abstract: The olfactory ecto-mesenchymal stem cell (OE-MSC) are mesenchymal stem cells originating from the lamina propria of the nasal mucosa. They have neurogenic and immune-modulatory properties and showed therapeutic potential in animal models of spinal cord trauma, hearing loss, Parkinsons disease, amnesia, and peripheral nerve injury. In this paper we designed a protocol that meet the requirements set by human health agencies to manufacture these stem cells for clinical applications. Once purified, OE-MSCs can be used per se or expanded in order to get the extracellular vesicles (EV) they secrete. A protocol for the extraction of these vesicles was validated and the EV from the OE-MSC were functionally tested on an in vitro model. Nasal mucosa biopsies from three donors were used to validate the manufacturing process of clinical grade OE-MSC. All stages were performed by expert staff of the cell therapy laboratory according to aseptic handling manipulations, requiring grade A laminar airflow. Enzymatic digestion provides more rapidly a high number of cells and is less likely to be contaminated. Foetal calf serum was replaced with human platelet lysate and allowed stronger cell proliferation, with the optimal percentage of platelet lysate being 10%. Cultivated OE-MSCs are sterile, highly proliferative (percentage of CFU-F progenitors was 15,5%) and their maintenance does not induce chromosomal rearrangement (karyotyping and chromosomal microarray analysis were normal). These cells express the usual phenotypic markers of OE-MSC. Purification of the EVs was performed with ultracentrifugation and size exclusion chromatography. Purified vesicles expressed the recognized markers of EVs (Minimal Information for Studies of Extracellular Vesicles (MISEV) guidelines) and promoted cell differentiation and neurite elongation in a model of neuroblastoma Neuro2a cell line. We developed a safer and more efficient manufacturing process for clinical-grade olfactory stem cells, these cells can now be used in humans. A phase I clinical trial will begin soon. An efficient protocol for the purification of the OE-MSC EVs have been validated. These EVs exert neurogenic properties in vitro. More studies are needed to understand the exact mechanisms of action of these EVs and prove their efficacy and safety in animal models.

Original post:
Culture of human nasal olfactory stem cells and their extracellular vesicles as advanced therapy medicinal products - Newswise

Spinal Cord Stem Cells Comments Off on Culture of human nasal olfactory stem cells and their extracellular vesicles as advanced therapy medicinal products – Newswise | August 10th, 2022

What is inside teeth? Nicholas, age 5, Australian Capital Territory

Great question, Nicholas. It is important for us to know whats inside teeth as they help us eat, and eating gives us the energy to do our daily activities.

Our teeth are not just for chewing, though. We also need teeth for speaking, because different teeth contribute to different sounds. For example, we need upper front teeth to speak words starting with f or v sounds.

The teeth in the upper jaw are called as maxillary or upper teeth, and those on the lower jaw are called as mandibular or lower teeth. Then each jaw has two side-to-side halves. All up, thats four quadrants of teeth.

We have two sets of teeth. There are 20 teeth in the first set. We commonly call these milk teeth or primary teeth. They start forming while we are in the womb, even before we are born! The first one starts coming out of the gums when we are six months old, and most people have all their milk teeth by the age of three.

We keep our milk teeth until we are six years old, when we start losing them and the adult teeth or permanent teeth start coming in. By 14 or 15 years of age, most of us will have all our adult teeth except the last tooth in each side of the jaws. Some people call these wisdom teeth. There are 32 teeth in an entire adult set, with an equal number of teeth on each side.

We have four different types of teeth:

Read more: Curious Kids: what is brain freeze?

Each tooth can be divided into two parts. The crown is the part of the tooth we can see in the mouth, while the root sits within the gum and bone of the jaw. Some teeth have more than one root.

And each tooth has two layers: enamel and dentine, with pulp at the centre which has nerves and blood. Roots do not have enamel but another layer called cementum.

Enamel is the hardest substance in the body and protects the dentine and pulp, just like a helmet protects your head.

Dentine is the second layer and makes up most of the tooth.

We feel pain in the tooth when the innermost part, pulp, is involved.

