Cellular mechanisms influencing corticospinal and sensory axonal regeneration into neural stem cell grafts after SCI

Abstract
Injured corticospinal tract axons regenerate robustly into caudalized neural progenitor cell (NPC) grafts and form functional synaptic connections with graft-derived neurons. However, the developmental fate of grafted NPCs, and whether those differentiated graft-derived neural subtypes might influence the regeneration of host axonal projections, remain unexplored. We demonstrate that upon maturation, embryonic spinal cord NPCs grafted into the injured, adult spinal cord contain clusters of dorsal spinal cord sensory interneurons that are potent zones of exclusion for regenerating corticospinal axons, but receive dense innervation by host CGRP+ sensory axons, reflecting the normal topographical projection patterns of these axons into distinct spinal cord laminae. Notably, these sensory neuron clusters form curved, layered structures populated by neuronal subtypes normally present in superficial dorsal horn laminae I-III, revealing the endogenous self-assembly of spinal cord dorsal horn-like structures within dissociated NPC grafts. These findings reveal a previously unknown barrier to corticospinal axon regeneration into otherwise highly permissive neural grafts, and more generally that axons of adult central and peripheral neurons reinnervate topographically appropriate regions of newly-born neurons after spinal cord injury. Moreover, these findings demonstrate the ability of transplanted dissociated embryonic NPCs to recapitulate assembly of adult spinal cord cytoarchitecture following engraftment into the injured, adult CNS.

Authors
*J. N. DULIN1, A. F. ADLER1, H. KUMAMARU1, M. H. TUSZYNSKI1,2;
1Dept. of Neurosciences, UCSD, La Jolla, CA; 2Veterans Affairs Med. Ctr., San Diego, CA
Disclosures
J.N. Dulin: None. A.F. Adler: None. H. Kumamaru: None. M.H. Tuszynski: None.

LINKS: Session 522 – Regenerative Approaches: Spinal Cord Injury

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Regenerative Medicine, Rehabilitation, Spinal Research, Stem Cell Research

Motor recovery after activity-based training with spinal cord epidural stimulation in a chronic motor complete paraplegic

Enrico Recj PhD

The prognosis for recovery of motor function in motor complete spinal cord injured (SCI) individuals is poor. Our research team has demonstrated that lumborsacral spinal cord epidural stimulation (scES) and activity-based training can progressively promote the recovery of volitional leg movements and standing in individuals with chronic clinically complete SCI. However, scES was required to perform these motor tasks. Herein, we show the progressive recovery of voluntary leg movement and standing without scES in an individual with chronic, motor complete SCI throughout 3.7 years of activity based interventions utilizing scES configurations customized for the different motor tasks that were specifically trained (standing, stepping, volitional leg movement). In particular, this report details the ongoing neural adaptations that allowed a functional progression from no volitional muscle activation to a refined, task-specific activation pattern and movement generation during volitional attempts without scES. Similarly, we observed the re-emergence of muscle activation patterns suffcient for standing with independent knee and hip extension. These findings highlight the recovery potential of the human nervous system after chronic clinically motor complete SCI.

By: Enrico Rejc, Claudia A. Angeli, Darryn Atkinson, Susan J. Harkema

Read the Full Open Article at Nature Scientific Reports HERE
Published online October 26, 2017

UL Press Conference Video:

WLKY News HERE:

Newsweek Article:

Science Daily Article:

Medical Xpress News Article HERE

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

Human neural stem cell grafts into non-human primate spinal cord contusion or hemisection lesions

Abstract
We previously demonstrated that human neural stem cells (hNSCs) and multipotent neural progenitor cells (hNPCs) grafted into sites of rodent spinal cord injury (SCI) survive, extend axons, form synapses, support host axon regeneration, and improve functional recovery (Lu et al., Cell, 2012; Lu et al., Neuron, 2014; Kadoya et al., Nat Med, 2016). We are translating this approach to non-human primates (Rhesus macaques).
Using the H9 human embryonic stem cell line, we generated neural stem cells using published protocols (Li et al., PNAS, 2011). Adult rhesus macaques underwent C7 lateral hemicontusions (N=2; Salegio et al., J Neurotrauma, 2016) or lateral hemisection lesions (N= 5; Rosenzweig et al., Nat Neuro 2010). H9-derived human NSCs were grafted into the SCI sites between 2 and 12 weeks after injury (2, 4, 6, 6, 8, and 12 wks). Subjects received 20 million GFP-expressing NSCs, suspended in a two-part fibrin matrix and growth factor cocktail (Lu et al., Cell, 2012). Subjects were immunosuppressed with prednisone, mycophenolate, and tacrolimus, and were sacrificed 3 – 21 weeks after grafting (3, 8, 16, 16, 18, 18, and 21 wks).
Five of the seven subjects (including both subjects with hemicontusions) had surviving grafts. All surviving grafts differentiated into both neurons and glia, and extended up to hundreds of thousands of new axons; some of these reached very long distances, up to 50 mm, in the host spinal cord. Graft filling of the lesion site varied, indicating the need for further optimization of the grafting method, immunosuppression protocol, or both.
These findings indicate that human neural stem cells can be grafted to sites of subacute to chronic primate SCI, survive, and extend remarkable numbers of axons over long distances. Grafting can be successfully accomplished in sites of contusive SCI, the most common mechanism of human injury. Further optimization of grafting methods is needed prior to potential human translation, highlighting the importance of utilization of larger animal models for methods development and safety assessments.

