Pia mater ( or [1]), often referred to as simply the pia, is the delicate innermost layer of the meninges, the membranes surrounding the brain and spinal cord. Pia mater is medieval Latin meaning "tender mother".[1] The other two meningeal membranes are the dura mater and the arachnoid mater. Both the pia and arachnoid mater are derivatives of the neural crest while the dura is derived from embryonic mesoderm. Pia mater is a thin fibrous tissue that is impermeable to fluid. This allows the pia mater to enclose cerebrospinal fluid. By containing this fluid the pia mater works with the other meningeal layers to protect and cushion the brain. The pia mater allows blood vessels to pass through and nourish the brain. The perivascular space created between blood vessels and pia mater functions as a lymphatic system for the brain. When the pia mater becomes irritated and inflamed the result is meningitis.[2]

Pia mater is the thin, translucent, mesh-like meningeal envelope, spanning nearly the entire surface of the brain. It is absent only at the natural openings between the ventricles, the median aperture, and the lateral aperture. The pia firmly adheres to the surface of the brain and loosely connects to the arachnoid layer.[3] Because of this continuum, the layers are often referred to as the pia arachnoid or leptomeninges. A subarachnoid space exists between the arachnoid layer and the pia, into which the choroid plexus releases and maintains the cerebrospinal fluid (CSF). The subarachnoid space contains trabeculae, or fibrous filaments, that connect and bring stability to the two layers, allowing for the appropriate protection from and movement of the proteins, electrolytes, ions, and glucose contained within the CSF.[4] Romanian biologist Viorel Pais, through recent electron microscopy studies, has demonstrated for the first time in the specialty literature that pia mater is formed by cordocytes and blood vessels.

The thin membrane is composed of fibrous connective tissue, which is covered by a sheet of flat cells impermeable to fluid on its outer surface. A network of blood vessels travels to the brain and spinal cord by interlacing through the pia membrane. These capillaries are responsible for nourishing the brain.[5] This vascular membrane is held together by areolar tissue covered by mesothelial cells from the delicate strands of connective tissue called the arachnoid trabeculae. In the perivascular spaces, the pia mater begins as mesothelial lining on the outer surface, but the cells then fade to be replaced by neuroglia elements.[6]

Although the pia mater is primarily structurally similar throughout, it spans both the spinal cords neural tissue and runs down the fissures of the cerebral cortex in the brain. It is often broken down into two categories, the cranial pia mater (pia mater encephali) and the spinal pia mater (pia mater spinalis).

The section of the pia mater enveloping the brain is known as the cranial pia mater. It is anchored to the brain by the processes of astrocytes, which are glial cells responsible for many functions, including maintenance of the extracellular space. The cranial pia mater joins with the ependyma, which lines the cerebral ventricles to form choroid plexuses that produce cerebrospinal fluid. Together with the other meningeal layers, the function of the pia mater is to protect the central nervous system by containing the cerebrospinal fluid, which cushions the brain and spine.[4]

The cranial pia mater covers the surface of the brain. This layer goes in between the cerebral gyri and cerebellar laminae, folding inward to create the tela chorioidea of the third ventricle and the choroid plexuses of the lateral and third ventricles. At the level of the cerebellum, the pia mater membrane is more fragile due to the length of blood vessels as well as decreased connection to the cerebral cortex.[6]

The spinal pia mater closely follows and encloses the curves of the spinal cord, and is attached to it through a connection to the anterior fissure. The pia mater attaches to the dura mater through 21 pairs of denticulate ligaments that pass through the arachnoid mater and dura mater of the spinal cord. These denticular ligaments help to anchor the spinal cord and prevent side to side movement, providing stability.[7] The membrane in this area is much thicker than the cranial pia mater, due to the two-layer composition of the pia membrane. The outer layer, which is made up of mostly connective tissue, is responsible for this thickness. Between the two layers are spaces which exchange information with the subarachnoid cavity as well as blood vessels. At the point where the pia mater reaches the conus medullaris or medullary cone at the end of the spinal cord, the membrane extends as a thin filament called the filum terminale or terminal filum, contained within the lumbar cistern. This filament eventually blends with the dura mater and extends as far as the coccyx, or tailbone. It then fuses with the periosteum, a membrane found at the surface of all bones, and forms the coccygeal ligament. There it is called the central ligament and assists with movements of the trunk of the body.[6]

In conjunction with the other meningeal membranes, pia mater functions to cover and protect the central nervous system (CNS), to protect the blood vessels and enclose the venous sinuses near the CNS, to contain the cerebrospinal fluid (CSF) and to form partitions with the skull.[8] The CSF, pia mater, and other layers of the meninges work together as a protection device for the brain, with the CSF often referred to as the fourth layer of the meninges.

Cerebrospinal fluid is circulated through the ventricles, cisterns, and subarachnoid space within the brain and spinal cord. About 150mL of CSF is always in circulation, constantly being recycled through the daily production of nearly 500mL of fluid. The CSF is primarily secreted by the choroid plexus; however, about one-third of the CSF is secreted by pia mater and the other ventricular ependymal surfaces (the thin epithelial membrane lining the brain and spinal cord canal) and arachnoidal membranes. The CSF travels from the ventricles and cerebellum through three foramina in the brain, emptying into the cerebrum, and ending its cycle in the venous blood via structures like the arachnoid granulations. The pia spans every surface crevice of the brain other than the foramina to allow the circulation of CSF to continue.[9]

Pia mater allows for the formation of perivascular spaces that help serve as the brains lymphatic system. Blood vessels that penetrate the brain first pass across the surface and then go inwards toward the brain. This direction of flow leads to a layer of the pia mater being carried inwards and loosely adhering to the vessels, leading to the production of a space, namely a perivascular space, between the pia mater and each blood vessel. This is critical because the brain lacks a true lymphatic system. In the remainder of the body, small amounts of protein are able to leak from the parenchymal capillaries through the lymphatic system. In the brain, this ends up in the interstitial space. The protein portions are able to leave through the very permeable pia mater and enter the subarachnoid space in order to flow in the cerebrospinal fluid (CSF), eventually ending up in the cerebral veins. The pia mater serves to create these perivascular spaces to allow passage of certain material, such as fluids, proteins, and even extraneous particulate matter such as dead white blood cells from the blood stream to the CSF, and essentially the brain.[9]

A function of the pia mater is that of the bloodbrain barrier (BBB), which keeps the CSF and brain fluid separate from the blood, allowing limited sodium, chlorine, and potassium through, and absolutely no plasma proteins nor organic molecules. Nearby, the ventricles are lined with the ependyma membrane. The CSF is only kept separate through the pia mater. Due to the ependyma and pia maters high permeability, nearly anything entering the CSF is able to enter the brain interstitial fluid.[9] However, regulation of this permeability is achieved through the abundant amount of astrocyte foot processes which are responsible for connecting the capillaries and the pia mater in a way that helps limit the amount of free diffusion going into the CNS.[10] The permeability of the pia then serves to closely connect the interstitial brain fluid and the CSF and allow them to remain nearly homogenous in terms of composition.[9]

The function of the pia mater is more simply visualized through these ordinary occurrences. This last property is evident in cases of head injury. When the head comes into contact with another object, the brain is protected from the skull due to the similarity in density between these two fluids so that the brain does not simply smash through into the skull, but rather its movement is slowed and stopped by the viscous ability of this fluid. The contrast in permeability between the BBB and pia mater mentioned before is also useful in the application of medicine. Drugs that enter the blood stream can not penetrate and function in the brain, but instead must be administered into the cerebrospinal fluid.[9]

The pia mater also functions to deal with the deformation of the spinal cord under compression. Due to the high elastic modulus of the pia mater, it is able to provide a constraint on the surface of the spinal cord. This constraint stops the elongation of the spinal cord, as well as providing a high strain energy. This high strain energy is useful and responsible for the restoration of the spinal cord to its original shape following a period of decompression.[11]

Ventral root afferents are unmyelinated sensory axons located within the pia mater. These ventral root afferents relay sensory information from the pia mater and allow for the transmission of pain from disc herniation and other spinal injury.[12]

The significant increase in the size of the cerebral hemisphere through evolution has been made possible in part through the evolution of the vascular pia mater, which allows nutrient blood vessels to penetrate deep into the intertwined cerebral matter, providing the necessary nutrients in this larger neural mass. Throughout the course of life on earth, the nervous system of animals has continued to evolve to a more compact and increased organization of neurons and other nervous system cells. This process is most evident in vertebrates and especially mammals in which the increased size of the brain is generally condensed into a smaller space through the presence of sulci or fissures on the surface of the hemisphere divided into gyri allowing more superficies of the cortical grey matter to exist. The development of the meninges and the existence of a defined pia mater was first noted in the vertebrates, and has been more and more significant membrane in the brains of mammals with larger brains.[13]

Meningitis is the inflammation of the pia and arachnoid mater. This is often due to bacteria that have entered the subarachnoid space, but can also be caused by viruses, fungi, as well as non-infectious causes such as certain drugs. It is believed that bacterial meningitis is caused by bacteria that enter the central nervous system through the blood stream. The molecular tools these pathogens would require to cross the meningeal layers and the bloodbrain barrier are not yet well understood. Inside the subarachnoid, bacteria replicate and cause inflammation from released toxins such as hydrogen peroxide (H2O2) . These toxins have been found to damage the mitochondria and produce a large scale immune response. Headache and meningismus are often signs of inflammation relayed via trigeminal sensory nerve fibers within the pia mater. Disabling neuropsychological effects are seen in up to half of bacterial meningitis survivors. Research into how bacteria invade and enter the meningeal layers is the next step in prevention of the progression of meningitis.[14]

A tumor growing from the meninges is referred to as a meningioma. Most meningiomas grow from the arachnoid mater inward applying pressure on the pia mater and therefore the brain or spinal cord. While meningiomas make up 20% of primary brain tumors and 12% of spinal cord tumors, 90% of these tumors are benign. Meningiomas tend to grow slowly and therefore symptoms may arise years after initial tumor formation. The symptoms often include headaches and seizures due to the force the tumor creates on sensory receptors. The treatments available for these tumors include surgery and radiation.[15]

Median sagittal section of brain

Coronal section of inferior horn of lateral ventricle

Diagrammatic representation of a section across the top of the skull, showing the membranes of the brain, etc.

Diagrammatic section of scalp

Ultrastructural diagram of the cerebral cortex (Viorel Pais, 2012)

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Pia mater - Wikipedia

Spinal Cord Stem Cells Comments Off on Pia mater – Wikipedia | January 8th, 2017

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Umbilical cord blood can be a promising source of hematopoietic stem cells (HSCs), used in treating blood diseases...

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Liver transplants save lives, plain and simple. But they also sentence recipients to a lifetime of immune-suppressive drugs, to prevent the body from rejecting the foreign addition....

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Its an exciting time for the Stem Cell Network! We have been very busy over the past few months ensuring that we are able to deliver on our mandate and see research funding and training opportunities provided for...

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Stem Cell Network

Spinal Cord Stem Cells Comments Off on Stem Cell Network | January 7th, 2017

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Neurology - Spinal Cord Introduction - YouTube

Spinal Cord Stem Cells Comments Off on Neurology – Spinal Cord Introduction – YouTube | January 6th, 2017

Clinical trials using neural stem cells

Neural stem cells (mouse)

StemCell Inc In December 2010 the Swiss regulatory agency for therapeutic products gave the go-ahead for aStemCell, Inc.-SponsoredPhase I/II clinical trial on chronic spinal cord injuryat the Balgrist University Hospital in Zurich (Switzerland). This trial had been inspired by the preclinical evidence of direct oligodendrocyte cell replacement through human neural stem cell (NSC) transplants in early chronic SCI in a particular mouse model. The trial uses a type of stem cell derived from human brain tissue and can make any of the three major kinds of neural cells found in the central nervous system. A single donor can provide eough cells for several transplanted patients). A single dose (20 x 106cells) of HuCNS-SC is directly implanted through multiple injections into thethoracicspinal cord of patients with chronic thoracic (T2T11) SCI, and immune suppression administered for 9 months after transplantation. This trial had enrolled patients 312 months after complete and incomplete cord injuries. The estimated completion date of this study is March 2016 (clinicaltrials.govidentifier no. NCT01321333). Interim analysis of clinical data to May 2014, presented at the Annual Meeting of the American Spinal Injury Association in San Antonio, Texas has shown that the significant post-transplant gains in sensory function first reported in two patients have now been observed in two additional patients.

The next group of patients currently being recruited in North America (University of Calgary) as well as in Switzerland has included some with incomplete injuries (ie some retained sensory or motor function) (clinicaltrials.govidentifier no. NCT01725880).

Earlier last year, the same company completed enrollment in multicentre open-label Phase I/II clinical titled "Study of Human Central Nervous System (CNS) Stem Cell Transplantation in Cervical Spinal Cord Injury" (Pathway Study website;clinicaltrials.govidentifier no. NCT02163876). The Pathway Study is the first clinical study designed to evaluate both the safetyandefficacy of transplanting stem cells. A total of 52 patients with traumatic injury to the cervical spinal cord are enrolled in the trial. The trial will be conducted as a randomized, controlled, single blind study and efficacy will be primarily measured by assessing motor function according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). The primary efficacy outcome will focus on change in upper extremity strength as measured in the hands, arms, and shoulders. The trial will follow the patients for one year from the time of enrollment.

The hope is that when transplanted into the injured spinal cord, these cells may re-establish some of the circuitries important for the network of nerves that carry information around the body.

Neuralstem Neuralstembegan surgeries in a Phase I safety trial of its NSI-566 neural stem cells for chronic spinal cord injury (cSCI) at the University of California, San Diego School of Medicine, with support from the UC San Diego Sanford Stem Cell Clinical Center, in September 2014 (clinicaltrials.govidentifier no. NCT01772810). The FDA amended the Phase I trial protocol to include a total of four patients, as the safety of the same cells and a similar procedure were proven in Neuralstems NSI-566/ALS trials. The four cSCI patients, with thoracic spinal cord injuries (T2-T12), have an American Spinal Injury Association (AIS) grade A level of impairment one-to-two years post-injury. This means that they have no motor or sensory function in the relevant segments at or below the injury, and are considered to be completely paralysed.

