Positive Results from Phase 2 Study in Spinal Cord Injury


Stem Cells, Inc., has released the six-month results from cohort I of an ongoing Phase 2 clinical trial of human neural stem cells for the treatment of chronic cervical spinal cord injuries. The data displayed significant improvements in muscle strength had occurred in five of the six patients treated. Of these five patients, four of them also showed improved performance on functional tasks that assesses dexterity and fine motor skills. Furthermore, these four patients improved in the level of spinal cord injury according to the classification system provided by the International Standards for Neurological Classification of Spinal Cord Injury or ISNCSCI.

Stem Cells, Inc., expects to release their detailed final 12-month results on this first open-cohort later this quarter.

Chief medical officer, Stephen Huhn, presented these data at the American Spinal Injury Association annual meeting in Philadelphia, on Friday, April 15.  Dr. Huhn also believes that the interim results are very encouraging and reason to be quite hopeful.

“The emerging data continue to be very encouraging,” said Dr. Huhn. “We believe that these types of motor changes will improve the independence and quality of life of patients and are the first demonstration that a cellular therapy has the ability to impact recovery in chronic spinal cord injury. We currently have thirteen sites in the United States and Canada that are actively recruiting patients. We have enrolled and randomized 19 of the 40 total patients in the statistically powered, single-blind, randomized controlled, Cohort II. We are projecting to complete enrollment by the end of September so that we can have final results in 2017.”

The present Phase 2 clinical trial is a multi-center enterprise that includes physicians and scientists at 13 different sites in the united States and Canada. Incidentally, these sites are presently actively recruiting patients.

Stem Cells, Inc., has enrolled and randomized 19 of the 40 total patients in this statistically powered, single-blind, randomized controlled, cohort II.

The Phase 2 study, “Study of Human Central Nervous System (CNS) Stem Cell Transplantation in Cervical Spinal Cord Injury,” will determine the safety and efficacy of transplanting the company’s proprietary human neural stem cells (HuCNS-SC cells) into patients with traumatic injury of the cervical region of the spinal cord.

Cohort I is an open label dose-ranging cohort in six AIS-A or AIS-B subjects. For those of you not familiar with the American Spinal Injury Impairment Scale (ASI A-E scale), here is a summary of the classification scheme:

ASI – A = Complete paralysis; No sensory or motor function is preserved in the sacral segments S4-5.
ASI – B = Sensory Incomplete; Sensory but not motor function is preserved below the neurological level and includes the sacral segments S4-5 (light touch or pin prick at S4-5 or deep anal pressure) AND no motor function is preserved more than three levels below the motor level on either side of the body.
ASI – C = Motor Incomplete; Motor function is preserved below the neurological level**, and more than half of key muscle functions below the neurological level of injury (NLI) have a muscle grade less than 3 (Grades 0-2).
ASI – D = Motor Incomplete; Motor function is preserved below
the neurological level**, and at least half (half or more) of key muscle functions below the NLI have a muscle grade > 3.
ASI – E = Normal; If sensation and motor function as tested with the ISNCSCI are graded as normal in all segments, and the patient had prior deficits, then the AIS grade is E. Someone without an initial SCI does not receive an AIS grade.
Cohort II is a randomized, controlled, single-blinded cohort in forty AIS-B subjects. Cohort III, which will only be conducted at the discretion of the sponsor, is an open-label arm that involves six AIS-C subjects.
The primary efficacy outcome will focus on changes in the upper extremity strength as measured in the hands, arms, and shoulders.  This trial will enroll up to 52 subjects.
StemCells, Inc. has demonstrated the safety and efficacy of their HuCNS-SC cell in preclinical studies in laboratory rodents.  Additional Phase I studies yielded positive human safety data.  Furthermore, completed and ongoing clinical studies in which its proprietary HuCNS-SC cells have been transplanted directly into all three components of the central nervous system: the brain, the spinal cord and the retina of the eye, have further demonstrated the safety of HuCNS SC cells in human patients.
StemCells, Inc. clinicians and scientists believe that HuCNS-SC cells may have broad therapeutic application for many diseases and disorders of the CNS. Because the transplanted HuCNS-SC cells have been shown to engraft and survive long-term, there is the possibility of a durable clinical effect following a single transplantation.
The HuCNS-SC platform technology is a highly purified composition of human neural stem cells (tissue-derived or “adult” stem cells). Manufactured under cGMP standards, the Company’s HuCNS-SC cells are purified, expanded in culture, cryopreserved, and then stored as banks of cells, ready to be made into individual patient doses when needed.

