Overexpression of protrudin in primary cortical neurons enhances regeneration after laser axotomy through multiple mechanisms

Authors:
V. PETROVA, R.EVA, J.W. FAWCETT

Veselina Petrova, PhD student in James Fawcett lab.


Lab Abstract:

Numerous extracellular and intracellular processes contribute to the failure of long-range regeneration in the adult central nervous system (CNS) after injury. One reason why adult CNS axons have poor regenerative capabilities is that a developmental change occurs where essential growth molecules such as integrins and growth factor receptors become excluded from axons. These growth-promoting molecules are normally transported along axons in Rab11-positive recycling endosomes by motor proteins/adaptor complexes. However, this transport declines with maturation leading to a decline in regenerative capacity. Protrudin, a member of the ZFYVE family of zinc-binding proteins is a membrane-associated protein involved in neurite outgrowth and directional membrane trafficking in HeLa, PC12 and primary hippocampal cells (Shirane et al., 2006). Phosphorylated protrudin preferentially binds to Rab11-GDP, an association which is required for neurite outgrowth and for anterograde movement of this complex.
We hypothesised that increasing the phospho-protrudin/Rab11 interaction would result in anterograde transport of growth-promoting molecules to the tip of injured axons enabling regeneration of primary cortical neurons after laser axotomy. To test this, two phosphomimetic forms of protrudin were created at phosphorylation sites known to play an important role for its association with Rab11. We found that both constitutively phosphorylated protrudin forms (64%, 70%) and also wild-type protrudin (60%) increased the proportion of regenerating axons compared to control (27%). Live-cell imaging experiments are currently being performed to investigate whether the increase in regenerative capacity is indeed due to its association with Rab11 and increased anterograde transport of integrins. Protrudin is a complex molecule with numerous cellular functions such as ER shaping, vesicular transport, interactions with spastin – a microtubule-severing protein and many more. In order to unpick the mechanisms of action of protrudin on regeneration, five mutants were created – each targeting a specific region of the protein important for its involvement in various molecular pathways (ΔFYVE, ΔRab11-binding-domain, ΔKIF5, ΔFFAT, ΔSpastin). These mutants were overexpressed in primary cortical neurons and their effects on regeneration were tested. Protrudin was found to promote regeneration through multiple mechanisms, some of which, such as ER function have not previously been associated with the process of axon regeneration. Protrudin’s ability to promote regeneration is currently being tested in vivo in models of acute and chronic injury.

*V. PETROVA1, R. EVA1, J. W. FAWCETT1,2;
1Cambridge Univ., Cambridge, United Kingdom; 2Inst. of Exptl. Med., Ctr. of Reconstructive Neurosci., Prague, Czech Republic. Overexpression of protrudin in primary cortical neurons enhances regeneration after laser axotomy through multiple mechanisms. Program No. 115.05. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online.

Grant Support: MRC Grant R004463, MRC Grant G1000864, Gates Cambridge Studentship, Gates Cambridge Academic Development Award,
International Foundation for Research in Paraplegia P172

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Regenerative Medicine, Spinal Research, Stem Cell Research | Tagged , | Leave a comment

Lin28 protein regulates CNS axon regeneration in adult mammalians

Authors: Shuxin LI, F.NATHAN, Y.OHTAKE, H.GUO, A.SAMI

Shuxin Li, MD, PhD.
Associate Professor, Anatomy and Cell Biology
Associate Professor, Shriners Hospitals Pediatric Research Center