Scientists have been working hard to find how special cells called stem cells in pulp could be used to repair other parts of the teeth, gums and even other body parts such as the spinal cord, brain and heart.

Read more: Curious kids: why dont whales have teeth like we do?

Hopefully youve already got into the habit of brushing twice every day with a fluoridated toothpaste for at least two minutes.

Tooth decay is caused by germs that love to feast on sugary or treat food in our mouth. We can stop that happening by saving lollies and sweets for special occasions and cleaning every tooth really well.

When teeth are not well cared for, they can develop tooth decay, which could cause pain when it involves that pulp deep inside your teeth. Its important to visit an oral health professional (such as your family dentist or hygienist) regularly. They can tell you how to take good care of your teeth and treat damaged teeth when required.

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Curious kids: what is inside teeth? - The Conversation

Spinal Cord Stem Cells Comments Off on Curious kids: what is inside teeth? – The Conversation | August 10th, 2022

Glioblastoma multiforme (GBM) or simply glioblastoma, is a type of cancer characterized by the growth of an aggressive neoplasm (tumor) in the brain or spinal cord. This type of cancer often occurs in older adults, although the younger population may also be affected.

Read Also: Targeting Hox Gene Dysregulation a Promising Approach for the Treatment of Glioblastoma Multiforme

Glioblastoma

This cancer type is known to be difficult to treat because of its high tendency to reoccur in patients, even after the combination of the three known procedures to treat cancers: surgery, radiotherapy, and chemotherapy. Glioblastoma has been a thorn in the flesh in the world of medicine amongst all cancer types due to the low survival rate of patients affected by it (average survival of 18 months, with only 5% of patients living up to five years). The following factors make this possible: no specific signs or symptoms are noticed leading to late diagnosis and the ability of the cancer cells to resist treatment procedures (the major factor).

Studies have been ongoing to uncover the mechanism behind this major factor, and it has been revealed that Glioblastoma multiforme contains a functional subset of cells known as glioblastoma stem-like cells (GSCs) which are the brain behind its reoccurrence capacity. The identity of these cells remained hidden until a recent study done by a group of scientists finally uncovered it.

Read Also: Brain Cancer: A Promising New Treatment for Destroying Aggressive Glioblastoma Cell

The team found out that these functional subsets of cells can be identified through singular mitochondrial alternative metabolisms. After intensively studying the metabolic reactions of these cells, they developed a tumor model that possessed the features of the GBM cultured in the lab. This way, they discovered that GSCs use these two metabolic reactions alpha-ketoglutarate reductive carboxylation and pyruvate carboxylation within their cells. They also discovered that these reactions are catalyzed by the enzymes isocitrate dehydrogenase and pyruvate carboxylase respectively.

They were able to uncover that their high rate of survival which facilitated the recurrence of the tumor is linked to the pyruvate carboxylation reaction. This discovery is important as it means that doctors may now be able to tackle the reoccurring ability of the tumor effectively.

It has always been known that treating glioblastoma is difficult due to its high recurring ability. However, with the revelation from this study, it is now possible for physicians to come up with more effective treatment procedures that would result in a reduced recurrence of the tumors, and an increased survival rate of patients.

This study raises the hopes of both physicians and patients as it reveals a way to hinder the recurrence of glioblastoma tumors. More research is still ongoing to hasten the innovation of a more effective treatment technique.

Read Also: Brain Cancer: Researchers Reprogram Immune Cells to Improve the Effectiveness of Treatment

Pyruvate carboxylation identifies Glioblastoma Stem-like Cells opening new metabolic strategy to prevent tumor recurrence

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How the Regenerative Properties of Glioblastoma Can Be Terminated - Gilmore Health News

Spinal Cord Stem Cells Comments Off on How the Regenerative Properties of Glioblastoma Can Be Terminated – Gilmore Health News | August 2nd, 2022