All patients in the trial will receive six injections in, or around, the injury site, using the same cells and similar procedure as the companys Amyotrophic Lateral Sclerosis (ALS) trials (the first FDA-approved neural stem cell trial for the treatment of ALS). All patients will also receive physical therapy post-surgery to guide newly formed nerves to their proper connections and functionality. The patients will also receive immunosuppressive therapy, which will be for three months, as tolerated. The trial study period will end six months post-surgery of the last patient, with a one-year Phase I completion goal. An NSI-566/acute spinal cord injury Phase I/II trial is expected to commence in the first quarter of 2015 in Seoul, South Korea.

The Miami Project to Cure Paralysis The Miami Projectclinical researchers currently have several clinical trials and clinical studies available for people who have had a spinal cord injury; some are for acute injuries and some are for chronic injuries. The clinical trials are testing the safety and efficacy of different cellular, neuroprotective, reparative, or modulatory interventions. These include Phase I clinical trials with the patients own (peripheral nerve-derived) Schwann cells in bothsubacute thoracicandchronic cervical and thoracicSCIs and a multicenter Phase II clinical trial withHuCNS-SC in chronic cervical SCIs(as above). All these Miami Project cell therapy trials are recruiting patients (more info on clinicaltrials.gov).

Mesenchymal/stromal stem cellsare being investigated as possible treatments for spinal cord injuries. Clinical Trials (clinicaltrials.gov) identifies at present total of 9 trials tagged as MSC trials in spinal cord injuries. These include studies that investigate the safety and efficacy of MSCs derived from the patients own bone marrow (5), adipose tissue (fat) (3) or cord blood (1). MSCs are injected in a number of different ways in these trials - including directly into the spinal cord or the lesion itself, intravenously, or even just in the skin, in patients with chronic cervical to thoracic injuries showingASIA/ISCoS scoresbetween A (complete lack of motor and sensory function below the level of injury) and C (some muscle movement is spared below the level of injury, but 50 percent of the muscles below the level of injury cannot move against gravity).

The hope is that when transplanted into the injured spinal cord, these cells may provide tissue protective molecules/factors and help (indirectly from cell integration and differentiation) to re-establish some of the circuitries important for the network of nerves that carry information around the body.

California based biotech Geronhad a widely reported clinical trial under way for a treatment the first of its kind involving the injection of cells derived from human embryonic stem cells. The injected cells were precursors of oligodendrocytes, the cells that form the insulating myelin sheath around axons. Researchers hoped that these cells, once injected into the spinal cord, would mature and form a new coating on the nerve cells, restoring the ability of signals to cross the spinal cord injury site.

After treating four patients with these cells in a phase one (safety) trial, and reporting no serious adverse effects, Geron announced in November 2011 it was discontinuing its stem cell programme. The company said stem cells continue to hold great promise, but cited financial reasons for shifting focus to other areas of research.

Asterias Biotherapeutics Following up on the cellular technology initially developed by Geron, Asterias Biotherapeutics has developed a program that focuses on the development of a kind of nerve cell, oligodendrocyte progenitor cells (OPCs) for spinal cord injury. These cells, known as AST-OPC1, are produced from human embryonic stem (ES) cells.

In aPhase 1 clinical trial, five patients with neurologically complete, thoracic spinal cord injury were administered two million hES cell-derived OPCs at the spinal cord injury site 7-14 days post-injury. The subjects received low levels immunosuppression for the next 60 days. Delivery of OPCs was successful in all five subjects with no serious adverse events associated with the administration of the cells or the immunosuppressive regimen. In four of the five subjects, serial MRI scans suggested reduction of the volume of injury in the spinal cord

A second follow up (dose escalation)Phase I/II trialwith AST-OPC1 in acute (14-30 days after injury) sensorimotor complete cervical spinal cord injuries (SCI) is currently recruiting participants.

The hope is that when acutely transplanted into the injured spinal cord, OPCs may remyelinate and restore lost functions.

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Spinal cord injuries: how could stem cells help ...

Spinal Cord Stem Cells Comments Off on Spinal cord injuries: how could stem cells help … | December 25th, 2016

December 13, 2016 - Experimental implant shows promise for restoring voluntary movement after spinal cord injury

UCLA scientists test electrical stimulation that bypasses injury; technique boosts patients finger control, grip strength up to 300 percent A spinal stimulator being tested by doctors at Ronald Reagan UCLA Medical Center is showing promise in restoring hand strength and movement to a California man who broke his neck in a dirt bike accident five Continue Reading

Researchers have developed a urine test revealing the presence of a neurotoxin that likely worsens the severity and pain of spinal cord injuries, suggesting a new tool to treat the injuries. The neurotoxin, called acrolein, is produced within the body after nerve cells are damaged, increasing pain and triggering a cascade of biochemical events thought Continue Reading

We are trying to improve someones quality of life. If someone can breathe without a ventilator, then youve increased their independence, and that, to me, is a huge success. Michael Lane, PhD Walking is not the top priority for many patients who have suffered from cervical spinal cord injuries, according to Michael Lane, PhD, an Continue Reading

Scientists have developed a robotic interface which could help to restore fine hand movements in paraplegics. By combining an electrode cap with an exoskeleton worn over the fingers, the device translates brain signals to hand movements. The approach could provide paraplegic patients with the fine motor control needed to carry out everyday tasks such as Continue Reading

In the course of three years, Taylor Graham has accomplished many things: Survived a motorcycle accident, adjusted to a spinal cord injury and a new life in a wheelchair, picked up the sport of wheelchair tennis, graduated from Southeast Community College, and even got married. So what could possibly be next? We have a goal Continue Reading

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Spinal Cord Injury Zone!

Spinal Cord Stem Cells Comments Off on Spinal Cord Injury Zone! | December 25th, 2016

Spinal cord injuries result from damage to the vertebrae, ligaments or disks of the spinal column or to the spinal cord itself.

A traumatic spinal cord injury may stem from a sudden, traumatic blow to your spine that fractures, dislocates, crushes, or compresses one or more of your vertebrae. It also may result from a gunshot or knife wound that penetrates and cuts your spinal cord.

Additional damage usually occurs over days or weeks because of bleeding, swelling, inflammation and fluid accumulation in and around your spinal cord.

A nontraumatic spinal cord injury may be caused by arthritis, cancer, inflammation, infections or disk degeneration of the spine.

The central nervous system comprises the brain and spinal cord. The spinal cord, made of soft tissue and surrounded by bones (vertebrae), extends downward from the base of your brain and is made up of nerve cells and groups of nerves called tracts, which go to different parts of your body.

The lower end of your spinal cord stops a little above your waist in the region called the conus medullaris. Below this region is a group of nerve roots called the cauda equina.

Tracts in your spinal cord carry messages between the brain and the rest of the body. Motor tracts carry signals from the brain to control muscle movement. Sensory tracts carry signals from body parts to the brain relating to heat, cold, pressure, pain and the position of your limbs.

Whether the cause is traumatic or nontraumatic, the damage affects the nerve fibers passing through the injured area and may impair part or all of your corresponding muscles and nerves below the injury site.

A chest (thoracic) or lower back (lumbar) injury can affect your torso, legs, bowel and bladder control, and sexual function. In addition, a neck (cervical) injury affects movements of your arms and, possibly, your ability to breathe.

The most common causes of spinal cord injuries in the United States are:

.

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Spinal cord injury Causes - Mayo Clinic

Spinal Cord Stem Cells Comments Off on Spinal cord injury Causes – Mayo Clinic | November 27th, 2016

The spine has different sections. The level of paralysis depends on the location of the injury.The spinal cord is made up of millions of nerve cells that send projections up and down the cord and out into other parts of the body. The information that allows us to sit, run, go to the toilet and breathe travels along these projections, called nerves.

When the spinal cord is injured, the initial trauma causes cell damage and destruction, and triggersa cascade of eventsthat spread around the injury site affecting a number of different types of cells. Axons are crushed and torn, and oligodendrocytes, the nerve cells that make up the insulating myelin sheath around axons, begin to die. Exposed axons degenerate, the connection between neurons is disrupted and the flow of information between the brain and the spinal cord is blocked.

The body cannot replace cells lost when the spinal cord is injured, and its function becomes impaired permanently. Patients may end up with severe movement and sensation disabilities. They will generally be paralyzed and without sensation from the level of the injury downwards.

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What happens when the spinal cord is injured? | Europe's ...

Spinal Cord Stem Cells Comments Off on What happens when the spinal cord is injured? | Europe’s … | November 27th, 2016

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World Stem Cell Summit

Spinal Cord Stem Cells Comments Off on World Stem Cell Summit | November 21st, 2016

Spinal cord injury (SCI) causes the irreversible loss of spinal cord parenchyma including astroglia, oligodendroglia and neurons. In particular, severe injuries can lead to an almost complete neural cell loss at the lesion site and structural and functional recovery might only be accomplished by appropriate cell and tissue replacement. Stem cells have the capacity to differentiate into all relevant neural cell types necessary to replace degenerated spinal cord tissue and can now be obtained from virtually any stage of development. Within the last two decades, many in vivo studies in small animal models of SCI have demonstrated that stem cell transplantation can promote morphological and, in some cases, functional recovery via various mechanisms including remyelination, axon growth and regeneration, or neuronal replacement. However, only two well-documented neural-stem-cell-based transplantation strategies have moved to phase I clinical trials to date. This review aims to provide an overview about the current status of preclinical and clinical neural stem cell transplantation and discusses future perspectives in the field.

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Neural Stem Cells for Spinal Cord Repair

Spinal Cord Stem Cells Comments Off on Neural Stem Cells for Spinal Cord Repair | November 2nd, 2016

This article is about the medical therapy. For the cell type, see Stem cell.

Stem-cell therapy is the use of stem cells to treat or prevent a disease or condition.

Bone marrow transplant is the most widely used stem-cell therapy, but some therapies derived from umbilical cord blood are also in use. Research is underway to develop various sources for stem cells, and to apply stem-cell treatments for neurodegenerative diseases and conditions such as diabetes, heart disease, and other conditions.

Stem-cell therapy has become controversial following developments such as the ability of scientists to isolate and culture embryonic stem cells, to create stem cells using somatic cell nuclear transfer and their use of techniques to create induced pluripotent stem cells. This controversy is often related to abortion politics and to human cloning. Additionally, efforts to market treatments based on transplant of stored umbilical cord blood have been controversial.

For over 30 years, bone marrow has been used to treat cancer patients with conditions such as leukaemia and lymphoma; this is the only form of stem-cell therapy that is widely practiced.[1][2][3] During chemotherapy, most growing cells are killed by the cytotoxic agents. These agents, however, cannot discriminate between the leukaemia or neoplastic cells, and the hematopoietic stem cells within the bone marrow. It is this side effect of conventional chemotherapy strategies that the stem-cell transplant attempts to reverse; a donor's healthy bone marrow reintroduces functional stem cells to replace the cells lost in the host's body during treatment. The transplanted cells also generate an immune response that helps to kill off the cancer cells; this process can go too far, however, leading to graft vs host disease, the most serious side effect of this treatment.[4]

Another stem-cell therapy called Prochymal, was conditionally approved in Canada in 2012 for the management of acute graft-vs-host disease in children who are unresponsive to steroids.[5] It is an allogenic stem therapy based on mesenchymal stem cells (MSCs) derived from the bone marrow of adult donors. MSCs are purified from the marrow, cultured and packaged, with up to 10,000 doses derived from a single donor. The doses are stored frozen until needed.[6]

The FDA has approved five hematopoietic stem-cell products derived from umbilical cord blood, for the treatment of blood and immunological diseases.[7]

In 2014, the European Medicines Agency recommended approval of Holoclar, a treatment involving stem cells, for use in the European Union. Holoclar is used for people with severe limbal stem cell deficiency due to burns in the eye.[8]

In March 2016 GlaxoSmithKline's Strimvelis (GSK2696273) therapy for the treatment ADA-SCID was recommended for EU approval.[9]

Stem cells are being studied for a number of reasons. The molecules and exosomes released from stem cells are also being studied in an effort to make medications.[10]

Research has been conducted on the effects of stem cells on animal models of brain degeneration, such as in Parkinson's, Amyotrophic lateral sclerosis, and Alzheimer's disease.[11][12][13] There have been preliminary studies related to multiple sclerosis.[14][15]

Healthy adult brains contain neural stem cells which divide to maintain general stem-cell numbers, or become progenitor cells. In healthy adult laboratory animals, progenitor cells migrate within the brain and function primarily to maintain neuron populations for olfaction (the sense of smell). Pharmacological activation of endogenous neural stem cells has been reported to induce neuroprotection and behavioral recovery in adult rat models of neurological disorder.[16][17][18]

Stroke and traumatic brain injury lead to cell death, characterized by a loss of neurons and oligodendrocytes within the brain. A small clinical trial was underway in Scotland in 2013, in which stem cells were injected into the brains of stroke patients.[19]

Clinical and animal studies have been conducted into the use of stem cells in cases of spinal cord injury.[20][21][22]

The pioneering work[23] by Bodo-Eckehard Strauer has now been discredited by the identification of hundreds of factual contradictions.[24] Among several clinical trials that have reported that adult stem-cell therapy is safe and effective, powerful effects have been reported from only a few laboratories, but this has covered old[25] and recent[26] infarcts as well as heart failure not arising from myocardial infarction.[27] While initial animal studies demonstrated remarkable therapeutic effects,[28][29] later clinical trials achieved only modest, though statistically significant, improvements.[30][31] Possible reasons for this discrepancy are patient age,[32] timing of treatment[33] and the recent occurrence of a myocardial infarction.[34] It appears that these obstacles may be overcome by additional treatments which increase the effectiveness of the treatment[35] or by optimizing the methodology although these too can be controversial. Current studies vary greatly in cell-procuring techniques, cell types, cell-administration timing and procedures, and studied parameters, making it very difficult to make comparisons. Comparative studies are therefore currently needed.