Lab Abstract:
Severed CNS axons fail to regenerate in adult mammals and there are no effective regenerative strategies to treat patients with CNS injuries. Several genes, including PTEN and Krüppel-like factors, regulate intrinsic growth capacity of mature neurons. However, none of these approaches were translated to clinics yet and thus there is a persistent need to identify better targets and improved delivery methods. Lin28, an RNA-binding protein, enhances translation of multiple genes including metabolic enzymes for increasing glycolysis and oxidative phosphorylation, and is essential for cell development and pluripotency in worms and mammals. Lin28 is a gatekeeper molecule to control switch between pluripotency and committed cells and its reactivation stimulates repair of several tissue systems, including hair, cartilage, bone, and mesenchyme. In this study, we reprogram mature CNS neurons with Lin28 activation to increase their growth capacity after CNS injuries. Especially, we evaluated the role of Lin28a in regulating regenerative capacity of different types of CNS neurons in adult mammals. Using neuron-specific Thy1 promoter, we generated transgenic mice that overexpress Lin28a protein in multiple neuronal populations, including multiple descending projection tracts and retinal ganglion cells. We demonstrate that upregulation of Lin28a in adult transgenic mice induces significant long distance regeneration of descending motor axons after spinal cord injury and optic fibres following optic nerve axotomy. Importantly, overexpression of Lin28a by post-injury treatment with AAV2 vector also stimulates dramatic regeneration of corticospinal tracts after spinal cord injury and optic axons after optic injury. Upregulation of Lin28a also enhances survival of retinal ganglion cells after injury and activity of Akt/mTOR signalling pathway in various CNS neurons. Therefore, Lin28a is critical for regulating growth capacity of CNS neurons and may become an important molecular target for treating for CNS injuries, including traumatic spinal cord and brain injury.

*S. LI, F. NATHAN, Y. OHTAKE, H. GUO, A. SAMI;
Shriners Hosp. Pediatric Res. Ctr., Temple Univ. Sch. of Med., Philadelphia, PA. Lin28 protein regulates CNS axon regeneration in adult mammalians. Program No. 115.07. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online.

Grant Support: NIH 1R01NS079432 and 1R01EY024575,  SHC-85100, SHC-86300-PHI, SHC-86200-PHI-16, SHC-85112-PHI-18


Also taking place in the Li Lab: 

Lab 2018 NIH Grant:  Acute Neural Injury and Epilepsy Study Section (ANIE) {R01-NS105961-01}  Develop a combinatorial therapy for spinal cord injury 

Temple Health Article:  Temple Scientists Identify Novel Target for Neuron Regeneration and Functional Recovery in Spinal Cord Injury

Technology Networks:  Protein Therapy Boosts Spinal Cord Regeneration in Mice

Molecular Therapy: Promoting axon regeneration in adult CNS by targeting liver kinase B1

 

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Regenerative Medicine, Spinal Research, Stem Cell Research | Tagged , , , | 1 Comment

Case Western Reserve Researchers Restore Breathing and Partial Forelimb Function in Rats with Chronic Spinal Cord Injuries

Promising results provide hope for humans suffering from chronic paralysis

“Millions of people worldwide are living with chronic spinal cord injuries, with 250,000 to 500,000 new cases each year—most from vehicle crashes or falls. The most severe spinal cord injuries completely paralyze their victims and more than half impair a person’s ability to breathe. Now, a breakthrough study published in Nature Communications has demonstrated, in animal models of chronic injury, that long-term, devastating effects of spinal cord trauma on breathing and limb function may be reversible.

The new study describes a treatment regimen that helps reawaken certain special types of nerve cells that can regenerate extensions, called axons, within the damaged spinal cord. Rats with spinal cords half severed at the second cervical vertebrae (C2) regained complete diaphragm and partial forelimb function on the severed side after treatment. The recuperative effects of the therapy were fully maintained six months after treatment end.”

SEE THE FULL ARTICLE AT CASE WESTERN RESERVE NEWS CENTER:

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Elevated phosphoinositide 3-kinase activity promotes axon regeneration of central nervous system neurons

Authors: B. NIEUWENHUIS, R.EVANS, C.S. PEARSON, A.C. BARBER, J. CAVE, P.D. SMITH, J. FUCHS, B.J. EICKHOLT, H.M. GELLER, K.R. MARTIN, R. EVA, J.W. FAWCETT

Bart Nieuwenhuis

Lab Abstract:

Injury to the central nervous system (CNS) has severe consequences because adult CNS axons do not regenerate. PtdIns-3,4,5-P3 (PIP3) signaling is essential for axon growth during development of the nervous system. Silencing PIP3 phosphatase PTEN leads to increased regeneration in the corticospinal tract and optic nerve after injury, showing that PIP3 is crucial for axonal regeneration. However as neurons mature, phosphoinositide 3-kinases (PI3Ks) activating receptors are excluded from axons. We hypothesize that a developmental decline in axonal PIP3 signaling contributes to restricted axonal regeneration in the CNS. The objective of this study is to explore whether overexpression of PI3Ks, which generates PIP3, could promote axonal regeneration of CNS neurons.
We first confirmed that there is a decline of PIP3 levels in cultured cortical neurons in line with maturation by using immunocytochemistry. Overexpression of activated PI3K increased axonal growth by 50% in developing neurons (4 days in vitro, DIV). Expression of activated PI3K in matured cortical neurons (14 DIV) resulted in an enlarged the soma size (by 100%) and more complex dendritic morphology in vitro. Expression of constitutively activated PI3K, but not wildtype PI3K, resulted in a six-fold increase of the PIP3 signaling pathway in these neurons – visualized by staining for the phosphorylated ribosomal protein S6. To investigate whether PI3Ks can enhance the regeneration capacity of CNS neurons, we overexpressed these in cortical neurons and applied in vitro laser axotomy. We confirmed that 14 DIV neurons have a restricted axon regeneration capacity after in vitro laser axotomy (only 15% of the axotomised neurons regenerate). Importantly, expression of PI3Ks increases the success rate of axonal regeneration (approximately 60% of the axotomised neurons regenerate). We recently started to explore whether PI3K can promote optic nerve regeneration in vivo. Using a transgenic mouse line with cre-inducible expression of constitutively activated PI3K, we found that the AAV2-cre condition had significantly increased axon regeneration beyond the optic nerve crush site compared to controls.
In summary, cultured cortical neurons have a decline of PIP3 signaling and this could contribute to their decreasing regeneration capacity during maturation. Overexpression of activated PI3Ks promotes developmental axon growth, and axonal regeneration of CNS neurons in vitro and in vivo. The mechanisms of PI3K-induced axon regeneration have not been investigated in great detail. We are currently investigating whether PI3K acts by stimulating axonal transport of regeneration-associated proteins.

*B. NIEUWENHUIS1,2, R. EVANS1, C. S. PEARSON3, A. C. BARBER1, J. CAVE1, P. D. SMITH4, J. FUCHS5, B. J. EICKHOLT5, H. M. GELLER3, K. R. MARTIN1, R. EVA1, J. W. FAWCETT1,6;
1Univ. of Cambridge, Cambridge, United Kingdom; 2Netherlands Inst. for Neurosci., Amsterdam, Netherlands; 3NIH, Bethesda, MD; 4Carleton Univ., Ottawa, ON, Canada; 5Charite Univ. Med., Berlin, Germany; 6Inst. of Exptl. Med., Prague, Czech Republic. Elevated phosphoinositide 3-kinase activity promotes axon regeneration of central nervous system neurons. Program No. 115.06. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online.

Grant Support:
International Spinal Research Trust (NRB110) ERANET NEURON grant AxonRepair (013-16-002) Christopher and Dana Reeve Foundation (JFC-2013(3), JFC-2013(4)) Medical Research Council (G1000864 018556) Cambridge Eye Trust (RG80564) Fight for Sight (RG74504)

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Regenerative Medicine, Spinal Research, Stem Cell Research | Tagged , | Leave a comment

Identifying the most effective types of integration-free human iPS cell-derived neural stem/progenitor cells in the treatment of spinal cord injury

Identifying the most effective types of integration-free human iPS cell-derived neural stem/progenitor cells in the treatment of spinal cord injury