Abstract: Background Spinal cord injury (SCI) due to lack of restoration of damaged axons is associated with sensorimotor impairment. This study was focused on using the human Placental mesenchymal stem cells- exosome (hPMSCs- exosomes) in an animal model of severe SCI under a new myelogram protocol to confirm lumbar puncture (LP) injection accuracy and evaluate intrathecal space. Methods Mesenchymal stem cells (MSC) were extracted from human placenta tissue and were characterized. HPMSCs- exosomes were isolated by ultracentrifuge. After creating the severe SCI model, LP injection of exosomes was performed in the acute phase. Myelogram was also employed. The improved functional recovery of the animals in the treatment and control groups was followed by recording movement scores for 6 weeks. Hematoxylin-Eosin (H&E) staining was used to evaluate to detect pathological changes and glial scar size. The Immunohistochemistry (IHC) of GFAP and NF200 factors as well as the apoptosis tunnel test was investigated in the tissue samples from the injury site Results The results demonstrated that the use of the myelogram can be a feasible, appropriate and cost-effective method to confirm the accuracy of therapeutic agents LP injection and examine the subarachnoid space in the model of laboratory animals. Furthermore, intrathecal injection of hPMSCs-exosomes in the acute phase of SCI can improve motor function by attenuating apoptosis of neurons at the site of injury, decreased GFAP expression and increased NF200 in the treatment group, reducing glial scarring, and increasing axonal regeneration. Improving functional recovery by not creating bedsores in the treatment group and preventing hematuria were other effects of the exosome Conclusions In conclusion, the effects of hPMSCs-exosome can be considered to be not only in restoring function but also in preventing complications and managing symptoms. Thus, the neuroregenerative and anti-apoptotic potential of hPMSCs-exosome can be considered a therapeutic approach in SCI reconstructive medicine.

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Human placental mesenchymal stem cells derived exosomes improved functional recovery via attenuating apoptosis and increasing axonal regeneration...

Spinal Cord Stem Cells Comments Off on Human placental mesenchymal stem cells derived exosomes improved functional recovery via attenuating apoptosis and increasing axonal regeneration… | August 2nd, 2022

The company is developing a novel, non-invasive, bio-guided treatment to restore function of patients with acute spinal cord injuries.

Over two hundred and fifty thousand people suffer from spinal cord injuries in the US every year, with patients typically experiencing major, and mostly irreversible, loss of function that requires millions of dollars in lifetime care per patient.

NurExone is developing a revolutionary bio-guided treatment. The technology is based on exosomes, small particles that are created when stem cells proliferate, to deliver therapeutic agents to a specific location in the body. Nurexones proprietary agents, delivered by the exosomes, create an environment may support Nerves regeneration. For spine injuries, the bio-guided treatment is an agent that inhibits the PTEN protein in nerve cells, allowing nerves regeneration to occur.

The company carried out preclinical, animal studies that demonstrated that bio-guided treatment led to significant improvement, sensory recovery, and faster reflex restoration. The study reveals that Nurexones proprietary technology caused new connections in the spinal cord, repairing the damage from injuries, at least in part.

Studies also suggested that Nurexones technology may be useful for other indications including strokes and traumatic brain injuries (TBI).

The company was founded in 2020, based on research by Professor Shulamit Levenberg, Head of the Biomedical Engineering Department at Technion, and by Professor Daniel Offen, Head of the Lab for Neurosciences at the Felsenstein Medical Research Center in Tel Aviv University.

Spine related injuries are expected to increase in the future owing to motor accidents, workplace injuries, stroke, and cancer related motor disabilities. Currently, between 250,000 and 500,000 people become spinal cord injured every year worldwide, and the lifetime costs of treatments range from $1.6 million to nearly $5 million for 25-year-olds, to $1.1 million to nearly $2.7 million for 50-year-olds. The total addressable market for spinal cord trauma injuries is expected to reach $3.04 billion by 2025, with a CAGR of 3.7%.

Stepping back to look solely at exosome technology (not necessarily related to SCI), since 2018, exosomes are an emerging therapeutic field, with hundreds of millions of US dollars invested in exosome technologies by companies including Eli Lilly, Roche, and Takeda.

NurExone has obtained exclusive rights to an advanced exosome manufacturing process developed at the Technion, Israel Institute of Technology, Haifa. NurExone will be responsible for additional exosome research, management of clinical studies and commercialization of the technology for different indications not limited to Central Nerve System (CNS).