Stem Cell-Based Spinal Cord Repair Enables Robust Corticospinal Regeneration


In the March 28th, 2016 issue of the journal Nature Medicine, Mark Tuszynski and his colleagues from the University of California, San Diego, in collaboration with colleagues from Japan and Wisconsin, report that they were able to successfully coax stem cell-derived neurons to regenerate damaged corticospinal tracts in rats. Furthermore, this regeneration produced observable, functional benefits.

What is the “corticospinal tract” you ask? The corticospinal tracts are part of the “pyramidal tracts” that include the corticospinal and corticobulbar tracts. The pyramidal tracts are the main controllers of voluntary movement and connect their nerve fibers eventually to cells that serve voluntary muscles and allow them to contract. We call such nerves “motor nerves,” and the corticospinal nerve tracts are among the most important of the motor nerve tracts.

These neural tracts are collectively called “pyramidal tracts” because they pass through a small area of the brain stem known as the pyramids, which lie on the ventral side of the medulla oblongata. Both pyramidal tracts originate in the forebrain; specifically from the so-called “motor cortex” of the forebrain. The motor cortex lies just in front of the central sulcus of the forebrain. In the motor cortex, lies thousands of “upper motor neurons” that extend their axons down to the brain stem and spinal cord.

Forebrain areas

In the brain stem, the majority of these corticospinal tracts crossover (or decussate) to the other side of the brain stem and travel down the opposite side of the spinal cord. The corticospinal axons extend all the way down the spinal cord, until they make a connection (synapse) with a “lower motor neuron” that extends its axon to the skeletal muscles that it will direct to contract. The corticobulbar tract contains nerves that conduct nerve impulses from cranial nerves and these help the muscles of the face and neck contract, and are involved in facial expressions, swallowing, chewing, and so on.

Corticospinal tracts

Damage to the upper motor neurons as a result of a stroke can rob a person of the ability to move, since the muscles that are attached to the upper motor neurons cannot receive any signals to contract. Likewise, damage to the axonal tracts (also known as nerve fibers) can paralyze a patient and rob them of their ability to move.

The director of this research project, Mark Tuszynski, MD, PhD, professor in the UC San Diego School of Medicine Department of Neurosciences and director of the UC San Diego Translational Neuroscience Institute, said: “The corticospinal projection is the most important motor system in humans. It has not been successfully regenerated before. Many have tried, many have failed – including us, in previous efforts.”

Dr. Tuszynski continued, “The new thing here was that we used neural stem cells for the first time to determine whether they, unlike any other cell type tested, would support regeneration. And to our surprise, they did.”

In this experiment, Tuszynski, and his colleagues and collaborators used rats that had suffered spinal cord injuries and had trouble moving their forelimbs. Then they implanted grafted multipotent neural progenitor cells (MNPCs) into those sites within the spinal cord that had suffered injury, where corticospinal axonal tracts had been severed or damaged. The MNPCs had been previously treated to differentiate into spinal cord-specific motor neurons. Fortunately, the MNPCs prodigiously formed lower motor neurons that made good, solid, functional synapses with interneurons and upper motor neurons that improved forelimb movements in the rats. This work put the lie to previous beliefs about corticospinal neurons; namely that they lacked any of the internal mechanisms required to regenerate severed or damaged connections.