Authors: T. IIDA, N. NAGOSHI, J. KOHYAMA, O. TSUJI, M. MATSUMOTO, M. NAKAMURA, H. OKANO
Lab Abstract:
INTRODUCTION: We have previously demonstrated the therapeutic potential of transplanting human iPS cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) in the treatment of spinal cord injury (SCI) models. Recently, we have produced integration-free hiPSCs using episomal vectors which is safer for clinical use. The purpose of this study is to assess the efficacy of integration-free hiPSC-NS/PCs, and to investigate their genetic profiles in order to evaluate factors related to therapeutic efficacy. METHODS: Two integration-free human iPS cell lines were prepared (836B3-, 414C2-hiPSCs), and were induced to hiPSC-NS/PCs (836B3-, 414C2-NS/PCs). ES cells were also used for analysis as a target for comparison of hiPSCs. hiPSC-NS/PCs were transplanted into the injured spinal cord of NOD-SCID mice, and phosphate buffered saline (PBS) was injected to the control group (414C2-NS/PCs; n=27, 836B3-NS/PCs; n=23, control; n=15). Transplanted cells were monitored using bio-imaging and evaluated histologically; and motor function was evaluated by basso mouse scale (BMS) score. HumanHT-12 was used to evaluate gene-expression analyses and single-cell-RNA-sequence was performed using Illumina-Hiseq2500. RESULTS: In the in-vivo study, better motor functional recovery was observed in the 414C2-NS/PCs group compared with the control group (p< 0.001). In contrast, 836B3-NS/PCs group showed no improvement in motor function, and formed undifferentiated tissues. The gene-expression profile of 414C2-hiPSCs resembled that of ES cells with clustering analysis, and 12 genes which included genome-stabilization gene such as DPPA3 and differentiation related genes such as IRX2 were highly expressed in 414C2-hiPSCs, similar to those found in ES cells. None of these findings, however, were observed in 836B3-hiPSCs. In single-cell-RNA-sequence, Delta-Notch signal positive cells which are important for neural differentiation were more abundant in 414C2-NS/PCs, whereas 836B3-NS/PCs only contained a small population (12% and 5%, respectively).

DISCUSSION: In order to pursue our mission of conducting a clinical trial for SCI patients within the next several years, it is critical to build guidelines for selecting “effective” hiPSC-NS/PCs, such as 414C2-NS/PCs. Herein we showed that the key to good motor function recovery is to transplant integration-free hiPSC-NS/PCs that differentiate well within the spinal cord tissue. Our results suggest that examining hiPSCs quality with 12-gene markers and establishing hiPSC-NS/PCs that contain Delta-Notch (+) cells for more than 10% could be the criteria to select “effective” hiPSC-NS/PCs for SCI treatment.

Abstract Citation
*T. IIDA1, N. NAGOSHI1, J. KOHYAMA2, O. TSUJI1, M. MATSUMOTO1, M. NAKAMURA1, H. OKANO2;
1Dept of Orthop, Sch. of Med, Keio Univ., Shinjyuku-Ku Tokyo, Japan; 2Dept of Physiology, Sch. of Med, Keio Univ., Shinjyuku-Ku Tokyo, Japan. Identifying the most effective types of integration-free human iPS cell-derived neural stem/progenitor cells in the treatment of spinal cord injury. Program No. 213.06. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online.

Keio researchers plan to treat spinal cord injuries with stem cells  at The Japan Times News LINK

Keio Univ. to OK transplant of iPS-derived cells for spine injury treatment in world 1st   at The Mainichi LINK

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Regenerative Medicine, Spinal Research, Stem Cell Research | Tagged , , , , | Leave a comment

Alterations in spinal cord injury-induced plasticity of spinal rhythm generating interneurons following treadmill training with epidural stimulation in mouse