NurExones listing on the TSX.V under the symbol NRX was accomplished through an agreed reverse takeover (RTO) of EnerSpar signed on January 3, 2022. EnerSpar will acquire each ordinary share of NurExone in exchange for 17 post-consolidation EnerSpar shares, resulting in a total of 48,383,963 total shares outstanding following completion of the transaction.

Despite limited financial analyses available on the stock, it seems like a potentially unique opportunity given the fact that the market for spinal-cord treatment continues to grow, thus enabling new players in the field to partake in this ever-growing industry. Moreover, any company that delivers therapy that has the potential to unlock the secret of restoring function to patients who have experienced traumatic spinal injury, seems to be worth considering

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New TSXV listing looks to address the $3B spinal cord injury treatment market (NRX.V) - FXStreet

Spinal Cord Stem Cells Comments Off on New TSXV listing looks to address the $3B spinal cord injury treatment market (NRX.V) – FXStreet | July 25th, 2022

Ethics statement

All human material (blood RNA, primary microglia RNA, iPSCs) used in this study was derived after signed informed consent: for blood, according to University of Oxford OHS policy document 1/03; all procedures related to the use of the primary microglia followed established institutional (McGill University, Montreal, QC, Canada) and Canadian Institutes of Health Research guidelines for the use of human cells; for iPSC, with approval from the South Central Berkshire Research Ethics Committee, U.K. (REC 10/H0505/71). The blood RNA and primary microglia RNA samples have been published previously26, as have the iPSC lines (see below).

Four healthy control iPSC lines, SFC840-03-03 (female, 67years old,35), SFC841-03-01 (male, 36,18), SFC856-03-04 (female, 78,36), OX3-06 (male, 49,37), generated from skin biopsy fibroblasts and characterized as described before, were used in this study. Additionally, the previously reported26 line AH016-3 Lenti_IP_RFP (male, 80years old), which constitutively expresses Red Fluorescent Protein (RFP) under continuous puromycin selection, was used for some live-imaging experiments.

iPSCs were cultured in mTeSR1 (StemCell Technologies) or OXE8 medium38 on Geltrex (Thermo Fisher)-coated tissue culture plates with daily medium changes. Passaging was done as clumps using EDTA in PBS (0.5mM). Cells were initially expanded at low passage to create a master stock, which was used for all experiments to ensure consistency. Cells were regularly tested negative for mycoplasma using MycoAlert Mycoplasma Detection Kit (Lonza).

iPSCs were differentiated to MNs according to our previously published protocol18,19,27. Briefly, neural induction of iPSC monolayers was performed using DMEM-F12/Neurobasal 50:50 medium supplemented with N2 (1X), B27 (1X), 2-Mercaptoethanol (1X), AntibioticAntimycotic (1X, all ThermoFisher), Ascorbic Acid (0.5M), Compound C (1M, both Merck), and Chir99021 (3M, R&D Systems). After two days in culture, Retinoic Acid (RA, 1M, Merck) and Smoothened Agonist (SAG, 500nM, R&D Systems) were additionally added to the medium. Two days later, Compound C and Chir99021 were removed from the medium. After another 5days in culture, neural precursors were dissociated using accutase (ThermoFisher), and split 1:3 onto Geltrex-coated tissue culture plates in medium supplemented with Y-27632 dihydrochloride (10M, R&D Systems). After one day, Y-27632 dihydrochloride was removed from the medium, and then the cells were cultured for another 8days with medium changes every other day. For terminal maturation, the cells were dissociated on day in vitro (DIV) 18 using accutase and plated onto coverslips or tissue culture plates coated with polyethylenimine (PEI, 0.07%, Merck) and Geltrex or tissue culture dishes coated with PDL (Sigma-Aldrich)/ Laminin (R&D Systems)/ Fibronectin (Corning). For this step, the medium was additionally supplemented with BDNF (10ng/mL), GDNF (10ng/mL), Laminin (0.5g/mL, all ThermoFisher), Y-27632 dihydrochloride (10M), and DAPT (10M, R&D Systems). Three days later, Y-27632 dihydrochloride was removed from the medium. After another three days, DAPT was removed from the medium. Full medium changes were then performed every three days.