Even though several previous studies have demonstrated functional recovery in spinal cord-injured rats through the use of stem cell-based treatments, none of these studies has convincingly demonstrated regeneration of corticospinal axons.

“We humans use corticospinal axons for voluntary movement,” said Tuszynski. “In the absence of regeneration of this system in previous studies, I was doubtful that most therapies taken to humans would improve function. Now that we can regenerate the most important motor system for humans, I think that the potential for translation is more promising.”

This is certainly exciting work, but even though it worked in rats, it may not yet work in humans. The road from pre-clinical studies in animals to clinical trials in humans is a long, tedious, frustrating, and uncertain pathway, pockmarked with the failures of past therapies that worked well in animals but failed to translate into successes in human patients.

“There is more work to do prior to moving to humans,” Tuszynski said. We must establish long-term safety and long-term functional benefit in animals. We must devise methods for transferring this technology to humans in larger animal models. And we must identify the best type of human neural stem cell to bring to the clinic.”

Combination of Mesenchymal Stem Cells and Schwann Cells Used to Treat Spinal Cord Injury


Spinal cord injuries represent an immensely difficult problem for regenerative medicine. The extensive nature of the damage to the spinal cord is difficult to repair, and the transformation that the injury wrecks in the spinal cord makes the spinal cord inhospitable to cellular repair.

Fortunately some headway is being made, and several clinical trials have shown some success with particular stem cells. Neural stem cells can differentiate into new neurons and glial cells and replace dead or damaged cells (see Tsukamoto A., et Al., Stem Cell Res Ther 4,102, 2013 ). Oligodendrocyte progenitor cells (OPCs) derived from embryonic stem cells or other sources can replace the myelin sheath that died off as a result of the injury (Alsanie WF, Niclis JC, Petratos S. Stem Cells Dev. 2013 Sep 15;22(18):2459-76).  Olfactory ensheathing cells can move across the glial scar and facilitate the regrowth of severed axons across the scar (Tabakow P, et al., Cell Transplant. 2014;23(12):1631-55). Mesenchymal stem cells can mitigate the inflammation in the damaged spinal cord, and, maybe, stimulate endogenous stem cell populations to repair the spinal cord (Geffner L.F., et al., Cell Transplant 17,1277, 2008). Therefore, several cell types seem to have some ability to heal the damaged spinal cord.

A new clinical trial from the Zali laboratory at Shahid Beheshti University of Medical Sciences, in Tehran, Iran, has examined the used of two different stem cells to treat spinal cord injury patients. This trial was a small, Phase I trial that only tested the safety of these treatments.

Zali and his colleagues assessed the safety and feasibility of transplanting a combination of bone marrow mesenchymal stem cells (MSCs) and Schwann cells (SCs) into the cerebral spinal fluid (CSF) of patients with chronic spinal cord injury. SCs are cells that insulate peripheral nerves with a myelin sheath. Even though SCs are not found in the central nervous system, they do the same job as oligodendrocytes, and several experiments have shown that when transplanted into the central nervous system, SCs can do the job of oligodendrocytes in the central nervous system.

In this trial, six subjects with complete spinal cord injury according to International Standard of Neurological Classification for Spinal Cord Injury (ISNCSCI) developed by the American Spinal Injury Association were treated with co-transplantation of their own MSCs and SCs by means of a lumbar puncture. The neurological status of these patients was ascertained by the ISNCSCI and by assessment of each patient’s functional status according to the Spinal Cord Independent Measure. Before and after cell transplantation, the spinal cord of each patient was imaged by means of magnetic resonance imaging (MRI). All patients also underwent electromyography, urodynamic study (UDS) and MRI tractograghy before the procedure and after the procedure if patients reported any changes in motor function or any changes in urinary sensation.