Stem-cell therapy for treatment of myocardial infarction usually makes use of autologous bone-marrow stem cells (a specific type or all), however other types of adult stem cells may be used, such as adipose-derived stem cells.[36] Adult stem cell therapy for treating heart disease was commercially available in at least five continents as of 2007.[citation needed]

Possible mechanisms of recovery include:[11]

It may be possible to have adult bone-marrow cells differentiate into heart muscle cells.[11]

The first successful integration of human embryonic stem cell derived cardiomyocytes in guinea pigs (mouse hearts beat too fast) was reported in August 2012. The contraction strength was measured four weeks after the guinea pigs underwent simulated heart attacks and cell treatment. The cells contracted synchronously with the existing cells, but it is unknown if the positive results were produced mainly from paracrine as opposed to direct electromechanical effects from the human cells. Future work will focus on how to get the cells to engraft more strongly around the scar tissue. Whether treatments from embryonic or adult bone marrow stem cells will prove more effective remains to be seen.[37]

In 2013 the pioneering reports of powerful beneficial effects of autologous bone marrow stem cells on ventricular function were found to contain "hundreds" of discrepancies.[38] Critics report that of 48 reports there seemed to be just five underlying trials, and that in many cases whether they were randomized or merely observational accepter-versus-rejecter, was contradictory between reports of the same trial. One pair of reports of identical baseline characteristics and final results, was presented in two publications as, respectively, a 578 patient randomized trial and as a 391 patient observational study. Other reports required (impossible) negative standard deviations in subsets of patients, or contained fractional patients, negative NYHA classes. Overall there were many more patients published as having receiving stem cells in trials, than the number of stem cells processed in the hospital's laboratory during that time. A university investigation, closed in 2012 without reporting, was reopened in July 2013.[39]

One of the most promising benefits of stem cell therapy is the potential for cardiac tissue regeneration to reverse the tissue loss underlying the development of heart failure after cardiac injury.[40]

Initially, the observed improvements were attributed to a transdifferentiation of BM-MSCs into cardiomyocyte-like cells.[28] Given the apparent inadequacy of unmodified stem cells for heart tissue regeneration, a more promising modern technique involves treating these cells to create cardiac progenitor cells before implantation to the injured area.[41]

The specificity of the human immune-cell repertoire is what allows the human body to defend itself from rapidly adapting antigens. However, the immune system is vulnerable to degradation upon the pathogenesis of disease, and because of the critical role that it plays in overall defense, its degradation is often fatal to the organism as a whole. Diseases of hematopoietic cells are diagnosed and classified via a subspecialty of pathology known as hematopathology. The specificity of the immune cells is what allows recognition of foreign antigens, causing further challenges in the treatment of immune disease. Identical matches between donor and recipient must be made for successful transplantation treatments, but matches are uncommon, even between first-degree relatives. Research using both hematopoietic adult stem cells and embryonic stem cells has provided insight into the possible mechanisms and methods of treatment for many of these ailments.[citation needed]

Fully mature human red blood cells may be generated ex vivo by hematopoietic stem cells (HSCs), which are precursors of red blood cells. In this process, HSCs are grown together with stromal cells, creating an environment that mimics the conditions of bone marrow, the natural site of red-blood-cell growth. Erythropoietin, a growth factor, is added, coaxing the stem cells to complete terminal differentiation into red blood cells.[42] Further research into this technique should have potential benefits to gene therapy, blood transfusion, and topical medicine.

In 2004, scientists at King's College London discovered a way to cultivate a complete tooth in mice[43] and were able to grow bioengineered teeth stand-alone in the laboratory. Researchers are confident that the tooth regeneration technology can be used to grow live teeth in human patients.

In theory, stem cells taken from the patient could be coaxed in the lab turning into a tooth bud which, when implanted in the gums, will give rise to a new tooth, and would be expected to be grown in a time over three weeks.[44] It will fuse with the jawbone and release chemicals that encourage nerves and blood vessels to connect with it. The process is similar to what happens when humans grow their original adult teeth. Many challenges remain, however, before stem cells could be a choice for the replacement of missing teeth in the future.[45][46]

Research is ongoing in different fields, alligators which are polyphyodonts grow up to 50 times a successional tooth (a small replacement tooth) under each mature functional tooth for replacement once a year.[47]

Heller has reported success in re-growing cochlea hair cells with the use of embryonic stem cells.[48]

Since 2003, researchers have successfully transplanted corneal stem cells into damaged eyes to restore vision. "Sheets of retinal cells used by the team are harvested from aborted fetuses, which some people find objectionable." When these sheets are transplanted over the damaged cornea, the stem cells stimulate renewed repair, eventually restore vision.[49] The latest such development was in June 2005, when researchers at the Queen Victoria Hospital of Sussex, England were able to restore the sight of forty patients using the same technique. The group, led by Sheraz Daya, was able to successfully use adult stem cells obtained from the patient, a relative, or even a cadaver. Further rounds of trials are ongoing.[50]

In April 2005, doctors in the UK transplanted corneal stem cells from an organ donor to the cornea of Deborah Catlyn, a woman who was blinded in one eye when acid was thrown in her eye at a nightclub. The cornea, which is the transparent window of the eye, is a particularly suitable site for transplants. In fact, the first successful human transplant was a cornea transplant. The absence of blood vessels within the cornea makes this area a relatively easy target for transplantation. The majority of corneal transplants carried out today are due to a degenerative disease called keratoconus.

The University Hospital of New Jersey reports that the success rate for growth of new cells from transplanted stem cells varies from 25 percent to 70 percent.[51]

In 2014, researchers demonstrated that stem cells collected as biopsies from donor human corneas can prevent scar formation without provoking a rejection response in mice with corneal damage.[52]

In January 2012, The Lancet published a paper by Steven Schwartz, at UCLA's Jules Stein Eye Institute, reporting two women who had gone legally blind from macular degeneration had dramatic improvements in their vision after retinal injections of human embryonic stem cells.[53]

In June 2015, the Stem Cell Ophthalmology Treatment Study (SCOTS), the largest adult stem cell study in ophthalmology ( http://www.clinicaltrials.gov NCT # 01920867) published initial results on a patient with optic nerve disease who improved from 20/2000 to 20/40 following treatment with bone marrow derived stem cells.[54]

Diabetes patients lose the function of insulin-producing beta cells within the pancreas.[55] In recent experiments, scientists have been able to coax embryonic stem cell to turn into beta cells in the lab. In theory if the beta cell is transplanted successfully, they will be able to replace malfunctioning ones in a diabetic patient.[56]

Human embryonic stem cells may be grown in cell culture and stimulated to form insulin-producing cells that can be transplanted into the patient.

However, clinical success is highly dependent on the development of the following procedures:[11]

Clinical case reports in the treatment orthopaedic conditions have been reported. To date, the focus in the literature for musculoskeletal care appears to be on mesenchymal stem cells. Centeno et al. have published MRI evidence of increased cartilage and meniscus volume in individual human subjects.[57][58] The results of trials that include a large number of subjects, are yet to be published. However, a published safety study conducted in a group of 227 patients over a 3-4-year period shows adequate safety and minimal complications associated with mesenchymal cell transplantation.[59]

Wakitani has also published a small case series of nine defects in five knees involving surgical transplantation of mesenchymal stem cells with coverage of the treated chondral defects.[60]

Stem cells can also be used to stimulate the growth of human tissues. In an adult, wounded tissue is most often replaced by scar tissue, which is characterized in the skin by disorganized collagen structure, loss of hair follicles and irregular vascular structure. In the case of wounded fetal tissue, however, wounded tissue is replaced with normal tissue through the activity of stem cells.[61] A possible method for tissue regeneration in adults is to place adult stem cell "seeds" inside a tissue bed "soil" in a wound bed and allow the stem cells to stimulate differentiation in the tissue bed cells. This method elicits a regenerative response more similar to fetal wound-healing than adult scar tissue formation.[61] Researchers are still investigating different aspects of the "soil" tissue that are conducive to regeneration.[61]

Culture of human embryonic stem cells in mitotically inactivated porcine ovarian fibroblasts (POF) causes differentiation into germ cells (precursor cells of oocytes and spermatozoa), as evidenced by gene expression analysis.[62]

Human embryonic stem cells have been stimulated to form Spermatozoon-like cells, yet still slightly damaged or malformed.[63] It could potentially treat azoospermia.

In 2012, oogonial stem cells were isolated from adult mouse and human ovaries and demonstrated to be capable of forming mature oocytes.[64] These cells have the potential to treat infertility.

Destruction of the immune system by the HIV is driven by the loss of CD4+ T cells in the peripheral blood and lymphoid tissues. Viral entry into CD4+ cells is mediated by the interaction with a cellular chemokine receptor, the most common of which are CCR5 and CXCR4. Because subsequent viral replication requires cellular gene expression processes, activated CD4+ cells are the primary targets of productive HIV infection.[65] Recently scientists have been investigating an alternative approach to treating HIV-1/AIDS, based on the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem and progenitor cells (GM-HSPC).[66]

On 23 January 2009, the US Food and Drug Administration gave clearance to Geron Corporation for the initiation of the first clinical trial of an embryonic stem-cell-based therapy on humans. The trial aimed evaluate the drug GRNOPC1, embryonic stem cell-derived oligodendrocyte progenitor cells, on patients with acute spinal cord injury. The trial was discontinued in November 2011 so that the company could focus on therapies in the "current environment of capital scarcity and uncertain economic conditions".[67] In 2013 biotechnology and regenerative medicine company BioTime (NYSEMKT:BTX) acquired Geron's stem cell assets in a stock transaction, with the aim of restarting the clinical trial.[68]

Scientists have reported that MSCs when transfused immediately within few hours post thawing may show reduced function or show decreased efficacy in treating diseases as compared to those MSCs which are in log phase of cell growth(fresh), so cryopreserved MSCs should be brought back into log phase of cell growth in invitro culture before these are administered for clinical trials or experimental therapies, re-culturing of MSCs will help in recovering from the shock the cells get during freezing and thawing. Various clinical trials on MSCs have failed which used cryopreserved product immediately post thaw as compared to those clinical trials which used fresh MSCs.[69]

Research currently conducted on horses, dogs, and cats can benefit the development of stem cell treatments in veterinary medicine and can target a wide range of injuries and diseases such as myocardial infarction, stroke, tendon and ligament damage, osteoarthritis, osteochondrosis and muscular dystrophy both in large animals, as well as humans.[70][71][72][73] While investigation of cell-based therapeutics generally reflects human medical needs, the high degree of frequency and severity of certain injuries in racehorses has put veterinary medicine at the forefront of this novel regenerative approach.[74] Companion animals can serve as clinically relevant models that closely mimic human disease.[75][76]

There is widespread controversy over the use of human embryonic stem cells. This controversy primarily targets the techniques used to derive new embryonic stem cell lines, which often requires the destruction of the blastocyst. Opposition to the use of human embryonic stem cells in research is often based on philosophical, moral, or religious objections.[110] There is other stem cell research that does not involve the destruction of a human embryo, and such research involves adult stem cells, amniotic stem cells, and induced pluripotent stem cells.

Stem-cell research and treatment was practiced in the People's Republic of China. The Ministry of Health of the People's Republic of China has permitted the use of stem-cell therapy for conditions beyond those approved of in Western countries. The Western World has scrutinized China for its failed attempts to meet international documentation standards of these trials and procedures.[111]

Since 2008 many universities, centers and doctors tried a diversity of methods; in Lebanon proliferation for stem cell therapy, in-vivo and in-vitro techniques were used, Thus this country is considered the launching place of the Regentime[112] procedure. http://www.researchgate.net/publication/281712114_Treatment_of_Long_Standing_Multiple_Sclerosis_with_Regentime_Stem_Cell_Technique The regenerative medicine also took place in Jordan and Egypt.[citation needed]

Stem-cell treatment is currently being practiced at a clinical level in Mexico. An International Health Department Permit (COFEPRIS) is required. Authorized centers are found in Tijuana, Guadalajara and Cancun. Currently undergoing the approval process is Los Cabos. This permit allows the use of stem cell.[citation needed]

In 2005, South Korean scientists claimed to have generated stem cells that were tailored to match the recipient. Each of the 11 new stem cell lines was developed using somatic cell nuclear transfer (SCNT) technology. The resultant cells were thought to match the genetic material of the recipient, thus suggesting minimal to no cell rejection.[113]

As of 2013, Thailand still considers Hematopoietic stem cell transplants as experimental. Kampon Sriwatanakul began with a clinical trial in October 2013 with 20 patients. 10 are going to receive stem-cell therapy for Type-2 diabetes and the other 10 will receive stem-cell therapy for emphysema. Chotinantakul's research is on Hematopoietic cells and their role for the hematopoietic system function in homeostasis and immune response.[114]

Today, Ukraine is permitted to perform clinical trials of stem-cell treatments (Order of the MH of Ukraine 630 "About carrying out clinical trials of stem cells", 2008) for the treatment of these pathologies: pancreatic necrosis, cirrhosis, hepatitis, burn disease, diabetes, multiple sclerosis, critical lower limb ischemia. The first medical institution granted the right to conduct clinical trials became the "Institute of Cell Therapy"(Kiev).

Other countries where doctors did stem cells research, trials, manipulation, storage, therapy: Brazil, Cyprus, Germany, Italy, Israel, Japan, Pakistan, Philippines, Russia, Switzerland, Turkey, United Kingdom, India, and many others.

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Stem-cell therapy - Wikipedia

Spinal Cord Stem Cells Comments Off on Stem-cell therapy – Wikipedia | November 2nd, 2016

The transplantation of neural stem/progenitor cells (NPCs) is a promising therapeutic strategy for spinal cord injury (SCI). However, to date NPC transplantation has exhibited only limited success in the treatment of chronic SCI. Here, we show that chondroitin sulfate proteoglycans (CSPGs) in the glial scar around the site of chronic SCI negatively influence the long-term survival and integration of transplanted NPCs and their therapeutic potential for promoting functional repair and plasticity. We targeted CSPGs in the chronically injured spinal cord by sustained infusion of chondroitinase ABC (ChABC). One week later, the same rats were treated with transplants of NPCs and transient infusion of growth factors, EGF, bFGF, and PDGF-AA. We demonstrate that perturbing CSPGs dramatically optimizes NPC transplantation in chronic SCI. Engrafted NPCs successfully integrate and extensively migrate within the host spinal cord and principally differentiate into oligodendrocytes. Furthermore, this combined strategy promoted the axonal integrity and plasticity of the corticospinal tract and enhanced the plasticity of descending serotonergic pathways. These neuroanatomical changes were also associated with significantly improved neurobehavioral recovery after chronic SCI. Importantly, this strategy did not enhance the aberrant synaptic connectivity of pain afferents, nor did it exacerbate posttraumatic neuropathic pain. For the first time, we demonstrate key biological and functional benefits for the combined use of ChABC, growth factors, and NPCs to repair the chronically injured spinal cord. These findings could potentially bring us closer to the application of NPCs for patients suffering from chronic SCI or other conditions characterized by the formation of a glial scar.

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Synergistic effects of transplanted adult neural stem ...