Authors: D. GARCIA-RAMIREZ, N. HA, L. YAO, K. A. SCHMIDT, S. F. GISZTER, K. J. DOUGHERTY

D. Garcia-Ramirez PhD.
Dougherty Lab – DREXEL


Lab Abstract:
“Neuronal circuitry generating locomotion is located in the thoracolumbar spinal cord. Spinal rhythm generating interneurons (INs) convert descending inputs into rhythmic outputs. Rhythm generating INs are strongly influenced by afferent feedback and supraspinal control, including serotonergic modulation. Spinal cord injury (SCI) disrupts the descending control of spinal locomotor circuits but this circuitry is located below the level of most SCIs and is relatively intact; however, plasticity occurs. Current clinical therapies to recover motor control after SCI include treadmill training and epidural stimulation (ES), targeting the locomotor circuitry. However, the state of the spinal circuits targeted after SCI and rehabilitation is poorly understood. Rhythm generating INs should be a prime access point for these treatments. Previously we found that rhythm generating INs expressing the transcription factor Shox2 are modulated by serotonin (5-HT) in a dose-dependent manner, producing inhibitory actions at low concentrations and excitatory actions at high concentrations. Further, Shox2 INs received mainly polysynaptic afferent input mediated by both excitatory and inhibitory pathways. After SCI, 5-HT only increased the excitability of Shox2 INs, regardless of concentration, and Shox2 INs received only excitatory inputs from afferent pathways. The main objective of the present study was to identify how the combination of treadmill training and ES then modifies the SCI-induced plastic changes in afferent-evoked inputs to and 5-HT modulation of Shox2 INs. Complete thoracic spinal transections were performed on adult Shox2::Cre;Rosa26-lsl-tdTomato mice. ES wires were implanted at lumbar level L2 for ES during treadmill training (SCI+ES) for 5 weeks after SCI. Whole cell patch clamp recordings targeted Shox2 INs in lumbar spinal slices, with dorsal roots attached for afferent stimulation, from SCI and SCI+ES mice. After treadmill traning with ES, 5-HT hyperpolarized Shox2 INs and there was a return of afferent-evoked inhibitory inputs to Shox2 INs. This suggests that treadmill training with ES shifts the balance of excitatory/inhibitory afferent pathways to Shox2 INs and the serotonergic control of Shox2 INs back towards that observed in the uninjured state.”

*D. GARCIA-RAMIREZ1, N. HA1, L. YAO1, K. A. SCHMIDT2, S. F. GISZTER1, K. J. DOUGHERTY1;

1Neurobio. and Anat., Drexel Univ. Col. of Med., Philadelphia, PA; 2Biomed. Engineering, Sci. and Hlth. Systems, Drexel Univ., Philadelphia, PA. Alterations in spinal cord injury-induced plasticity of spinal rhythm generating interneurons following treadmill training with epidural stimulation in mouse. Program No. 065.13. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online.

Grant Support NIH R01 NS095366 and Wings for life

Posted in Neuroscience Abstracts, Spinal Research | Tagged , ,

École Polytechnique Fédérale de Lausanne (EPFL) has implanted SCI trial patient walking 1/2 mile.

Spinal implant helps three paralysed men walk again
By Pallab Ghosh
Science correspondent, BBC News
“Three paralysed men, who were told they would spend the rest of their lives in a wheelchair, are able to walk again thanks to doctors in Switzerland.
An electrical device inserted around the men’s spines boosted signals from their brains to their legs.
And it also helped damaged nerves in the spinal cord to regrow.
The researchers hope that this unexpected bonus will enable some paralysed people ultimately to regain independent movement.
BBC News has had exclusive access to the patients in the clinical trial, the results of which are published in the journal Nature.
The first patient to be treated was 30-year-old Swiss man David M’zee, who suffered a severe spinal injury seven years ago in a sporting accident.
‘Try the impossible’
David’s doctor said he would never walk again.
However, thanks to an electrical implant developed by a team at École Polytechnique Fédérale de Lausanne (EPFL), he can walk more than half a mile with the implant turned on.”

See the full Article at BBC NEWS with Video.

Targeted Neurotechnology Restores Walking in Humans with Spinal Cord Injury 29 Page Open Access PDF at Nature

COURTINE LAB NEWS

Once Paralyzed, Three Men Take Steps Again With Spinal Implants (New Video) New York Times LINK

Related Links
Information flyer for patients: https://www.sci-research.uzh.ch/dam/jcr:17152b75-ed5d-425c-8ee4-4ef44c821483/STIMO_Flyer_E.pdf

The team behind
More about Prof. Courtine and his team: https://courtine-lab.epfl.ch/
More about Prof. Bloch: https://www.chuv.ch/fr/neurochirurgie/nch-home/le-service-en-bref/notre-equipe/nos-medecins/pre-jocelyne-bloch/
More about the robotic system FLOAT: https://www.thefloat.reha-stim.com

Nature Publications
Targeted neurotechnology restores walking in humans with spinal cord injury, Nature, Nov.
1st, 2018, https://doi.org/10.1038/s41586-018-0649-2