In a span of 30 months following the procedure, radiological findings were unchanged for each patients. There were no signs or indications of neoplastic tissue overgrowth in any patient. In one patients, their American Spinal Injury Association class was downgraded from A to B. This same patients had increased bladder compliance, which correlated quite well with the axonal regeneration detected in MRI tractography. None of these patients showed any improvement in motor function.

To summarize, there were no adverse effects detected around 30 months after the transplantations. These results suggest that this stem cell combination is safe as a treatment for spinal cord injury. While improvement of observed in one patients, because the trial was not designed to investigate the efficacy of the treatment, it is difficult to make any hard-and-fast conclusions about the efficacy of this treatment at this time. However, the fact that one patient did improve is at least encouraging.

These data were reported in the journal Spinal Cord (Spinal Cord. 2015 Nov 3. doi: 10.1038/sc.2015.142).

Regenerating Nerve Tissue in Spinal Cord Injuries


Severe injuries to the neck during recreational activities such as horseback riding or playing football can permanently alter someone’s life dramatically. With no options for the repair of spinal cord injuries, many are left with little hope for recovery.

New work by researchers at Rush University Medical Center (RUMC) in Chicago is investigating a new therapy that uses stem cells to treat spinal cord injuries within the first 14 to 30 days of injury. Rush is one of only two centers in the country currently studying this new approach.

“There are currently no therapies that successfully reverse the damage seen in the more than 12,000 individuals who suffer a spinal cord injury each year in the United States alone,” says Richard G. Fessler, MD, PhD, professor of neurological surgery at RUMC. An estimated 1.3 million Americans are living with a spinal cord injury.

“These injuries can be devastating, causing both emotional and physical distress, but there is now hope. This is a new era where we are now able to test whether a dose of stem cells delivered directly to the injured site can have an impact on motor or sensory function,” Fessler continued. “If we could generate even modest improvements in motor or sensory function, it would result in significant improvements in quality of life.”

Dr. Fessler is the principal investigator at RUMC of a clinical trial that involves progenitor cells that are likely to develop into a certain cell types. Specifically, this study is studying nerve cells known as oligodendrocyte progenitor cells, which potentially can make poorly functioning nerves function better. A San Francisco Bay-area biotechnology company known as Asterias Biotherapeutics, developed the cells and is sponsoring the trial.

This clinical trial is designed to assess the safety and efficacy of increasing doses of AST-OPC1 to treat individuals with a cervical spinal cord injury that resulted in tetraplegia, the partial or total paralysis of arms, legs and torso. As of mid-August, one individual has been enrolled in the study at Rush and there are high hopes that others will be enrolled as well in the near future.

Three escalating doses of AST-OPC1 will be examined in patients with subacute, neurologically complete injury to the cervical spinal cord (the spinal cord in the neck, specifically, the spinal nerves known as C5 to C7). These individuals essentially have lost all sensation and movement below their injury site and have severe paralysis of the upper and lower limbs.

In order for this therapy to work, the spinal cord must be continuous not severed. Patients must be able to begin treatment within 25 days of their injury.

Fessler and his group will administer AST-OPC1 between 14 to 30 days after sustaining the injury. Following the treatment, patients will receive frequent neurological exams and imaging in order to assess the efficacy of the treatment. Furthermore, patients will be followed for 15 years thereafter.

“If this treatment proves to be safe and effective, in the future, it also might be used for peripheral nerve injury or other conditions that affect the spinal cord, such as multiple sclerosis or ALS,” Fessler says.

The study is recruiting male and female patients ages 18 to 65 who have recently experienced a cervical spinal cord injury at the neck that resulted in partial or total paralysis of arms, legs and torso. All participants must be able to provide consent and commit to a long-term follow-up study.