For MNs differentiated in co-culture medium alone, all steps were performed similarly until three days after the terminal re-plating (D21). MNs were then cultured in co-culture medium as described below.

iPSCs were differentiated to macrophage/microglia precursors as described previously20,21. Briefly, embryoid body (EB) formation was induced by seeding iPSCs into Aggrewell 800 wells (STEMCELL Technologies) in OXE838 or mTeSR1 medium supplemented with Bone Morphogenetic Protein 4 (BMP4, 50ng/mL), Vascular Endothelial Growth Factor (VEGF, 50ng/mL, both Peprotech), and Stem Cell Factor (SCF, 20ng/mL, Miltenyi Biotec). After four days with daily medium changes, EBs were transferred to T175 flasks (~150 EBs each) and differentiated in X-VIVO15 (Lonza), supplemented with Interleukin-3 (IL-3, 25ng/mL, R&D Systems), Macrophage Colony-Stimulating Factor (M-CSF, 100ng/mL), GlutaMAX (1X, both ThermoFisher), and 2-Mercaptoethanol (1X). Fresh medium was added weekly. After approximately one month, precursors emerged into the supernatant and could be harvested weekly. Harvested cells were passed through a cell strainer (40M, Falcon) and either lysed directly for RNA extraction or differentiated to microglia in monoculture or co-culture as described below.

Three days after the final re-plating of differentiating MNs (DIV21), macrophage/microglia precursors were harvested as described above and resuspended in co-culture medium comprised of Advanced DMEM-F12 (ThermoFisher) supplemented with GlutaMAX (1X), N2 (1X), AntibioticAntimycotic (1X), 2-Mercaptoethanol (1X), Interleukin-34 (IL-34, 100ng/mL, Peprotech), BDNF (10ng/mL), GDNF (10ng/mL), and Laminin (0.5g/mL). MNs were quickly rinsed with PBS, and macrophage/microglia precursors re-suspended in co-culture medium were added to each well. Co-cultures were then maintained for at least 14days before assays were conducted as described below. Half medium changes were performed every 23days.

For comparisons between co-cultures and monocultures, MNs and monocultured microglia were also differentiated alone in co-culture medium.

Cells cultured on coverslips were pre-fixed with 2% paraformaldehyde in PBS for 2min and then fixed with 4% paraformaldehyde in PBS for 15min at room temperature (RT). After permeabilization and blocking with 5% donkey/goat serum and 0.2% Triton X-100 in PBS for 1h at RT, the coverslips were incubated with primary antibodies diluted in 1% donkey/goat serum and 0.1% Triton X-100 in PBS at 4C ON. The following primary antibodies were used: rabbit anti-cleaved caspase 3 (1:400, 9661S, Cell Signaling), mouse anti-ISLET1 (1:50, 40.2D6, Developmental Studies Hybridoma Bank), mouse anti-TUJ1 (1:500, 801201, BioLegend), rabbit anti-TUJ1 (1:500, 802001, BioLegend), chicken anti-TUJ1 (1:500, GTX85469, GeneTex), rabbit anti-IBA1 (1:500, 019-19741, FUJIFILM Wako Pure Chemical Corporation), goat anti-IBA1 (1:500, ab5076, abcam), rabbit anti-synaptophysin (1:200, ab14692, abcam), goat anti-ChAT (1:100, ab114P, abcam), rat anti-TREM2 (1:100, MAB17291-100, R&D Systems), rabbit anti-TMEM119 (1:100, ab185337, abcam), rat anti-CD11b (1:100, 101202, BioLegend).

After three washes with PBS-0.1% Triton X-100 for 5min each, coverslips were incubated with corresponding fluorescent secondary antibodies Alexa Fluor 488/568/647 donkey anti-mouse/rabbit/rat/goat, goat anti-chicken (all 1:1000, all ThermoFisher). Coverslips were then washed twice with PBS-0.1% Triton X-100 for 5min each and incubated with 4,6-diamidino-2-phenylindole (DAPI, 1g/mL, Sigma-Aldrich) in PBS for 10min. After an additional 5min-washing step with PBS-0.1% Triton X-100, the coverslips were mounted onto microscopy slides using ProLong Diamond Antifade Mountant (ThermoFisher). Confocal microscopy was then performed using an LSM 710 microscope (Zeiss).