Spinal Cord Stem Cells Comments Off on Synergistic effects of transplanted adult neural stem … | September 27th, 2016

SAN FRANCISCO Researchers have successfully transplanted healthy human cells into mice with spinal cord injuries, bringing the world one step closer to easing the chronic pain and incontinence suffered by people with paralysis.

The research team did not focus on restoring the rodents ability to walk; rather, it helped remedy these two other debilitating side effects of spinal cord injury.

If successful in humans, thefindingscould someday ease the lives of those with these distressing conditions, said Dr. Arnold Kriegstein, co-senior author of the study and director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UC San Francisco. The research was published in Thursdays issue of the journal Cell Stem Cell.

This is a very important step, Kriegstein said. The treated animals improved in pain relief and bladder function.The research offers the promising potential of using a new therapeutic approach cell therapy to repair damaged neural tissue, showing that new cells can be integrated into an injured spinal cord.

A similar approach also has helped mice with epilepsy and Parkinsons disease.

More than aquarter of a million Americans live with spinal cord injuries, and 17,000 new cases occur each year, according to the National Spinal Cord Injury Statistical Center. More than half of those people go on to develop chronic pain in their limbs, called neuropathy. And nearly all develop bladder problems, which can result in kidney damage.

The spinal cord is the major highway for nerve cells to relay information between the brain and the rest of the body. When the spinal cord is injured, tears and inflammation harm surrounding cells.

The field has been very focused on restoring patients ability to walk, perhaps because thats often their most visible impairment, study co-authorLinda Noble-Haeusslein, a professor of physical therapy and rehabilitation at UCSF, said in a statement.

But a recent study showing that patients complained of pain and loss of bladder control more than paralysis suggested that we had really missed the boat as a field, she said. It caused us to dramatically shift what we do in the lab.

The cells used in the study, called neurons, were grown from human embryonic stem cells the bodys building blocks, capable of generating more than1,000 different types of adult cells.

They arent just any garden-variety neuron. These cells have the ability to inhibit, rather than excite, the neural network of the spine. Thats important because the pain and loss of bladder control are believed to be caused by overactivated neural circuits.

The healthy body keeps this excitable circuitry under control.But inflammation caused by a spinal cord injury causes a loss of this control.

The UCSF team grew the replacement cells in a South San Francisco biotech lab ofNeurona Therapeutics, founded by study co-authorCory Nicholasand Kriegstein, UCSFprofessor of developmental and stem cell biology. The company hopes to mass-produce these cells for use in future clinical trials.

They injected the young human cells into the spines of mice about two weeks afterinjury. They targeted the thoracic region about halfway up the spinal cord because thats a common site of injury for humans.But they were careful not to inject the young cells directly into the injured areas because that is a toxic place full of inflammation.

Remarkably, over the next six months the human cells matured, migrated toward the site of the injury and made connections with the spinal cords of the mice.

Compared to untreated mice, the treated rodents showed significantly less hypersensitivity to touch and painful stimuli and reduced abnormal scratching. Treated mice also had improved bladder function and produced more normal, voluntary patterns of urination in their cages.

A different research team is focusing on a fix for paralysis. This necessitatesa different strategy, requiring treatment with stem cell-derived neurons whose job it is to conduct electrical impulses down the spine. And these cells may face a more daunting environment if injected directly into injured areas.

The first trial by Geron Corp. stalled in late 2011, mostly because of financial concerns. But a Fremont-based biotech company calledAsterias Biotherapeutics, a subsidiary of BioTime, bought Gerons intellectual property and is continuing the research. It recently received approval fromthe U.S. Food and Drug Administration for a safety and early trial of the cells for treating spinal cord injury.

Meanwhile, the UCSF team is working to replicate their findings of improved bladder control and chronic pain. And they seek to learn the best time to inject the cells. Funders for the research included the National Institutes of Health and the California Institute of Regenerative Medicine.

The team is hoping to scale up their production of their specialized cells with the goal of entering human trials, after proving to the FDA that their effort is safe.

We are eager to move in that direction as quickly as we can, Kriegstein said.

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spinal cord injury, embryonic stem cells, paralysis, pain ...

Spinal Cord Stem Cells Comments Off on spinal cord injury, embryonic stem cells, paralysis, pain … | September 26th, 2016

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They suffer many complications in addition to paralysis and numbness and some of these problems are caused by a lack of the neurotransmitter GABA in the injured spinal cord.

A new University of California, San Francisco study in mice found human embryonic stem cells reduced two of the most severe side effects - incontinence and pain sensitivity.

Co-first author Assistant Professor Dr Cory Nicholas said: Chronic pain and bladder dysfunction remain significant quality-of-life issues for many people with spinal cord injuries.

Inhibitory cell-based neuro-therapy is a new approach and has shown promise to date in early animal studies, warranting further development."

The stem cell treatment differentiated into medial ganglionic eminence (MGE)-like cells, which produce GABA (gamma-Aminobutyric acid), an inhibitory neurotransmitter that is found throughout the central nervous system.

Our hope is that this treatment would last a long time, or maybe even be permanent

Dr Thomas Fandel

It plays an important role in reducing the excitability of neurons by binding to receptors that act on synapses.

Neuropathic pain and bladder dysfunction are at least in part attributed to overactive spinal cord circuits.

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Senior author Professor Dr Arnold Kriegstein said: We reasoned if we could take inhibitory neurons and directly place them into the spinal cord in the regions that are overactive, they might integrate into those circuits and suppress the activity.

In the study researchers used GABAergic inhibitory neuron precursors called MGE-like cells that were derived from human embryonic stem cells.

The neural precursor cells were placed into the spinal cords of mice two weeks after injury had been induced, where they could differentiate into GABA-producing neuron subtypes and form synaptic connections.

Co-author Dr Thomas Fandel, a research specialist at UCSF added: Rather than implanting these cells into the site of injury, at the mid-thoracic level, we injected them in the lumbosacral region, where the circuits are known to be overactive.

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Six months later we could see broad dispersion of the cells in that area. They were integrated into the spinal cord.

Tests showed the mice were not incontinent and had significantly reduced pain sensitivities.

Current treatments for neuropathic pain in people with spinal cord injuries most often involve opioids and other pain medications, as well as certain antidepressants, which have many side effects and tend to have limited efficacy.

Treatments for bladder dysfunction are often anticholinergics, but these drugs have side effects like dizziness and dry mouth.

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Botox may help with bladder spasms, but the benefits tend to be transient.

Dr Fandel added: The current approaches for treatment are not very effective and clearly more options are needed.

Our hope is that this treatment would last a long time, or maybe even be permanent.

The study was published in the journal Cell Stem Cell.

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Human stem cells could provide relief for spinal cord ...

Spinal Cord Stem Cells Comments Off on Human stem cells could provide relief for spinal cord … | September 26th, 2016

Engrafted NSPCs Form Presynaptic Connectivity with Spared Host Neurons after SCI (A) The gene expression levels of pan-presynaptic markers in engrafted NSPCs at 6weeks after transplantation, as determined by qRT-PCR, are shown (n= 8 mice per group). (B) Triple-staining for GFP (green), HU (blue), and the presynaptic marker BASSOON (red) at 6weeks after transplantation. The images showed that the engrafted NSPCs expressed BASSOON-positive synaptic boutons (arrowhead) in their axon terminals, which surrounded HU-positive host neurons. The right image is a magnification of the boxed area in the left image. (C) Quantification of the GFP/BASSOON-positive synaptic boutons in engrafted NSPCs is shown (n= 60 neurons; six mice per group). (D and E) The gene expression levels of inhibitory presynaptic markers (Vgat, Gad65, and Gad67) and excitatory presynaptic markers(Vglut1 and Vglut2) in engrafted NSPCs at 6weeks after transplantation, as determined by qRT-PCR, are shown (n= 8 mice per group). (F) Triple-staining for GFP (green), HU (blue), and the excitatory presynaptic marker VGLUT2 (red) at 6weeks after transplantation. The images showed that the GFP/VGLUT2-positive excitatory synaptic boutons (arrowhead) contacted HU-positive host neurons. The right image is a magnification of the boxed area in the left image. (G) Quantification of the GFP/VGLUT2-positive synaptic boutons in engrafted NSPCs is shown (n= 60 neurons; six mice per group). p< 0.05, p< 0.0001, Wilcoxon rank-sum test (A, C, D, E, and G). The data are presented as the means SEM. Scale bars, 20m (B and F) and 2m (insets).

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Engrafted Neural Stem/Progenitor Cells Promote Functional ...

Spinal Cord Stem Cells Comments Off on Engrafted Neural Stem/Progenitor Cells Promote Functional … | September 7th, 2016

3.1 Introduction

Figure 3.1 Schematic dorsal and lateral view of the spinal cord and four cross sections from cervical, thoracic, lumbar and sacral levels, respectively.

The spinal cord is the most important structure between the body and the brain. The spinal cord extends from the foramen magnum where it is continuous with the medulla to the level of the first or second lumbar vertebrae. It is a vital link between the brain and the body, and from the body to the brain. The spinal cord is 40 to 50 cm long and 1 cm to 1.5 cm in diameter. Two consecutive rows of nerve roots emerge on each of its sides. These nerve roots join distally to form 31 pairs of spinal nerves. The spinal cord is a cylindrical structure of nervous tissue composed of white and gray matter, is uniformly organized and is divided into four regions: cervical (C), thoracic (T), lumbar (L) and sacral (S), (Figure 3.1), each of which is comprised of several segments. The spinal nerve contains motor and sensory nerve fibers to and from all parts of the body. Each spinal cord segment innervates a dermatome (see below and Figure 3.5).

3.2 General Features

Although the spinal cord constitutes only about 2% of the central nervous system (CNS), its functions are vital. Knowledge of spinal cord functional anatomy makes it possible to diagnose the nature and location of cord damage and many cord diseases.

3.3 Segmental and Longitudinal Organization

The spinal cord is divided into four different regions: the cervical, thoracic, lumbar and sacral regions (Figure 3.1). The different cord regions can be visually distinguished from one another. Two enlargements of the spinal cord can be visualized: The cervical enlargement, which extends between C3 to T1; and the lumbar enlargements which extends between L1 to S2 (Figure 3.1).

The cord is segmentally organized. There are 31 segments, defined by 31 pairs of nerves exiting the cord. These nerves are divided into 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal nerve (Figure 3.2). Dorsal and ventral roots enter and leave the vertebral column respectively through intervertebral foramen at the vertebral segments corresponding to the spinal segment.

Figure 3.2 Drawing of the 8, 12, 5, 5 and 1 cervical, thoracic, lumbar, sacral and coccygeal spinal nerves and their exit from the vertebrate, respectively.

The cord is sheathed in the same three meninges as is the brain: the pia, arachnoid and dura. The dura is the tough outer sheath, the arachnoid lies beneath it, and the pia closely adheres to the surface of the cord (Figure 3.3). The spinal cord is attached to the dura by a series of lateral denticulate ligaments emanating from the pial folds.

Figure 3.3 The three spinal cord meninges. The denticulate ligament, the dorsal root ganglion (A), and an enlarged drawing of the meninges (B).

During the initial third month of embryonic development, the spinal cord extends the entire length of the vertebral canal and both grow at about the same rate. As development continues, the body and the vertebral column continue to grow at a much greater rate than the spinal cord proper. This results in displacement of the lower parts of the spinal cord with relation to the vertebrae column. The outcome of this uneven growth is that the adult spinal cord extends to the level of the first or second lumbar vertebrae, and the nerves grow to exit through the same intervertebral foramina as they did during embryonic development. This growth of the nerve roots occurring within the vertebral canal, results in the lumbar, sacral, and coccygeal roots extending to their appropriate vertebral levels (Figure 3.2).

All spinal nerves, except the first, exit below their corresponding vertebrae. In the cervical segments, there are 7 cervical vertebrae and 8 cervical nerves (Figure 3.2). C1-C7 nerves exit above their vertebrae whereas the C8 nerve exits below the C7 vertebra. It leaves between the C7 vertebra and the first thoracic vertebra. Therefore, each subsequent nerve leaves the cord below the corresponding vertebra. In the thoracic and upper lumbar regions, the difference between the vertebrae and cord level is three segments. Therefore, the root filaments of spinal cord segments have to travel longer distances to reach the corresponding intervertebral foramen from which the spinal nerves emerge. The lumbosacral roots are known as the cauda equina (Figure 3.2).

Each spinal nerve is composed of nerve fibers that are related to the region of the muscles and skin that develops from one body somite (segment). A spinal segment is defined by dorsal roots entering and ventral roots exiting the cord, (i.e., a spinal cord section that gives rise to one spinal nerve is considered as a segment.) (Figure 3.4).

Figure 3.4 (A) Drawing of the spinal cord with its spinal roots. (B) Drawing of the spinal vertebrate. (C) Section of the spinal cord, its meninges and the dorsal and ventral roots of three segments.

A dermatome is an area of skin supplied by peripheral nerve fibers originating from a single dorsal root ganglion. If a nerve is cut, one loses sensation from that dermatome. Because each segment of the cord innervates a different region of the body, dermatomes can be precisely mapped on the body surface, and loss of sensation in a dermatome can indicate the exact level of spinal cord damage in clinical assessment of injury (Figure 3.5). It is important to consider that there is some overlap between neighboring dermatomes. Because sensory information from the body is relayed to the CNS through the dorsal roots, the axons originating from dorsal root ganglion cells are classified as primary sensory afferents, and the dorsal root's neurons are the first order (1) sensory neuron. Most axons in the ventral roots arise from motor neurons in the ventral horn of the spinal cord and innervate skeletal muscle. Others arise from the lateral horn and synapse on autonomic ganglia that innervate visceral organs. The ventral root axons join with the peripheral processes of the dorsal root ganglion cells to form mixed afferent and efferent spinal nerves, which merge to form peripheral nerves. Knowledge of the segmental innervation of the cutaneous area and the muscles is essential to diagnose the site of an injury.

Figure 3.5 Innervation arising from single dorsal root ganglion supplied specific skin area (a dermatome). The numbers refer to the spinal segments by which each nerve is named C = cervical; T = thoracic; L = lumbar; S = sacral spinal cord segments (dermatome).