Stem Cells Inc Spinal Cord Injury Trial Shows Sustained Improvements in Sensory Function


A cellular therapeutic company known as Stem Cells, Incorporated has been carrying out a Phase I/II clinical trial that was specifically designed to assess both safety and preliminary efficacy of their proprietary HuCNS-SC cells as a treatment for chronic spinal cord injury. Recently, Dr. Armin Curt, the principal investigator of this clinical trial, presented a summary of the safety and preliminary efficacy data from this Phase I/II study at the 4th Joint International Spinal Cord Society (ISCoS) and American Spinal Injury Association (ASIA) meeting which was held in Montreal, Canada.

Spinal cord injury patients are classified by a system that was developed by the American Spinal Injury Association (ASIA) and uses grades A through E on the American Spinal Injury Association Impairment Scale (AIS) to indicate the severity of the spinal cord injury. AIS Grade A injuries consist of a loss of all spinal cord function (sensation and movement) below the level of injury is lost. This is known as a complete injury. All the other AIS grades are considered incomplete. Patients with Grade B injuries have some sensation below the level of injury, but there is no movement below the injury.. In patients with AIS Grade C injuries, there is both sensation and movement, but most of the muscles below the injury cannot function against resistance and that includes gravity. Those with AIS Grade D spinal cord injuries have some sensation and movement, but more than half of the muscles below the injury can function against resistance. Finally those with AIS Grade E injuries have both normal sensation and movement, but there may be other signs of injury, for example, pain.

For this trial, Stem Cell Inc enrolled 12 subjects who had suffered from a severe spinal cord injury at the thoracic or chest level (T2-T11); seven AIS A and 5 AIS B patients.. In order to qualify for this study, all patients had to be classified as either AIS A or B and a minimum of 3 months from injury.

The trial involved internationally prominent medical centers for spinal cord injury and rehabilitation, and associated principal investigators; Dr. Armin Curt at the University of Zurich and Balgrist University Hospital, Dr. Steve Casha at the University of Calgary, and Dr. Michael Fehlings at the University of Toronto.

All subjects in this trial received HuCNS-SC cells by means of direct transplantation into the spinal cord and they were also treated, temporarily, with immunosuppressive drugs to prevent the immune system from rejecting the implanted cells. Patients were regularly evaluated for safety of the treatment protocol, and to determine if patients showed any change in neurological function. To determine this, patients were given a standard battery of movement and sensory tests before the surgery and at routine intervals after the procedure. Thus all patients were simultaneously enrolled in a safety evaluation and separate evaluation that tested the efficacy of the procedure as well.

In the safety analyses of these subjects, all the data demonstrated that the surgical transplantation technique and cell dose were safe and well tolerated by all patients. HuCNS-SC cells were injected directly into the spinal cord both above and below the level of injury and none of the patients in sequential examinations over the course of twelve months showed any abnormal changes in spinal cord function associated with the transplantation technique. Additionally, there were no adverse events that could be attributed to the HuCNS-SC cells.

Analyses of the functional data after twelve-months revealed sustained improvements in sensory function that emerged consistently around three months after transplantation and persisted until the end of the study. These gains in sensory function involved multiple sensory pathways and were observed more frequently in the patients with less severe spinal cord injuries. Three of the seven AIS A patients and four of the five AIS B patients showed signs of positive sensory gains. Two patients in the study progressed from AIS A, to the lesser degree of injury grade, AIS B.

“It has been a privilege to be a part of the first study to test the potential of neural stem cell transplantation in thoracic spinal cord injury,” said Dr. Armin Curt, Professor and Chairman of the Spinal Cord Injury Center at Balgrist University Hospital, University of Zurich. “The gains we have detected indicate that areas of sensory function have returned in more than half the patients. Such gains are unlikely to have occurred spontaneously given the average time from injury. This patient population represents a form of spinal cord injury that has historically defied responses to experimental therapies, and the measurable gains we have found strongly argue for a biological result of the transplanted cells. These gains are exciting evidence that we are on the right track for developing this approach for spinal cord injury. This early outcome in thoracic injury firmly supports testing in cervical spinal cord injury.”