For the analysis of neuronal and MN markers after differentiation, three z-stacks (2m intervals) of randomly selected visual fields (425.1425.1m) were taken for each coverslip at 20magnification. The ratios of TUJ1-positive, ChAT-positive, ISLET1-positive, ChAT-positive/ TUJ1-positive, and ISLET1-positive/ TUJ1-positive cells were then quantified using Fiji in a blinded fashion.

For the analysis of microglial markers in monoculture and co-culture, three z-stacks (1m intervals) of randomly selected visual fields (212.55212.55m) were taken for each coverslip at 40magnification. The expression of CD11b, TMEM119, and TREM2 in IBA1-positive cells in monoculture and co-culture was then quantified using Fiji.

For the analysis of apoptosis in neurons, five z-stacks images of randomly selected visual fields (212.55212.55m) were taken at 40magnification for each coverslip. The ratios of cleaved caspase 3/ TUJ1-positive cells were then quantified for neurons in monoculture and co-culture in a blinded fashion. For the analysis of apoptosis in microglia, three z-stacks images of randomly selected visual fields (212.55212.55m) were taken at 40magnification for each coverslip. The ratios of cleaved caspase 3/ IBA1-positive cells were then quantified for microglia in monoculture and co-culture.

For the analysis of microglial ramifications, five z-stacks images of randomly selected visual fields (212.55212.55m) were taken at 40magnification for each coverslip. To analyze the branching of IBA1-positive microglia in monoculture and co-culture, the average branch length, number of branch points and number of branch endpoints was determined using 3DMorph39, a Matlab-based script for the automated analysis of microglial morphology.

From the same harvest, macrophage precursors (pMacpre) were either lysed directly or differentiated to microglia in monoculture (pMGL) or microglia in co-culture with MNs (co-pMG) for 14days. pMGL were rinsed with PBS and directly lysed in the dish. For both pMacpre and pMGL, RNA was extracted using an RNAeasy Mini Plus kit (Qiagen) according to the manufacturers instructions. Co-cultures were first dissociated by 15min incubation with papain (P4762, Sigma-Aldrich) diluted in accutase (20 U/mL) and gentle trituration based on a previously published protocol40. The cell suspension was then passed through a cell strainer (70m, Falcon) to remove cell clumps. To extract co-pMG, magnetic-activated cell sorting (MACS) was then performed using CD11b-MACS beads (130093-634, Miltenyi Biotec) according to the manufacturers instructions. The panned cell population was lysed for RNA extraction using an RNAeasy Micro kit (Qiagen) according to the manufacturers instructions. In addition, RNA from human fetal microglia and blood monocytes from three different healthy genetic backgrounds wasre-used from our previous study26.

RNA from the four different healthy control lines (listed earlier) per condition (pMacpre, pMGL, co-pMG) was used for RNA sequencing analysis. Material was quantified using RiboGreen (Invitrogen) on the FLUOstar OPTIMA plate reader (BMG Labtech) and the size profile and integrity analysed on the 2200 or 4200 TapeStation (Agilent, RNA ScreenTape). RIN estimates for all samples were between 9.2 and 9.9. Input material was normalised to 100ng prior to library preparation. Polyadenylated transcript enrichment and strand specific library preparation was completed using NEBNext Ultra II mRNA kit (NEB) following manufacturers instructions. Libraries were amplified (14 cycles) on a Tetrad (Bio-Rad) using in-house unique dual indexing primers (based on41). Individual libraries were normalised using Qubit, and the size profile was analysed on the 2200 or 4200 TapeStation. Individual libraries were normalised and pooled together accordingly. The pooled library was diluted to~10nM for storage. The 10nM library was denatured and further diluted prior to loading on the sequencer. Paired end sequencing was performed using a NovaSeq6000 platform (Illumina, NovaSeq 6000 S2/S4 reagent kit, v1.5, 300 cycles), generating a raw read count of a minimum of 34M reads per sample.