3.4 Internal Structure of the Spinal Cord

A transverse section of the adult spinal cord shows white matter in the periphery, gray matter inside, and a tiny central canal filled with CSF at its center. Surrounding the canal is a single layer of cells, the ependymal layer. Surrounding the ependymal layer is the gray matter a region containing cell bodies shaped like the letter H or a butterfly. The two wings of the butterfly are connected across the midline by the dorsal gray commissure and below the white commissure (Figure 3.6). The shape and size of the gray matter varies according to spinal cord level. At the lower levels, the ratio between gray matter and white matter is greater than in higher levels, mainly because lower levels contain less ascending and descending nerve fibers. (Figure 3.1 and Figure 3.6).

Figure 3.6 Spinal cord section showing the white and the gray matter in four spinal cord levels.

The gray matter mainly contains the cell bodies of neurons and glia and is divided into four main columns: dorsal horn, intermediate column, lateral horn and ventral horn column. (Figure 3.6).

The dorsal horn is found at all spinal cord levels and is comprised of sensory nuclei that receive and process incoming somatosensory information. From there, ascending projections emerge to transmit the sensory information to the midbrain and diencephalon. The intermediate column and the lateral horn comprise autonomic neurons innervating visceral and pelvic organs. The ventral horn comprises motor neurons that innervate skeletal muscle.

At all the levels of the spinal cord, nerve cells in the gray substance are multipolar, varying much in their morphology. Many of them are Golgi type I and Golgi type II nerve cells. The axons of Golgi type I are long and pass out of the gray matter into the ventral spinal roots or the fiber tracts of the white matter. The axons and dendrites of the Golgi type II cells are largely confined to the neighboring neurons in the gray matter.

A more recent classification of neurons within the gray matter is based on function. These cells are located at all levels of the spinal cord and are grouped into three main categories: root cells, column or tract cells and propriospinal cells.

The root cells are situated in the ventral and lateral gray horns and vary greatly in size. The most prominent features of the root cells are large multipolar elements exceeding 25 m of their somata. The root cells contribute their axons to the ventral roots of the spinal nerves and are grouped into two major divisions: 1) somatic efferent root neurons, which innervate the skeletal musculature; and 2) the visceral efferent root neurons, also called preganglionic autonomic axons, which send their axons to various autonomic ganglia.

The column or tract cells and their processes are located mainly in the dorsal gray horn and are confined entirely within the CNS. The axons of the column cells form longitudinal ascending tracts that ascend in the white columns and terminate upon neurons located rostrally in the brain stem, cerebellum or diencephalon. Some column cells send their axons up and down the cord to terminate in gray matter close to their origin and are known as intersegmental association column cells. Other column cell axons terminate within the segment in which they originate and are called intrasegmental association column cells. Still other column cells send their axons across the midline to terminate in gray matter close to their origin and are called commissure association column cells.

The propriospinal cells are spinal interneurons whose axons do not leave the spinal cord proper. Propriospinal cells account for about 90% of spinal neurons. Some of these fibers also are found around the margin of the gray matter of the cord and are collectively called the fasciculus proprius or the propriospinal or the archispinothalamic tract.

3.5 Spinal Cord Nuclei and Laminae

Spinal neurons are organized into nuclei and laminae.

3.6 Nuclei

The prominent nuclear groups of cell columns within the spinal cord from dorsal to ventral are the marginal zone, substantia gelatinosa, nucleus proprius, dorsal nucleus of Clarke, intermediolateral nucleus and the lower motor neuron nuclei.

Figure 3.7 Spinal cord nuclei and laminae.

Marginal zone nucleus or posterior marginalis, is found at all spinal cord levels as a thin layer of column/tract cells (column cells) that caps the tip of the dorsal horn. The axons of its neurons contribute to the lateral spinothalamic tract which relays pain and temperature information to the diencephalon (Figure 3.7).

Substantia gelatinosa is found at all levels of the spinal cord. Located in the dorsal cap-like portion of the head of the dorsal horn, it relays pain, temperature and mechanical (light touch) information and consists mainly of column cells (intersegmental column cells). These column cells synapse in cell at Rexed layers IV to VII, whose axons contribute to the ventral (anterior) and lateral spinal thalamic tracts. The homologous substantia gelatinosa in the medulla is the spinal trigeminal nucleus.

Nucleus proprius is located below the substantia gelatinosa in the head and neck of the dorsal horn. This cell group, sometimes called the chief sensory nucleus, is associated with mechanical and temperature sensations. It is a poorly defined cell column which extends through all segments of the spinal cord and its neurons contribute to ventral and lateral spinal thalamic tracts, as well as to spinal cerebellar tracts. The axons originating in nucleus proprius project to the thalamus via the spinothalamic tract and to the cerebellum via the ventral spinocerebellar tract (VSCT).

Dorsal nucleus of Clarke is a cell column located in the mid-portion of the base form of the dorsal horn. The axons from these cells pass uncrossed to the lateral funiculus and form the dorsal (posterior) spinocerebellar tract (DSCT), which subserve unconscious proprioception from muscle spindles and Golgi tendon organs to the cerebellum, and some of them innervate spinal interneurons. The dorsal nucleus of Clarke is found only in segments C8 to L3 of the spinal cord and is most prominent in lower thoracic and upper lumbar segments. The homologous dorsal nucleus of Clarke in the medulla is the accessory cuneate nucleus, which is the origin of the cuneocerebellar tract (CCT).

Intermediolateral nucleus is located in the intermediate zone between the dorsal and the ventral horns in the spinal cord levels. Extending from C8 to L3, it receives viscerosensory information and contains preganglionic sympathetic neurons, which form the lateral horn. A large proportion of its cells are root cells which send axons into the ventral spinal roots via the white rami to reach the sympathetic tract as preganglionic fibers. Similarly, cell columns in the intermediolateral nucleus located at the S2 to S4 levels contains preganglionic parasympathetic neurons (Figure 3.7).

Lower motor neuron nuclei are located in the ventral horn of the spinal cord. They contain predominantly motor nuclei consisting of , and motor neurons and are found at all levels of the spinal cord--they are root cells. The a motor neurons are the final common pathway of the motor system, and they innervate the visceral and skeletal muscles.

3.7 Rexed Laminae

The distribution of cells and fibers within the gray matter of the spinal cord exhibits a pattern of lamination. The cellular pattern of each lamina is composed of various sizes or shapes of neurons (cytoarchitecture) which led Rexed to propose a new classification based on 10 layers (laminae). This classification is useful since it is related more accurately to function than the previous classification scheme which was based on major nuclear groups (Figure 3.7).

Laminae I to IV, in general, are concerned with exteroceptive sensation and comprise the dorsal horn, whereas laminae V and VI are concerned primarily with proprioceptive sensations. Lamina VII is equivalent to the intermediate zone and acts as a relay between muscle spindle to midbrain and cerebellum, and laminae VIII-IX comprise the ventral horn and contain mainly motor neurons. The axons of these neurons innervate mainly skeletal muscle. Lamina X surrounds the central canal and contains neuroglia.

Rexed lamina I Consists of a thin layer of cells that cap the tip of the dorsal horn with small dendrites and a complex array of nonmyelinated axons. Cells in lamina I respond mainly to noxious and thermal stimuli. Lamina I cell axons join the contralateral spinothalamic tract; this layer corresponds to nucleus posteromarginalis.

Rexed lamina II Composed of tightly packed interneurons. This layer corresponds to the substantia gelatinosa and responds to noxious stimuli while others respond to non-noxious stimuli. The majority of neurons in Rexed lamina II axons receive information from sensory dorsal root ganglion cells as well as descending dorsolateral fasciculus (DLF) fibers. They send axons to Rexed laminae III and IV (fasciculus proprius). High concentrations of substance P and opiate receptors have been identified in Rexed lamina II. The lamina is believed to be important for the modulation of sensory input, with the effect of determining which pattern of incoming information will produce sensations that will be interpreted by the brain as being painful.

Rexed lamina III Composed of variable cell size, axons of these neurons bifurcate several times and form a dense plexus. Cells in this layer receive axodendritic synapses from A fibers entering dorsal root fibers. It contains dendrites of cells from laminae IV, V and VI. Most of the neurons in lamina III function as propriospinal/interneuron cells.

Rexed lamina IV The thickest of the first four laminae. Cells in this layer receive A axons which carry predominantly non-noxious information. In addition, dendrites of neurons in lamina IV radiate to lamina II, and respond to stimuli such as light touch. The ill-defined nucleus proprius is located in the head of this layer. Some of the cells project to the thalamus via the contralateral and ipsilateral spinothalamic tract.

Rexed lamina V Composed neurons with their dendrites in lamina II. The neurons in this lamina receive monosynaptic information from A, Ad and C axons which also carry nociceptive information from visceral organs. This lamina covers a broad zone extending across the neck of the dorsal horn and is divided into medial and lateral parts. Many of the Rexed lamina V cells project to the brain stem and the thalamus via the contralateral and ipsilateral spinothalamic tract. Moreover, descending corticospinal and rubrospinal fibers synapse upon its cells.

Rexed lamina VI Is a broad layer which is best developed in the cervical and lumbar enlargements. Lamina VI divides also into medial and lateral parts. Group Ia afferent axons from muscle spindles terminate in the medial part at the C8 to L3 segmental levels and are the source of the ipsilateral spinocerebellar pathways. Many of the small neurons are interneurons participating in spinal reflexes, while descending brainstem pathways project to the lateral zone of Rexed layer VI.

Rexed lamina VII This lamina occupies a large heterogeneous region. This region is also known as the zona intermedia (or intermediolateral nucleus). Its shape and boundaries vary along the length of the cord. Lamina VII neurons receive information from Rexed lamina II to VI as well as visceral afferent fibers, and they serve as an intermediary relay in transmission of visceral motor neurons impulses. The dorsal nucleus of Clarke forms a prominent round oval cell column from C8 to L3. The large cells give rise to uncrossed nerve fibers of the dorsal spinocerebellar tract (DSCT). Cells in laminae V to VII, which do not form a discrete nucleus, give rise to uncrossed fibers that form the ventral spinocerebellar tract (VSCT). Cells in the lateral horn of the cord in segments T1 and L3 give rise to preganglionic sympathetic fibers to innervate postganglionic cells located in the sympathetic ganglia outside the cord. Lateral horn neurons at segments S2 to S4 give rise to preganglionic neurons of the sacral parasympathetic fibers to innervate postganglionic cells located in peripheral ganglia.

Rexed lamina VIII Includes an area at the base of the ventral horn, but its shape differs at various cord levels. In the cord enlargements, the lamina occupies only the medial part of the ventral horn, where descending vestibulospinal and reticulospinal fibers terminate. The neurons of lamina VIII modulate motor activity, most probably via g motor neurons which innervate the intrafusal muscle fibers.

Rexed lamina IX Composed of several distinct groups of large a motor neurons and small and motor neurons embedded within this layer. Its size and shape differ at various cord levels. In the cord enlargements the number of motor neurons increase and they form numerous groups. The motor neurons are large and multipolar cells and give rise to ventral root fibers to supply extrafusal skeletal muscle fibers, while the small motor neurons give rise to the intrafusal muscle fibers. The motor neurons are somatotopically organized.

Rexed lamina X Neurons in Rexed lamina X surround the central canal and occupy the commissural lateral area of the gray commissure, which also contains decussating axons.

In summary, laminae I-IV are concerned with exteroceptive sensations, whereas laminae V and VI are concerned primarily with proprioceptive sensation and act as a relay between the periphery to the midbrain and the cerebellum. Laminae VIII and IX form the final motor pathway to initiate and modulate motor activity via , and motor neurons, which innervate striated muscle. All visceral motor neurons are located in lamina VII and innervate neurons in autonomic ganglia.

3.8 White Matter

Surrounding the gray matter is white matter containing myelinated and unmyelinated nerve fibers. These fibers conduct information up (ascending) or down (descending) the cord. The white matter is divided into the dorsal (or posterior) column (or funiculus), lateral column and ventral (or anterior) column (Figure 3.8). The anterior white commissure resides in the center of the spinal cord, and it contains crossing nerve fibers that belong to the spinothalamic tracts, spinocerebellar tracts, and anterior corticospinal tracts. Three general nerve fiber types can be distinguished in the spinal cord white matter: 1) long ascending nerve fibers originally from the column cells, which make synaptic connections to neurons in various brainstem nuclei, cerebellum and dorsal thalamus, 2) long descending nerve fibers originating from the cerebral cortex and various brainstem nuclei to synapse within the different Rexed layers in the spinal cord gray matter, and 3) shorter nerve fibers interconnecting various spinal cord levels such as the fibers responsible for the coordination of flexor reflexes. Ascending tracts are found in all columns whereas descending tracts are found only in the lateral and the anterior columns.

Figure 3.8 The spinal cord white matter and its three columns, and the topographical location of the main ascending spinal cord tracts.

Four different terms are often used to describe bundles of axons such as those found in the white matter: funiculus, fasciculus, tract, and pathway. Funiculus is a morphological term to describe a large group of nerve fibers which are located in a given area (e.g., posterior funiculus). Within a funiculus, groups of fibers from diverse origins, which share common features, are sometimes arranged in smaller bundles of axons called fasciculus, (e.g., fasciculus proprius [Figure 3.8]). Fasciculus is primarily a morphological term whereas tracts and pathways are also terms applied to nerve fiber bundles which have a functional connotation. A tract is a group of nerve fibers which usually has the same origin, destination, and course and also has similar functions. The tract name is derived from their origin and their termination (i.e., corticospinal tract - a tract that originates in the cortex and terminates in the spinal cord; lateral spinothalamic tract - a tract originated in the lateral spinal cord and ends in the thalamus). A pathway usually refers to the entire neuronal circuit responsible for a specific function, and it includes all the nuclei and tracts which are associated with that function. For example, the spinothalamic pathway includes the cell bodies of origin (in the dorsal root ganglia), their axons as they project through the dorsal roots, synapses in the spinal cord, and projections of second and third order neurons across the white commissure, which ascend to the thalamus in the spinothalamic tracts.

3.9 Spinal Cord Tracts

The spinal cord white matter contains ascending and descending tracts.