Stephen Huhn, M.D., FACS, FAAP, Vice President, Clinical Research and CMO at StemCells, Inc., said, “This research program has the potential to revolutionize the therapeutic paradigm for spinal cord injury patients. The clinical gains observed in this first study are a great beginning. We found evidence of sensory gains in multiple segments of the injured thoracic spinal cord across multiple patients. Our primary focus in this study for spinal cord injury was to evaluate safety and also to look for even small signs of an effect that went beyond the possibility of spontaneous recovery. We are obviously very pleased that the pattern of sensory gains observed in this study are both durable and meaningful, and indicate that the transplantation has impacted the function of damaged neural pathways in the cord. The Company’s development program has now advanced to a Phase II controlled study in cervical spinal cord injury where the corollary of sensory improvements in thoracic spinal cord injury could well be improved motor function in the upper extremities of patients with cervical spinal cord injuries.”

Prenatal Stem Cell Treatment Improves Mobility in Lambs With Spina Bifida


UC Davis fetal surgeon Dr. Diana Farmer has been at the forefront of treating spina bifida in infants while they are still in their mother’s womb. Now, Dr. Farmer and her colleagues have used a large animal model system to study the use of stem cells to improve the clinical outcomes of children who undergo these types of in utero procedures.

Spina bifida is a congenital birth defect that results from abnormal development of the spinal cord. During development, the spinal cord, which beings as a tube (the neural tube), is open at both ends, and these ends eventually close. However, if the posterior opening to the neural tube does not close properly, then the developing spinal cord will have severe structural defects. These structural defects adversely affect the nerves that issue from the spinal cord and spinal bifida can cause lifelong cognitive, urological, musculoskeletal and motor disabilities.

Dr. Farmer’s chief collaborator was another UC Davis science named Aijun Wang, who serves as the co-director of the UC Davis Surgical Bioengineering Laboratory.

“Prenatal surgery revolutionized spina bifida treatment by improving brain development, but it didn’t benefit motor function as much as we hoped,” said Farmer, who serves as chair of the UC Davis Department of Surgery and is the senior author of this study, which was published online in the journal Stem Cells Translational Medicine.

“We now think that when it’s augmented with stem cells, fetal surgery could actually be a cure,” said Wang.

Years ago, Farmer and her colleagues showed in an extensive clinical trial called the Management of Myelomeningocele Study (MOMS) that babies who were diagnosed with spina bifida and were eligible for in utero surgery had better outcomes that babies who underwent surgery after they were born. Babies with spina bifida who were operated on in utero had a better chance of walking, and not needing a shunt to deal with the pressure problems in the brain that some children with spina bifida experience (see N. Scott Adzick, et al., New England Journal of Medicine 2011;364(11):993-1004). Even with this study, the majority of the babies who were treated with in utero surgery were still unable to walk. To improve a baby’s chances of walking, Farmer and her collaborators turned to stem cell treatments.

Farmer and Wang combined fetal surgery with a the transplantation of stem cells from human placentas to improve neurological capabilities of babies born with spina bifida. In children, spina bifida can range from barely noticeable to rather severe. Myelomeningocele is the most common and, unfortunately, the most disabling form of spina bifida. In babies with myelomeningocele, the spinal emerges through the back and usually pulls brain tissue into the spinal column, which causes cerebrospinal fluid to fill the interior of the brain. Therefore, such patients require permanent shunts in their brains in order to drain the extra cerebrospinal fluid.

Myelomeningocele
Myelomeningocele

In this study, lambs with myelomeningocele were operated on in utero in order to return exposed spinal cord tissue into the vertebral column. Then human placenta-derived mesenchymal stromal cells (PMSCs), which have demonstrated neuroprotective qualities (see Yun HM, et al., Cell Death Dis. 2013;4:e958), were embedded in hydrogel and applied to the site of the lesion. A scaffold was placed on top to hold the hydrogel in place, and the surgical opening was closed.