Further processing of the raw data was then performed using an in-house pipeline. For comparison, the RNA sequencing data (GSE89189) fromAbud et al.28 and the dataset (GSE85839) fromMuffat et al.29 were downloaded and processed in parallel. Quality control of fastq files was performed using FastQC (https://www.bioinformatics.babraham.ac.uk/projects/fastqc/) and MultiQC42. Paired-end reads were mapped to the human GRCh38.p13 reference genome (https://www.gencodegenes.org) using HISAT2 v2.2.143. Mapping quality control was done using SAMtools44 and Picard (http://broadinstitute.github.io/picard/) metrics. The counts table was obtained using FeatureCounts v2.0.145. Normalization of counts and differential expression analysis for the comparison of pMGL and co-pMG was performed using DESeq2 v1.28.146 in RStudio 1.4.1103, including the biological gender in the model and with the BenjaminiHochberg method for multiple testing correction. Exploratory data analysis was performed following variance-stabilizing transformation of the counts table, using heat maps and hierarchical clustering with the pheatmap 1.0.12 package (https://github.com/raivokolde/pheatmap) and principal component analysis. Log2 fold change (log2 fc) shrinkage for the comparison of pMGL and co-pMG was performed using the ashr package v2.2-4747. Genes with |log2 fc|>2 and adjusted p value<0.01 were defined as differentially expressed and interpreted with annotations from the Gene Ontology database using clusterProfiler v3.16.148 to perform over-representation analyses.

Equal amounts of RNA (30ng) were reverse-transcribed to cDNA using the High-Capacity cDNA Reverse Transcription Kit (ThermoFisher) according to the manufacturers instructions. Quantitative real-time PCR was performed with Fast SYBR Green Master Mix (ThermoFisher) according to the manufacturers instructions using a LightCycler 480 PCR System (Roche). The following primers (ChAT from Eurofins Genomics, all others from ThermoFisher) were used:

Quantification of the relative fold gene expression of samples was performed using the 2Ct method with normalization to the GAPDH reference gene.

AH016-3 Lenti-IP-RFP-microglia were co-cultured with healthy control motor neurons in PEI- and Geltrex-coated glass bottom dishes for confocal microscopy (VWR). The RFP signal was used to identify microglia in co-culture. To visualize microglial movement, images of the RFP signal and brightfield were taken every~30s for 1h (22 stitched images, 20magnification) using a Cell Observer spinning disc confocal microscope (Zeiss) equipped with an incubation system (37C, 5% CO2). To image phagocytic activity, co-cultures were rinsed with Live Cell Imaging Solution (1X, ThermoFisher), and pHrodo Green Zymosan Bioparticles Conjugates (P35365, ThermoFisher) diluted in Live Cell Imaging Solution (50g/mL), which become fluorescent upon phagocytic uptake, were added. The dish was immediately transferred to the spinning disc confocal microscope, and stitched images (33, 20magnification) were acquired every 5min for 2h.

To induce pro-inflammatory (M1) or anti-inflammatory (M2) microglial phenotypes, cells were treated with Lipopolysaccharides (LPS, 100ng/mL, Sigma) and Interferon- (IFN-, 100ng/mL, ThermoFisher), or Interleukin-4 (IL-4, 40ng/mL, R&D Systems) and Interleukin-13 (IL-13, 20ng/mL, Peprotech), respectively, for 18h. Vehicle-treated (co-culture medium) cells were used as an unstimulated (M0) control.

To analyze the clustering of microglia upon pro-inflammatory and anti-inflammatory stimulation, RFP-positive microglia were imaged directly before the addition of M1/M2 inducing agents, and at 9h and 18h post-stimulation using the Cell Observer spinning disc confocal microscope (55 stitched images, 10magnification). The number of individual microglial cells and size of microglial clusters was quantified using the analyze particle function in Fiji.

After stimulation with M1/M2-inducing agents, culture supernatants were collected and spun down at 1200g for 10min at 4C. Pooled samples from three different healthy control lines for each cell type were analyzed using the Proteome Profiler Human XL Cytokine Array Kit (R&D Systems) according to the manufacturers instructions. The signal was visualized on a ChemiDoc MP imaging system (Bio-Rad) and analyzed using ImageStudioLite v5.2.5 (LI-COR). Data was then plotted as arbitrary units using the pheatmap 1.0.12 package in RStudio 1.4.1103.