Ascending tracts (Figure 3.8). The nerve fibers comprise the ascending tract emerge from the first order (1) neuron located in the dorsal root ganglion (DRG). The ascending tracts transmit sensory information from the sensory receptors to higher levels of the CNS. The ascending gracile and cuneate fasciculi occupying the dorsal column, and sometimes are named the dorsal funiculus. These fibers carry information related to tactile, two point discrimination of simultaneously applied pressure, vibration, position, and movement sense and conscious proprioception. In the lateral column (funiculus), the neospinothalamic tract (or lateral spinothalamic tract) is located more anteriorly and laterally, and carries pain, temperature and crude touch information from somatic and visceral structures. Nearby laterally, the dorsal and ventral spinocerebellar tracts carry unconscious proprioception information from muscles and joints of the lower extremity to the cerebellum. In the ventral column (funiculus) there are four prominent tracts: 1) the paleospinothalamic tract (or anterior spinothalamic tract) is located which carry pain, temperature, and information associated with touch to the brain stem nuclei and to the diencephalon, 2) the spinoolivary tract carries information from Golgi tendon organs to the cerebellum, 3) the spinoreticular tract, and 4) the spino-tectal tract. Intersegmental nerve fibers traveling for several segments (2 to 4) and are located as a thin layer around the gray matter is known as fasciculus proprius, spinospinal or archispinothalamic tract. It carries pain information to the brain stem and diencephalon.

Descending tracts (Figure 3.9). The descending tracts originate from different cortical areas and from brain stem nuclei. The descending pathway carry information associated with maintenance of motor activities such as posture, balance, muscle tone, and visceral and somatic reflex activity. These include the lateral corticospinal tract and the rubrospinal tracts located in the lateral column (funiculus). These tracts carry information associated with voluntary movement. Other tracts such as the reticulospinal vestibulospinal and the anterior corticospinal tract mediate balance and postural movements (Figure 3.9). Lissauer's tract, which is wedged between the dorsal horn and the surface of the spinal cord carry the descending fibers of the dorsolateral funiculus (DFL), which regulate incoming pain sensation at the spinal level, and intersegmental fibers. Additional details about ascending and descending tracts are described in the next few chapters.

Figure 3.9 The main descending spinal cord tracts.

3.10 Dorsal Root

Figure 3.10 Spinal cord section with its ventral and dorsal root fibers and ganglion.

Information from the skin, skeletal muscle and joints is relayed to the spinal cord by sensory cells located in the dorsal root ganglia. The dorsal root fibers are the axons originated from the primary sensory dorsal root ganglion cells. Each ascending dorsal root axon, before reaching the spinal cord, bifurcates into ascending and descending branches entering several segments below and above their own segment. The ascending dorsal root fibers and the descending ventral root fibers from and to discrete body areas form a spinal nerve (Figure 3.10). There are 31 paired spinal nerves. The dorsal root fibers segregate into lateral and medial divisions. The lateral division contains most of the unmyelinated and small myelinated axons carrying pain and temperature information to be terminated in the Rexed laminae I, II, and IV of the gray matter. The medial division of dorsal root fibers consists mainly of myelinated axons conducting sensory fibers from skin, muscles and joints; it enters the dorsal/posterior column/funiculus and ascend in the dorsal column to be terminated in the ipsilateral nucleus gracilis or nucleus cuneatus at the medulla oblongata region, i.e., the axons of the first-order (1) sensory neurons synapse in the medulla oblongata on the second order (2) neurons (in nucleus gracilis or nucleus cuneatus). In entering the spinal cord, all fibers send collaterals to different Rexed lamina.

Axons entering the cord in the sacral region are found in the dorsal column near the midline and comprise the fasciculus gracilis, whereas axons that enter at higher levels are added in lateral positions and comprise the fasciculus cuneatus (Figure 3.11). This orderly representation is termed somatotopic representation.

Figure 3.11 Somatotopical representation of the spinal thalamic tract and the dorsal column.

3.11 Ventral Root

Ventral root fibers are the axons of motor and visceral efferent fibers and emerge from poorly defined ventral lateral sulcus as ventral rootlets. The ventral rootlets from discrete spinal cord section unite and form the ventral root, which contain motor nerve axons from motor and visceral motor neurons. The motor nerve axons innervate the extrafusal muscle fibers while the small motor neuron axons innervate the intrafusal muscle fibers located within the muscle spindles. The visceral neurons send preganglionic fibers to innervate the visceral organs. All these fibers join the dorsal root fibers distal to the dorsal root ganglion to form the spinal nerve (Figure 3.10).

3.12 Spinal Nerve Roots

The spinal nerve roots are formed by the union of dorsal and ventral roots within the intervertebral foramen, resulting in a mixed nerve joined together and forming the spinal nerve (Figure 3.10). Spinal nerve rami include the dorsal primary nerves (ramus), which innervates the skin and muscles of the back, and the ventral primary nerves (ramus), which innervates the ventral lateral muscles and skin of the trunk, extremities and visceral organs. The ventral and dorsal roots also provide the anchorage and fixation of the spinal cord to the vertebral cauda.

3.13 Blood Supply of the Spinal Cord

The arterial blood supply to the spinal cord in the upper cervical regions is derived from two branches of the vertebral arteries, the anterior spinal artery and the posterior spinal arteries (Figure 3.12). At the level of medulla, the paired anterior spinal arteries join to form a single artery that lies in the anterior median fissure of the spinal cord. The posterior spinal arteries are paired and form an anastomotic chain over the posterior aspect of the spinal cord. A plexus of small arteries, the arterial vasocorona, on the surface of the cord constitutes an anastomotic connection between the anterior and posterior spinal arteries. This arrangement provides uninterrupted blood supplies along the entire length of the spinal cord.

Figure 3.12 The spinal cord arterial circulation.

At spinal cord regions below upper cervical levels, the anterior and posterior spinal arteries narrow and form an anastomotic network with radicular arteries. The radicular arteries are branches of the cervical, trunk, intercostal & iliac arteries. The radicular arteries supply most of the lower levels of the spinal cord. There are approximately 6 to 8 pairs of radicular arteries supplying the anterior and posterior spinal cord (Figure 3.12).

Test Your Knowledge

The spinal cord...

A. Occupies the lumbar cistern

B. Has twelve (12) cervical segments

C. Contains the cell bodies of postganglionic sympathetic efferent neurons

D. Ends at the conus medullaris

E. Has no arachnoid membrane

The spinal cord...

A. Occupies the lumbar cistern This answer is INCORRECT.

The spinal cord does not occupy the lumbar cistern.

B. Has twelve (12) cervical segments

C. Contains the cell bodies of postganglionic sympathetic efferent neurons

D. Ends at the conus medullaris

E. Has no arachnoid membrane

The spinal cord...

A. Occupies the lumbar cistern

B. Has twelve (12) cervical segments This answer is INCORRECT.

The spinal cord has seven (7) cervical segments.

C. Contains the cell bodies of postganglionic sympathetic efferent neurons

D. Ends at the conus medullaris

E. Has no arachnoid membrane

The spinal cord...

A. Occupies the lumbar cistern

B. Has twelve (12) cervical segments

C. Contains the cell bodies of postganglionic sympathetic efferent neurons This answer is INCORRECT.

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Anatomy of the Spinal Cord (Section 2, Chapter 3 ...

Spinal Cord Stem Cells Comments Off on Anatomy of the Spinal Cord (Section 2, Chapter 3 … | November 2nd, 2015

An illustration of GRNOPC1, a drug based on human embryonic stem cells, which contains oligodendrocyte progenitor cells.

Geron/UC Irvine

The hope: that one day this treatment may help the paralyzed walk again.

On Friday at the Shepherd Center, a spinal cord and brain injury rehabilitation center in Atlanta, a patient with a recent spinal cord injury made medical history: The paraplegic was injected with two million embryonic stem cells.

The goal: To regenerate spinal cord tissue.

The process, reports CBS Station KPIX correspondent Dr. Kim Mulvihill, involves coaxing the cells into becoming specialized nerve cells, and then injecting them directly into the injured area of the spinal cord.

The embryonic stem cells come from a donated human embryo left over from a fertility treatment, an embryo that would have otherwise been discarded.

Embryonic stem cells have been at the center of funding controversies because the research involves destroying the embryos, which some have argued is akin to abortion. But, many researchers consider embryonic stem cells the most versatile types of stem cells, as they can morph into any type of cell.

While there are some restrictions on federal funding for stem cell lines for research, companies such as Geron do not use federal funding and are therefore free from those restrictions.

The study is approved by the FDA but is privately funded.

The drug - known as GRNOPC1 - contains cells called oligodendrocyte progenitor cells. Those progenitor cells turn into oligodendrocytes, a type of cell that produces myelin, a coating that allows impulses to move along nerves. When those cells are lost because of injury, paralysis can follow.

If GRNOPC1 works, the progenitor cells will produce new oligodendrocytes in the injured area of the patient's spine, potentially allowing for new movement.

The therapy will be injected into the patients' spines one to two weeks after they suffer an injury between their third and 10th thoracic vertebrae, or roughly the middle to upper back. Later trials would include patients with less severe spinal injuries and damage to other parts of the spine.

In lab animals, the results were dramatic - paralyzed rodents moved again.

Dr. Thomas Okarma, President and CEO of Geron, told CBS Station KPIX, "This therapy goes far beyond the reach of pills or scalpels and will achieve a new level of healing with a single injection of healthy replacement cells."

So far, Geron of Menlo Park, Calif., has spent $175 million in developing this treatment.

However, Dr. Arnold Kriegstein, who heads Regeneration Medicine & Stem Cell Research at University of California-San Francisco, told KPIX, "People are just so different from rodents."

Though optimistic, he urged caution. "I think that people looking at the outcome of this trial should really lower their expectations if they're really thinking people will get out of their wheelchairs. It's unlikely to happen."

The drug still faces many years of testing for effectiveness and tolerance if all goes well in the early stage study.

This initial trial is not aimed at a cure for patients, but to establish if the treatment is safe.

Patients must be treated within 14 days of a spinal cord injury and they must undergo short term immune suppression therapy to make sure their bodies don't reject the cells.

If the treatment is deemed safe, the next trial will aim at testing effectiveness and will use a higher quantity of stem cells.

Shepherd Center is one of seven potential sites in the United States for the trial.

The company has said it plans to enroll eight to 10 patients in the study at sites nationwide. The trial will take about two years, with each patient being studied for one year.

Geron is among several companies focusing on embryonic stem cell therapy. Advanced Cell Technology Inc. hopes to develop the embryonic stem cell therapy called retinal pigment epithelium, or RPE. That therapy is designed to treat Stargart disease, an inherited condition that affects children and can lead to blindness in adulthood.

Meanwhile, other companies such as StemCells Inc. are focusing on adult stem cells, which can be gathered from a person's skin.

For more info: clinicaltrials.goc - Safety Study of GRNOPC1 in Spinal Cord Injury

2010 CBS Interactive Inc. All Rights Reserved. This material may not be published, broadcast, rewritten, or redistributed. The Associated Press contributed to this report.

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Embryonic Stem Cell Test on Spinal Cord Injury - CBS News

Spinal Cord Stem Cells Comments Off on Embryonic Stem Cell Test on Spinal Cord Injury – CBS News | October 4th, 2015

Combined NSC transplantation and VPA administration improves functional recovery of hind limbs without CST axon reextension. As VPA has been shown to have effects that are likely to be beneficial to treatment of the injured CNS, such as neuroprotection (2731), induction of neuronal differentiation (26), and promotion of neurite outgrowth (32), we examined the response of SCI model mice to different combinations of VPA administration and NSC transplantation. We prepared NSCs from embryonic forebrains of 3 different Tg mouse lines ubiquitously expressing either GFP (GFP-Tg) (33), GFP and LUC (GFP.LUC-Tg), or GFP, LUC, and the diphtheria toxin (DT) receptor human heparin-binding EGF-like growth factor (TR6) (TR6.GFP.LUC-Tg) (see Methods). The expression of GFP, LUC, and TR6 in NSCs enabled us to distinguish transplanted cells from host cells, to trace the survival of transplanted cells based on LUC activity in a noninvasive fashion, and to specifically ablate transplanted cells (see below), respectively. To obtain a homogeneous population of NSCs, we used adherent monolayer culture (3436). The embryonic forebrains were dissociated and cultured with EGF and basic FGF (bFGF) (36) (Supplemental Figure 1, A and B; supplemental material available online with this article; doi:10.1172/JCI42957DS1). These cells uniformly expressed the stem cell markers Sox2 and nestin but did not express differentiation markers (Supplemental Figure 1, C and D). Under the appropriate conditions for each lineage, these NSCs differentiated into neurons, astrocytes, or oligodendrocytes (Supplemental Figure 1, E and F). NSCs from different Tg mice behaved similarly in these culture conditions (data not shown). NSCs that had been cultured and passaged 510 times in the presence of both EGF and bFGF to maintain the undifferentiated state were used for transplantation studies.

Undifferentiated NSCs were transplanted into the SCI epicenter 7 days after injury. Nontransplanted control and transplanted mice were then intraperitoneally administered VPA or saline daily for 7 days (Figure 1A), whereafter we monitored their hind limb motor function using the open field locomotor scale (BBB score) (79, 37) for 6 weeks. Remarkably, we found that the simultaneous treatment of SCI model mice with NSCs and VPA resulted in a dramatic recovery of hind limb function compared with either treatment alone (Figure 1B and Supplemental Videos 14). There were no significant differences among the data obtained from each SCI model mouse group transplanted with the 3 distinct NSCs. Functional recovery of each treated SCI model mouse reached a plateau at around 6 weeks, the level of which was sustained for more than 3 months. Since mice treated with VPA alone showed no further improvement compared with untreated mice, it is most likely that VPA affected the function of transplanted cells.

A combination of NSC transplantation and VPA administration improves functional recovery of hind limbs without CST axon reextension. (A) Schematic of the NSC transplantation and VPA injection protocol. (B) Time course of functional recovery of hind limbs after SCI. GFP-NSCs, GFP.LUC-NSCs, and TR6.GFP.LUC-NSCs were transplanted into the SCI epicenter 7 days after injury as indicated. Combined treatment with NSC transplantation and VPA administration resulted in the greatest functional recovery. Data represent mean SEM. **P < 0.001 compared with SCI models with no treatment; *P < 0.01 compared with SCI models with no treatment (repeated measures ANOVA). NSC+VPA, total n = 21. (C) Representative pictures of BDA-labeled CST fibers at 5 mm rostral and 5 mm caudal to the lesion site. BDA was injected into the motor cortices 12 weeks after SCI. 2 weeks after the injection, mice were fixed and spinal cord sections were stained. Representative results for a GFP-NSCtransplanted spinal cord are shown. Blue, Hoechst nuclear staining. Scale bar: 20 m. (D) Quantification of the labeled CST fibers in the spinal cords of intact mice, SCI mice receiving no treatment, and SCI mice undergoing combined NSC/VPA treatment. Eight 30-mthick serial parasagittal sections from individual spinal cords were evaluated. The x axis indicates specific locations along the rostrocaudal axis of the spinal cord, and the y axis indicates the ratio of the number of BDA-labeled fibers at the indicated site to that at 6 mm rostral to the lesion site (Th9). **P < 0.001 compared with SCI models without treatment; *P = 0.188 There is no significant difference in the number of BDA-labeled fibers between NSC+VPA-treated mice (blue line) and SCI model mice with no treatment (yellow line) (repeated measures ANOVA). All data shown are from at least 3 experiments in parallel conditions, with error bars representing SEM.