Six of the animals that received the stem cell treatment were able to walk without noticeable disability within a few hours following birth. However, the six control animals that received only the hydrogel and scaffold were unable to stand.

“We have taken a very important step in expanding what MOMS started,” said Wang. “Next we need to confirm the safety of the approach and determine optimal dosing.”

Farmer and Wang will continue their efforts with funding from the California Institute for Regenerative Medicine. With additional evaluation and FDA approval, the new therapy could be tested in human clinical trials.

“Fetal surgery provided hope that most children with spina bifida would be able to live without shunts,” Farmer said. “Now, we need to complete that process and find out if they can also live without wheelchairs.”

NG2-Expressing Neural Lineage Cells Derived from Embryonic Stem Cells Penetrate Glial Scar and Promote Axonal Outgrowth After Spinal Cord Injury


After a spinal cord injury, resident stem cells in the spinal cord contribute to the production of a glial scar that is rich in chondroitin sulfate proteoglycan (CSPG). The glial scar is a formidable barrier to axonal regeneration in the injured spinal cord, since CSPG actively repels growing axonal growth cones. Even though the glial scar seals off the spinal cord from further damage from inflammation, the long-term effects of the glial scar are to prevent regeneration of spinal nerves, which have the ability to regenerate in culture.

The major components of the site of injury include myelin debris, the scar-forming astrocytes, activated resident microglia and infiltrating blood-borne immune cells, chondroitin sulfate proteoglycans (CSPGs) and other growth-inhibitory matrix components. All of them are potential targets for therapeutic intervention. Many of the interventions can be optimized by considering the beneficial aspects of the scar tissue and fine-tuning the optimal time window for their application. Each target and the strategies directed at its modulation are shown.
The major components of the site of injury include myelin debris, the scar-forming astrocytes, activated resident microglia and infiltrating blood-borne immune cells, chondroitin sulfate proteoglycans (CSPGs) and other growth-inhibitory matrix components. All of them are potential targets for therapeutic intervention. Many of the interventions can be optimized by considering the beneficial aspects of the scar tissue and fine-tuning the optimal time window for their application. Each target and the strategies directed at its modulation are shown.

New work by Sudhakar Vadivelu, in the laboratory of John McDonald at the International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at the Kennedy Krieger Institute, Baltimore, Maryland has discovered new ways to breach the glial scar. Vadivelu and colleagues used a cell culture system that tested the ability of particular cells to help growing axonal growth cones penetrate glial scar material. This culture system showed that embryonic stem cell-derived neural lineage cells (ESNLCs) with prominent expression of nerve glial antigen 2 (NG2) survived, and passed through an increasingly inhibitory gradient of CSPG. These cells also expressed matrix metalloproteinase 9 (MMP-9) at the appropriate stage of their development, which helped poke holes in the CSPG. The outgrowth of axons from ESNLCs followed the NG2-expressing cells because the migrating cells chiseled pathways through the CSPG for the outgrowth of new axons.

To confirm these results in a living animal, Vadivelu and others transplanted embryonic stem cell-derived ESNLCs directly into the cavities of a contused spinal cord of laboratory animals 9 days after injury. One week later, implanted ESNLCs survived and expressed NG2 and MMP-9. The axons of these neurons had grown through long distances (>10 mm), although they preferred to grow across white rather than gray matter.

These data are consistent with CSPG within the injury scar acting as an important impediment to neuronal regeneration, but that NG2+ progenitors derived from ESNLCs can alter the microenvironment within the injured spinal cord to allow axons to grow through such a barrier. This beneficial action seems to be due, in part, at least, to the developmentally-regulated expression of MMP-9. Vadivelu and others conclude from these data that it might be possible to induce axonal regeneration in the human spinal cord by transplanting ESNLCs or other cells that express NG2.