In addition, to confirm the relative expression of Serpin E1 and CHI3L1 in cell culture supernatants, the Human Human Chitinase 3-like 1 Quantikine ELISA Kit (DC3L10) and Human Serpin E1/PAI-1 Quantikine ELISA Kit (DSE100, both R&D Systems) were used according to the manufacturers instructions.

pNeuron, pMGL and co-cultures were plated and maintained in WillCo-dish Glass Bottom Dishes (WillCo Wells) for 14days. Calcium transients were measured using the fluorescent probe Fluo 4-AM according to the manufacturers instructions (ThermoFisher). Cells were incubated with 20M Fluo 4-AM resuspended in 0.2% dimethyl sulfoxide for 30min at RT in Live Imaging Solution (ThermoFisher). After a washing step with Live Imaging Solution, cells were allowed to calibrate at RT for 1520min before imaging. Ca2+ images were taken by fluorescence microscopy at RT. The dye was excited at 488nm and images were taken continuously with a baseline recorded for 30s before stimulation. The stimuli used for calcium release were 50mM KCl (Sigma-Aldrich) for 30s, followed by a washing step for one minute. Microglial calcium release was stimulated by 50M ADP (Merck) under continuous perfusion for 1min, followed by a 1-min wash. Analysis of fluorescence intensity was performed using Fiji. Fluorescence measurements are expressed as a ratio (F/Fo) of the mean change in fluorescence (F) at a pixel relative to the resting fluorescence at that pixel before stimulation (Fo). The responses were analysed in 2040 cells per culture.

MNs on DIV 3345 were maintained in a bath temperature of 25C in a solution containing 167mM NaCl, 2.4mM KCl, 1mM MgCl2, 10mM glucose, 10mM HEPES, and 2mM CaCl2 adjusted to a pH of 7.4 and 300mOsm. Electrodes with tip resistances between 3 and 7M were produced from borosilicate glass (0.86mm inner diameter; 1.5mm outer diameter). The electrode was filled with intracellular solution containing 140mMK-Gluconate, 6mM NaCl, 1mM EGTA, 10mM HEPES, 4mM MgATP, 0.5mM Na3GTP, adjusted to pH 7.3 and 290mOsm. Data acquisition was performed using a Multiclamp 700B amplifier, digidata 1550A and clampEx 6 software (pCLAMP Software suite, Molecular Devices). Data was filtered at 2kHz and digitized at 10kHz. Series resistance (Rs) was continuously monitored and only recordings with stable<50 M and Rs<20% were included in the analysis. Voltage gated channel currents were measured on voltage clamp, neurons were pre-pulsed for 250ms with 140mV and subsequently a 10mV-step voltage was applied from 70 to+70mV. Induced action potentials were recorded on current clamp, neurons were held at 70mV and 8 voltage steps of 10mV, from 10 to 60mV, were applied. Data was analyzed using Clampfit 10.7 (pCLAMP Software suite).

Statistical analyses were conducted using GraphPad Prism 9 (GraphPad Software, San Diego, California USA, http://www.graphpad.com). Comparisons of two groups were performed by two-tailed unpaired t-tests and multiple group comparisons by one-way or two-way analysis of variance (ANOVA) with appropriate post-hoc tests as indicated in the figure legends. The statistical test and number of independent experiments used for each analysis are indicated in each figure legend. Data are presented as single data points and meansSEM. Differences were considered significant when P<0.05 (*P<0.05; **P<0.01; ***P<0.001; ns: not significant). GraphPad Prism 9 or RStudio 1.4.1103 were used to plot data. Final assembly and preparation of all figures was done using Adobe Illustrator 25.4.1.

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Human iPSC co-culture model to investigate the interaction between microglia and motor neurons | Scientific Reports - Nature.com

Spinal Cord Stem Cells Comments Off on Human iPSC co-culture model to investigate the interaction between microglia and motor neurons | Scientific Reports – Nature.com | July 25th, 2022