We next sought to determine the basis for this improvement in locomotor function. Since transplanted NSCs have been reported to play a supportive role in the reextension of injured axons (14), we analyzed whether CST axons were regenerated by anterograde labeling using biotinylated dextran amine (BDA) (6, 16, 17). Because BDA was injected into the motor cortex, only the axons of first-order neurons in the CST could be visualized (Figure 1C). In our SCI model mice, the caudal part of the injured site was completely devoid of CST axons (Figure 1, C and D), and the same was true in mice that had undergone combined NSC transplantation and VPA administration (Figure 1, C and D). These data indicated that CST axons did not reextend in mice treated with both NSCs and VPA and therefore that some other mechanism was responsible for the animals dramatic functional locomotor improvement.

Transplanted NSCs encompass the lesion site and extend their processes. Given that host CST axon reextension was not involved in the observed hind limb recovery, we decided to focus on the transplanted cells. We analyzed the migration, morphology, neuronal marker expression, and viability of these cells after coadministration with VPA. Transplant-derived cells migrated to both rostral and caudal areas and displayed processes that extended into the gray matter and dorsal funiculus within 5 weeks of transplantation (Figure 2). Between 20% and 40% of the transplanted cells were found to be surviving in the injured spinal cord after 8 weeks, and 17% still remained viable more than 1 year after transplantation (data not shown). About 20% of the surviving cells had differentiated into microtubule-associated protein 2positive (MAP2-positive) neurons with elongated processes within 5 weeks after transplantation (Figure 2, B and C, and Figure 3, E and F). Survival of the transplanted NSCs was not significantly influenced by VPA administration (Supplemental Figure 8).

Transplanted NSCs migrate from the injection site and encompass the lesion site. Representative results of GFP-NSCtransplanted SCI model mice are shown. (A) A series of immunostaining images of injured spinal cord at 6 weeks after injury. SCI mice received combination treatment with NSC transplantation and VPA administration. Specimens were picked up every 150 m and stained with anti-GFP (green) and MAP2 (not shown) antibodies and Hoechst (blue). The epicenter of the SCI is indicated (*). Scale bar: 1 mm. (B and C) Higher-magnification images of the white boxes in A. GFP-positive transplanted NSCs differentiated into MAP2-positive neurons and extended their processes. Scale bar: 50 m.

VPA promotes neuronal differentiation of transplanted NSCs. Representative results of GFP-NSCtransplanted SCI model mice are shown. (A) Confocal images of NSCs 1 week after transplantation into the injured spinal cords. Spinal cord sections from VPA-treated (+) and untreated () mice were stained with anti-GFP (green), anti-doublecortin (DCX) (immature neuronal marker, red) and anti-GFAP (magenta) antibodies, and Hoechst (blue). VPA administration resulted in an increase in the number of DCX-positive neuronal precursors among transplanted cells (lower panel). Scale bar: 20 m. (BD) The percentages of DCX-, GFAP-, and MBP-positive cells in GFP-positive transplanted cells were quantified. **P < 0.01; *P < 0.05 compared with controls (Students t test). (E) Confocal images of NSCs 5 weeks after transplantation into injured spinal cords. Spinal cord sections from VPA-treated (+) and untreated () mice were stained with anti-GFP (green), anti-MAP2 (neuronal marker, red) and anti-GFAP (magenta) antibodies, and Hoechst (blue). VPA administration increased the numbers of MAP2-positive neurons (lower panel). Scale bar: 20 m. (F and G) The percentages of cells positive for MAP2 or GFAP in GFP-positive transplanted cells in E were quantified. **P < 0.01; *P < 0.05 compared with control (Students t test). All data shown in BD, F, and G are from at least 15 confocal images of 3 individuals in parallel experiments, with error bars representing the SD.

HDAC inhibition promotes neuronal differentiation of NSCs and is critical for transplantation-induced hind limb recovery. In contrast to previous studies, which have indicated that very few transplanted NSCs differentiate into neurons in the injured CNS environment (8, 10, 11, 20), many neurons were observed in the spinal cord after coadministration with VPA. We next examined in more detail the contribution of VPA to differentiation of cultured and transplanted NSCs. To analyze differentiation in vitro, NSCs were treated with either VPA or valpromide (VPM), an amide analog of VPA that is also an antiepileptic but is not an HDAC inhibitor (24), under differentiation culture conditions. VPA enhanced histone acetylation (Supplemental Figure 2A) and promoted neuronal differentiation and neurite outgrowth of the NSCs (Supplemental Figure 3, AC); it also inhibited astrocytic and oligodendrocytic differentiation of NSCs (Supplemental Figure 3, DG). A different HDAC inhibitor, trichostatin A (TSA), also enhanced histone acetylation (Supplemental Figure 2A) and neuronal differentiation of NSCs (not shown) (26). In contrast, VPM neither enhanced histone acetylation nor induced neuronal differentiation, suggesting that HDAC inhibition has an important role in regulating fate determination in NSCs.

We then assessed the histone acetylation status and differentiation profiles of transplanted NSCs. VPA administration enhanced histone acetylation in transplanted cells in the spinal cord (Supplemental Figure 2, B and C). When we examined the differentiation status of transplanted cells 1 week after transplantation, neuronal but not glial differentiation was greatly enhanced by VPA administration (Figure 3, AD, and Supplemental Figure 4A). A similar differentiation tendency of transplanted NSCs to that at 1 week was observed at 5 weeks after transplantation: there was a dramatic increase in the number of cells positive for MAP2 (a relatively late differentiation marker of neurons in comparison with DCX) in VPA-administered mice (Figure 3, EG, and Supplemental Figure 4B). Furthermore, VPM administration to the SCI mice neither promoted neuronal differentiation nor enhanced hind limb motor function, suggesting that HDAC inhibition has an essential role in regulating fate determination of transplanted NSCs and improvement of motor function in vivo (Supplemental Figure 5, AC). In light of the above findings that the percentage of neurons generated from transplanted NSCs increased dramatically with VPA administration, whereas those of astrocytes and oligodendrocytes declined, we anticipated that these neurons would be likely to play a major role in regenerating the disrupted neuronal circuitry of the injured spinal cord.

Transplant-derived neurons reconstruct disrupted neuronal circuits in a relay manner. We next asked how the disrupted neuronal circuits were regenerated following the combined treatment with NSC transplantation and VPA administration. Wheat germ agglutinin (WGA), which can be transsynaptically transported, is one of the best known tracers of neural pathways (38). WGA protein can be transferred across synapses to second- and third-order neurons, permitting functional neuronal circuits to be tracked in the CNS. We injected WGA-expressing adenoviruses into the motor cortex of mouse brain 12 weeks after SCI. In uninjured mice, WGA was detected as intracellular granule-like structures in neurons localized in the ventral horn throughout the spinal cord (Figure 4, A and B). In untreated SCI model mice, WGA granules were almost completely absent from the caudal region below the injured site (Figure 4, A and C). Surprisingly, although we could not observe CST axonal reextension through the lesion site (Figure 1, C and D), WGA granules were clearly present in caudal large neurons located in the spinal cords of mice treated with both NSC and VPA (Figure 4, A and D). Intriguingly, moreover, transplant-derived neurons in or close to the lesion site contained WGA granules (Figure 4E), which were received from more rostral neurons. These data imply that WGA was conveyed through the lesion site to the caudal area via transplant-derived neurons. Considering this finding, together with the fact that WGA could be detected in caudal neurons without CST axonal reextension in mice that had undergone the combined treatment, it seemed conceivable that the transplant-derived neurons reconstructed the disrupted neuronal circuits, thereby acting as relays for transmitting signals between endogenous neurons whose interconnection had been abolished by the injury. In mice that received NSC transplantation alone after SCI, the percentage of WGA-positive cells among MAP2ab-positive cells in the caudal region was higher than that in untreated mice (Figure 4C) but lower than that in mice receiving combined NSC transplantation and VPA administration (Supplemental Figure 6), reflecting the degree of hind limb functional improvement (Figure 1C).

Transplant-derived neurons reconstruct disrupted neuronal circuits in a relay manner. (A) Representative pictures of WGA-labeled neuronal cell bodies located in the ventral horn at 14 weeks after SCI. Spinal cord sections were stained with anti-WGA (red) and -MAP2ab (magenta) antibodies and Hoechst (blue). Scale bar: 20 m. Intense WGA immunoreactivity was observed as intracellular granule-like structures. Left panels show the rostral area (Th4Th7), and right panels show the caudal area (Th11 to lumbar vertebra [L] 1). In uninjured mice, WGA injected into the bilateral motor cortices was transsynaptically transported to neurons in areas rostral and caudal to the injured site (top panels). In the SCI model mice that did not receive treatment, very little WGA was observed in caudal areas (middle panels). However, in spinal cords of animals that underwent dual treatment with NSC and VPA, WGA was clearly observed in neurons in the caudal areas (bottom panels). Representative results of GFP-NSCtransplanted SCI model mice are shown. (BD) The percentages of WGA-positive cells in the neurons localized in the ventral horn were quantified. **P < 0.05 (Students t test). All data shown are from at least 30 images, containing more than 600 cells, from 3 individuals (5 images per area) in parallel experiments, with error bars representing SD. (E) Representative confocal images of WGA-labeled transplant-derived MAP2-positive neurons. Sections were stained with anti-WGA (red), anti-MAP2ab (magenta) and anti-GFP (green) antibodies, and Hoechst (blue). Granule-like WGA structures (yellow arrowheads) could be seen in the GFP and MAP2abdouble-positive transplant-derived neurons. Scale bar: 10 m.

In support of the notion of a relay function for transplant-derived neurons, immunoelectron microscopy revealed that GFP-positive transplant-derived neurons received projections from endogenous neurons (Figure 5, A and B) and that the axon terminals of transplant-derived neurons made synapses with endogenous neurons localized in the ventral horn (Figure 5, CE).

Transplant-derived neurons make synapses with endogenous neurons. (A) Immunoelectron microscopy image of a sagittal section of dual-treated (GFP-NSC and VPA) injured spinal cord (rostral area). A GFP-positive dendrite (Den) made synapses with GFP-negative endogenous axon termini (At) (yellow arrowheads). Scale bar: 1 m. (B) In other rostral regions, a dendrite of a GFP-positive transplant-derived neuron made a synapse (yellow arrowheads) with the axon terminus of a GFP-negative endogenous neuron. Scale bar: 1 m. (C) Sagittal section of dual-treated (NSC and VPA) injured spinal cord (caudal area) stained with anti-GFP antibody (dark brown). The epicenter of the SCI is indicated (*). Scale bar: 500 m. (D) High-magnification image of a large neuron localized in the ventral horn in the white rectangle in C. GFP-positive transplanted neurons extended their processes toward an endogenous neuron (yellow arrowheads). Scale bar: 100 m. (E) Immunoelectron microscopy image of the boxed area in D. GFP-positive axon termini made synapses with the dendrite of a GFP-negative endogenous large neuron (yellow arrowheads). Scale bar: 1 m.

Transplanted cells contribute directly to functional recovery of hind limb movement in SCI mice. To determine whether the transplanted cells made a direct contribution to the functional recovery of hind limbs after SCI, we performed specific ablation of transplanted cells using the toxin receptormediated cell knockout (TRECK) method (Figure 6A and refs. 39, 40). For this purpose, we prepared NSCs from the embryonic forebrains of GFP.LUC Tg and TR6.GFP.LUC Tg mice (Figure 6A and Supplemental Figure 7, A and B). Almost all of the transplanted TR6.GFP.LUC-NSCs were specifically ablated following DT administration (Figure 6, B and C). Furthermore, after ablation of the transplanted cells, the BBB scores of SCI model mice that had undergone combined TR6.GFP.LUC-NSC transplantation and VPA administration declined rapidly to levels similar to those observed in untreated and VPA onlytreated mice. These results were superimposed on the graph in Figure 1B, with the observation period extended to 12 weeks after SCI, as shown in Figure 6D (for clarity, the data for GFP-NSC.VPA and GFP.LUC-NS in Figure 1B were removed). These data indicate that the transplanted cells, in the presence of VPA, made a direct and major contribution to the functional recovery of hind limb movement in SCI model mice.

Ablation of transplanted cells abolishes hind limb motor function recovery. (A) Schematic of the protocols for NSC transplantation and for detection and ablation of transplanted cells. NSCs derived from GFP.LUC- or TR6.GFP.LUC-Tg mice were transplanted into SCI model mice 1 week after injury. VPA was intraperitoneally administered every day for 1 week. Survival of transplanted cells and locomotor function of the mice were monitored weekly for 14 weeks. (B) Survival of transplanted cells was checked every week using a bioluminescence imaging system. 6 weeks after injury (5 weeks after transplantation), each mouse received 2 DT administrations. By the following week, LUC activity had completely disappeared in mice transplanted with TR6.GFP.LUC-NSCs (lower panel). (C) Sagittal sections from SCI model mice transplanted with GFP.LUC- and TR6.GFP.LUC-NSCs 2 weeks after DT injection. All transplanted cells were ablated with DT (lower panel). Scale bar: 1 mm. (D) Time course of the changes in BBB scores in SCI model mice. The hind limb function of mice that had undergone dual treatment with TR6.GFP.LUC-NSCs and VPA dropped drastically after DT administration (black line). *P < 0.0001 compared with GFP.LUC-NSCtransplanted, VPA-administered, and DT-injected SCI model mice (blue line) (repeated measures ANOVA). Data are mean SEM. VPA, n = 8; no treatment, n = 8. (E) Twelve weeks after injury, groups of SCI model mice received NMDA injections, as indicated, into the injury epicenter, to ablate local neurons in the gray matter (blue, black, and yellow lines with triangles). *P < 0.0001 compared with non-NMDAinjected mice in each group (blue, black, and yellow lines with circles) (repeated measures ANOVA). Data represent mean SEM.