Electrical spinal cord stimulation must preserve proprioception to enable locomotion in
humans with spinal cord injury, Nature Neuroscience, Nov. 1st, 2018,
https://doi.org/10.1038/s41593-018-0262-6

Posted in Chronic Spinal Cord Injury Research, Rehabilitation, Spinal Research | Tagged , | 3 Comments

Nerve-on-a-Chip to Improve Functionality of Neuroprosthetic Devices

Read about the neuroprosthetic advancement at MEDGADGETS:

“Scientists at the École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland have created a special device to be able to stimulate and record signals from and to peripheral nerve fibers on a specialty chip. The device can be used to repeatedly stimulate and record the returning electric activity with high resolution, potentially helping to develop future neuroprosthetic implants that can help restore physical ability and sensory perception in people with a variety of disabilities.

Neuroprosthetics are implantable devices that have electrode arrays that can mimic some of the electrical activity of nerves. For example, spinal cord stimulation can help to restore walking and maybe even bring a sense of touch to prosthetic arms and hands.

Fine tuning of neuroprosthetic devices is currently challenging due to the small number of electrodes that can be currently simultaneously used in real patients. To overcome this, the EPFL team has developed a system that can stimulate and read nerve fibers explanted from the body as though they’re still inside.”

EPFL NEWS CENTER FOR NEUROPROSTHETICS

“EPFL scientists have developed a miniaturized electronic platform for the stimulation and recording of peripheral nerve fibers on a chip. By modulating and rapidly recording nerve activity with a high signal-to-noise ratio, the platform paves the way to using chips to improve neuroprosthetic designs.”

Prof. Stéphanie P. Lacour holds the Bertarelli Foundation Chair in Neuroprosthetic Technology at the School of Engineering at the Ecole Polytechnique Fédérale de Lausanne.


Read the Full Open Access Article at Nature Communications volume 9, Article number: 4403 (2018)

A microfabricated nerve-on-a-chip platform for rapid assessment of neural conduction in explanted peripheral nerve fibers

Authors: Sandra Gribi, Sophie du Bois de Dunilac, Diego Ghezzi & Stéphanie P. Lacour

Posted in Biomaterials, Chronic Spinal Cord Injury Research, Rehabilitation, Spinal Research | Tagged ,

Perspectives on “the biology of spinal cord regeneration success and failure”

Neural Regeneration Research Journal
Authors: Philippa Mary Warren, Amanda Phuong Tran, and Jerry Silver, Ph.D.

“In our recently co-authored Physiological Reviews manuscript entitled “The biology of regeneration failure and success after spinal cord injury” (Tran et al., 2018b), we sought to provide a comprehensive and up-to-date description of how the glial scar develops following spinal cord injury (SCI) to chronically inhibit axon regeneration. Our additional intention was to clarify some of the confusion in the field relating to an oversimplified view of the glial scar. We would like to take this opportunity to reiterate how the current body of literature, expounding details of the glial scar, has progressed beyond a simplified and outdated understanding of this structure as a mono-cellular arrangement consisting only of astrocytes that solely limit axon regeneration. Instead, our perception of the glial scar has evolved to acknowledge the nuances of this multi-cellular structure to one that is able to limit the expansion of inflammatory processes shortly following SCI and that also persists chronically to limit axon regeneration.”

See the Full Article at Neural Regeneration Research

Amanda Tran | Case Western Reserve University, Ohio | CWRU | Department of Neurosciences


Philippa Warren PhD, Kings College London, UK


The Biology of Regeneration Failure and Success After Spinal Cord Injury ABSTRACT

Tran, A. P., Warren, P. M., & Silver, J. (2018). The biology of regeneration failure and success after spinal cord injury. Physiological Reviews, 98(2), 881-917. DOI: 10.1152/physrev.00017.2017

(The Full Open Access Paper will be online April 1, 2019)

Posted in Chronic Spinal Cord Injury Research, Regenerative Medicine, Spinal Research | Tagged , , | 2 Comments

Neuroplasticity after Spinal Cord Injury

Dr. Francisco Benavides from Miami Project explains the neuroplasticity experiments taking place at Miami Project.

Posted in Chronic Spinal Cord Injury Research, Rehabilitation, Spinal Research | Tagged ,