Both endogenous and transplant-derived local neurons play an important role in improving hind limb motor function. It has been shown recently that local neurons in the spinal cord play an important role in spontaneous functional recovery after SCI (41, 42). In our SCI model, we also observed slight but significant spontaneous recovery of hind limb function in untreated mice, and similar levels of recovery were sustained after ablation of transplanted cells (Figure 6D). We thus hypothesized that these recoveries were attributable to endogenous local neurons in the spinal cord. Furthermore, it seemed likely that the much higher recovery observed in mice with the combined treatment but without cell ablation (Figure 6D) was effected by transplant-derived local neurons in addition to the endogenous ones. To evaluate the involvement of these local neurons in our treatment regime, we divided each treated mouse group analyzed in Figure 6D into 2 subgroups (except for the TR6.GFP.LUC-NCStransplanted only and VPA-administered only groups). The axon-sparing excitotoxin NMDA was injected at 12 weeks after SCI into the injury epicenter in the injured spinal cords of the mice in 1 subgroup for each treatment to ablate local neurons in the gray matter (4345). In uninjured mice, NMDA injections had no significant effect on hind limb function (data not shown). However, as shown in Figure 6E, NMDA injections completely reversed both spontaneous and treatment-provoked functional recovery of hind limb movement in SCI model mice, indicating that both endogenous and transplant-derived local neurons indeed play an important role in the restoration of hind limb motor function.

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JCI - Neurons derived from transplanted neural stem cells ...

Spinal Cord Stem Cells Comments Off on JCI – Neurons derived from transplanted neural stem cells … | September 25th, 2015

Ankylosing Spondilytis, is a kind of inflammatory, autoimmune disorder of unknown etiology primarily affecting the spine, axial skeleton and large proximal joints of the body, this may inturn lead to eventual fusion of the spine.It can rage from mild to progressively degenerating diseases.

Although autoimmune, 90% of the patients suffering from the condition have proved to express the presence of HLA-B27 geneotype, confirming the genetic association of the disorder. Estimates may vary but it is observed that young men between the age group 20-40 are affected. The characterization of AS is done various symptoms, three of them occur most generally and they are pain, stiffness,excessive fatigue etc. Although the symptoms are very generalized there are some telltale conditions such as severe back pain.

The current treatments include severe physiotherapy, medication and other rehabilitation approach. However with these treatment regimen the pathophysiology of the disease is not reversed neither the further progression is stopped. On the contrary, the cutting edge stem cell treatment can offer the solution for the condition. Stem cells are the original, naive cells capable of forming any cells of the same or different lineage.

Ankylosing Spondilytis is a kind of arthritis mainly affecting the spine, but sometimes other organs are also involved.

Mentioned below is case analysis of a patient who had been suffering from Ankylosing Spondilytis. And at a young age of 25 years, he was unable to walk. Now after stem cells treatment he has started walking and his quality of life has improved.

Case Study

Name of the patient:- Rahul (name is changed for privacy reasons)

Disease: Ankylosing Spondilytis

Rahul was suffering from Ankylosing Spondilytis since past 14 years. Painful joints, restricted movements and stiffness in the body was his way of life. Although Rahul doesn't have any family history of joint diseases.

Rahul's symptoms started with sudden onset of the back pain, which went on to be severe with the whole body aches, upto the extent that he could hardly walk or if he could, he started walking like an old man. Although the initial X ray analysis showed nothing, may be because practically it take several years to show changes associated with the spine. Consequently Rahul had to visit rheumatologists, who confirmed after almost 3 years that he is suffering from AS. His treatment regimen involved diet plan, some oral medications and restricted sports activities.

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Spinal Cord Injury Treatment, Stem Cell Therapy For Spinal ...

Spinal Cord Stem Cells Comments Off on Spinal Cord Injury Treatment, Stem Cell Therapy For Spinal … | August 1st, 2015

Characterization of isolated human SHEDs and DPSCs for use in transplantation studies. Flow cytometry analysis showed that the SHEDs and DPSCs expressed a set of mesenchymal stem cell (MSC) markers (i.e., CD90, CD73, and CD105), but not endothelial/hematopoietic markers (i.e., CD34, CD45, CD11b/c, and HLA-DR) (Table 1). Like human BMSCs, both the SHEDs and DPSCs exhibited adipogenic, chondrogenic, and osteogenic differentiation as described previously (refs. 16, 17, and data not shown). The majority of SHEDs and DPSCs coexpressed several neural lineage markers: nestin (neural stem cells), doublecortin (DCX; neuronal progenitor cells), III-tubulin (early neuronal cells), NeuN (mature neurons), GFAP (neural stem cells and astrocytes), S-100 (Schwann cells), and A2B5 and CNPase (oligodendrocyte progenitor cells), but not adenomatous polyposis coli (APC) or myelin basic protein (MBP) (mature oligodendrocytes) (Figure 1A and Table 1). This expression profile was confirmed by immunohistochemical analyses (Figure 1B).

Characterization of the SHEDs and DPSCs used for transplantation. (A) Flow cytometry analysis of the neural cell lineage markers expressed in SHEDs. Note that most of the SHEDs and DPSCs coexpressed neural stem and multiple progenitor markers, but not mature oligodendrocytes (APC and MBP). (B) Confocal images showing SHEDs coexpressed nestin, GFAP, and DCX. SHEDs also expressed markers for oligodendrocyte progenitor cells (A2B5 and CNPase), but not for mature oligodendrocytes (APC and MBP). Scale bar: 10 m. (C) Real-time RT-PCR analysis of the expression of neurotrophic factors. Results are expressed as fold increase compared with the level expressed in skin fibroblasts. Data represent the average measurements for each cell type from 3 independent donors. This set of experiments was repeated twice and yielded similar results. Data represent the mean SEM. *P < 0.01 compared with BMSCs and fibroblasts (Fbs).

Flow cytometry of stem cells from humans

Next, we examined the expression of representative neurotrophic factors by real-time PCR. Both the SHEDs and DPSCs expressed glial cellderived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF) at more than 3 to 5 times the levels expressed by skin-derived fibroblasts or BMSCs (Figure 1C).

We further characterized the transcriptomes of SHEDs and BMSCs by cDNA microarray analysis. This gene expression analysis revealed a 2.0-fold difference in the expression of 3,318 of 41,078 genes between SHEDs and BMSCs. Of these, 1,718 genes were expressed at higher levels in the SHEDs and 1,593 genes were expressed at lower levels (data not shown). The top 30 genes showing higher expression in the SHEDs were in the following ontology categories: extracellular and cell surface region, cell proliferation, and tissue/embryonic development (Table 2).

Functional gene classification in SHEDs versus BMSCs

SHEDs and DPSCs promoted locomotor recovery after SCI. To compare the neuroregenerative activities of human SHEDs and DPSCs with those of human BMSCs and human skin fibroblasts, we transplanted the cells into the completely transected SCs, as described in Methods, and evaluated locomotion recovery using the Basso, Beattie, Bresnahan locomotor rating scale (BBB scale) (24). Remarkably, the animals that received SHEDs or DPSCs exhibited a significantly higher BBB score during the entire observation period, compared with BMSC-transplanted, fibroblast-transplanted, or PBS-injected control rats (Figure 2A). Importantly, their superior recoveries were evident soon after the operation, during the acute phase of SCI. After the recovery period (5 weeks after the operation), the rats that had received SHEDs were able to move 3 joints of hind limb coordinately and walk without weight support (P < 0.01; Supplemental Videos 1 and 2), while the BMSC- or fibroblast-transplanted rats exhibited only subtle movements of 12 joints. These results demonstrate that the transplantation of SHEDs or DPSCs during the acute phase of SCI significantly improved the recovery of hind limb locomotor function. Since the level of recovery was similar in the SHED- and DPSC-transplanted rats, we focused on the phenotypical examination of SHED-transplanted rats to elucidate how tooth-derived stem cells promoted the regeneration of the completely transected rat SC.

Engrafted SHEDs promote functional recovery of the completely transected SC. (A) Time course of functional recovery of hind limbs after complete transection of the SC. A total of 1 106 SHEDs, DPSCs, BMSCs, or fibroblasts were transplanted into the SCI immediately after transection. Data represent the mean SEM. **P < 0.001, *P < 0.01 compared with SCI models injected with PBS. (BD) Representative images (B and C) and quantification (D) of NF-Mpositive nerve fibers in sagittal sections of a completely transected SC, at 8 weeks after SCI. Dashed lines outline the SC. Insets are magnified images of boxed areas in B and C. (D) Nerve fiber quantification, representing the average of 3 experiments performed under the same conditions. The x axis indicates specific locations along the rostrocaudal axis of the SC (3 mm rostral and caudal to the epicenter), and y axis indicates the percentage of NF-Mpositive fibers compared with that of the sham-operated SCs at the ninth thoracic spinal vertebrate (Th9) level. Data represent the mean SEM. *P < 0.05 compared with SCI models injected with PBS. Scale bars: 100 m and inset 20 m (B) and 50 m (C). Asterisks in B and C indicate the epicenter of the lesion.

SHEDs regenerated the transected corticospinal tract and raphespinal serotonergic axons. To examine whether engrafted SHEDs affect the preservation of neurofilaments, we performed immunohistochemical analyses with an antineurofilament M (NF-M) mAb, 8 weeks after transection. Compared with the PBS-treated control SCs, the SHED-transplanted SCs exhibited greater preservation of NF-positive axons from 3 mm rostral to 3 mm caudal to the transected lesion site (Figure 2, B and C; asterisk indicates epicenter). The percentages of NF-positive axons in the epicenter of the SHED-transplanted and control SCs were 35.8% 13.0% and 8.7% 3.4%, respectively, relative to sham-treated SCs (Figure 2D).

Regeneration of both the corticospinal tract (CST) and the descending serotonergic raphespinal axons is important for the recovery of hind limb locomotor function in rat SCI. We therefore examined whether these axons had extended beyond the epicenter in the SHED-transplanted SCs. The CST axons were traced with the anterograde tracer biotinylated dextran amine (BDA), which was injected into the sensorimotor cortex. The serotonergic raphespinal axons were immunohistochemically detected by a mAb that specifically reacts with serotonin (5-hydroxytryptamine [5-HT]), which is synthesized within the brain stem. We found that both BDA- and 5-HTpositive fibers extended as far as 3 mm caudal to the epicenter in the SHED-transplanted but not the control group (Figures 3 and 4). Furthermore, some BDA- and 5-HTpositive boutons could be seen apposed to neurons in the caudal stump (Figure 3D and Figure 4C), suggesting that the regenerated axons had established new neural connections. Notably, although the number of descending axons extending beyond the epicenter was small, we observed many of them penetrating the scar tissue of the rostral stump (Figure 3A and Figure 4A). The percentages of 5-HTpositive axons of the SHED-transplanted SCs at 1 and 3 mm rostral to the epicenter were 58.9% 3.9% and 78.3% 7.4% relative to sham-treated SC, respectively (Figure 4D). These results demonstrate that the engrafted SHEDs promoted the recovery of hind limb locomotion via the preservation and regeneration of transected axons, even in the microenvironment of the damaged CNS.

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Human Dental Pulp-Derived Stem Cells Promote Locomotor ...

Spinal Cord Stem Cells Comments Off on Human Dental Pulp-Derived Stem Cells Promote Locomotor … | July 17th, 2015

World J Stem Cells. 2014 Apr 26; 6(2): 120133.

Venkata Ramesh Dasari, Krishna Kumar Veeravalli, Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, United States

Dzung H Dinh, Department of Neurosurgery and Illinois Neurological Institute, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, United States

Correspondence to: Dzung H Dinh, MD, Department of Neurosurgery and Illinois Neurological Institute, University of Illinois College of Medicine at Peoria, One Illini Drive, Peoria, IL 61605, United States. ude.ciu@hnidd

Telephone: +1- 309-6552642 Fax: +1-309-6713442

Received 2013 Oct 30; Revised 2014 Feb 19; Accepted 2014 Mar 11.

With technological advances in basic research, the intricate mechanism of secondary delayed spinal cord injury (SCI) continues to unravel at a rapid pace. However, despite our deeper understanding of the molecular changes occurring after initial insult to the spinal cord, the cure for paralysis remains elusive. Current treatment of SCI is limited to early administration of high dose steroids to mitigate the harmful effect of cord edema that occurs after SCI and to reduce the cascade of secondary delayed SCI. Recent evident-based clinical studies have cast doubt on the clinical benefit of steroids in SCI and intense focus on stem cell-based therapy has yielded some encouraging results. An array of mesenchymal stem cells (MSCs) from various sources with novel and promising strategies are being developed to improve function after SCI. In this review, we briefly discuss the pathophysiology of spinal cord injuries and characteristics and the potential sources of MSCs that can be used in the treatment of SCI. We will discuss the progress of MSCs application in research, focusing on the neuroprotective properties of MSCs. Finally, we will discuss the results from preclinical and clinical trials involving stem cell-based therapy in SCI.

Keywords: Spinal cord injury, Mesenchymal stem cells, Bone marrow stromal cells, Umbilical cord derived mesenchymal stem cells, Adipose tissue derived mesenchymal stem cells

Core tip: Despite our deeper understanding of the molecular changes that occurs after the spinal cord injury (SCI), the cure for paralysis remains elusive. In this review, the pathophysiology of SCI and characteristics and potential sources of mesenchymal stem cells (MSCs) that can be used in the treatment of SCI were discussed. We also discussed the progress of application of MSCs in research focusing on the neuroprotective properties of MSCs. Finally, we discussed the results from preclinical and clinical trials involving stem cell-based therapy in SCI.

Traumatic spinal cord injury (SCI) continues to be a devastating injury to affected individuals and their families and exacts an enormous financial, psychological and emotional cost to them and to society. Despite years of research, the cure for paralysis remains elusive and current treatment is limited to early administration of high dose steroids and acute surgical intervention to minimize cord edema and the subsequent cascade of secondary delayed injury[1-3]. Recent advances in neurosciences and regenerative medicine have drawn attention to novel research methodologies for the treatment of SCI. In this review, we present our current understanding of spinal cord injury pathophysiology and the application of mesenchymal stem cells (MSCs) in the treatment of SCI. This review will be more useful for basic and clinical investigators in academia, industry and regulatory agencies as well as allied health professionals who are involved in stem cell research.

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Mesenchymal stem cells in the treatment of spinal cord ...

Spinal Cord Stem Cells Comments Off on Mesenchymal stem cells in the treatment of spinal cord … | July 13th, 2015