Authors
*E. S. ROSENZWEIG1, J. H. BROCK1,2, P. LU1,2, J. L. WEBER1, R. MOSEANKO3, S. HAWBECKER3, E. A. SALEGIO3, Y. S. NOUT4, L. A. HAVTON5, A. R. FERGUSON6, M. S. BEATTIE6, J. C. BRESNAHAN6, M. H. TUSZYNSKI1,2;
1Neurosciences, Univ. of California San Diego Dept. of Neurosciences, La Jolla, CA; 2VAMC, La Jolla, CA; 3California Natl. Primate Res. Center, Univ. Calif. Davis, Davis, CA; 4Col. of Vet. Med. and Biomed. Sciences, Colorado State Univ., Fort Collins, CO; 5Neurol., David Geffen Sch. of Medicine, Univ. of California, Los Angeles, Los Angeles, CA; 6Neurosurg., Univ. of California San Francisco, San Francisco, CA
Disclosures
E.S. Rosenzweig: None. J.H. Brock: None. P. Lu: None. J.L. Weber: None. R. Moseanko: None. S. Hawbecker: None. E.A. Salegio: None. Y.S. Nout: None. L.A. Havton: None. A.R. Ferguson: None. M.S. Beattie: None. J.C. Bresnahan: None. M.H. Tuszynski: None.

LINK:Session 323 – Spinal Cord Injury Models and Mechanisms

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

Two Leading Spinal Cord Injury Experts Join ReNetX Scientific Advisory Board

NEW HAVEN, Conn., Oct. 10, 2017 (GLOBE NEWSWIRE) — ReNetX Bio, a company developing first-in-class therapeutics to treat injury to the central nervous system, is expanding its Scientific Advisory Board with key opinion leaders specializing in spinal cord injury.

ReNetX Bio is developing first-in-class therapeutics to treat injury and damage to the central nervous system (CNS) in conditions such as spinal cord injury (SCI), stroke, and glaucoma. The company was founded based on innovative technology from Dr. Stephen Strittmatter’s work at Yale University to improve neurologic function after CNS injury – creating a significant and completely unmet need estimated at >$5B annually. The technology allows neurons to regrow by eliminating factors that inhibit growth and the technology platform has the potential to help restore function in patients who are suffering from spinal cord injuries, stroke and glaucoma.

Andrew Blight, PhD, brings experience as the former Chief Scientific Officer of Acorda Therapeutics, Inc., where he helped move forward therapies for stroke and spinal cord injury (SCI) and ran two of the largest multicenter clinical trials in chronic SCI around the potassium channel blocker, 4-aminopyridine, which achieved FDA approval for the treatment of walking impairment in persons with multiple sclerosis.

Andrew R. Blight PhD.

“I have closely followed the developing science behind ReNetX and I am delighted to see this technology ready to be brought to the clinic for testing in people with spinal cord injury,” Blight says.

In addition, ReNetX has added Daniel P. Lammertse, MD, to its Scientific Advisory Board. Lammertse served as Medical Director (1984-2008) and Medical Director of Research (2008-2016)at Craig Hospital in Englewood, Colorado, before becoming the hospital’s Emeritus Clinical Scientist upon retirement from clinical practice in 2016. He’s also Professor of Physical Medicine and Rehabilitation at the University of Colorado School of Medicine. Dr. Lammertse is an internationally recognized expert in SCI clinical care and rehabilitation. He has authored numerous scientific publications on topics in spinal cord injury, including ventilator-dependent tetraplegia, aging in persons with SCI, and the conduct of clinical trials in SCI.

Dr. Dan Lammertse

In joining the ReNetX Scientific Advisory Board, Lammertse says: “I was impressed with the preclinical work that will enable moving to clinical trials and by the positive effects seen in chronic injuries. My expertise is in the pragmatics of conducting clinical trials in persons with spinal cord injury. I hope that my participation on the Scientific Advisory Board can be translated into a successful clinical trial research program.”

Read the full article at First Word Pharma HERE

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

Get registered for Working 2 Walk 2017 today!

Hilton Miami Airport Hotel Working 2 Walk 2017 October 13-14

Plan to join us in Miami for our 12th annual Working 2 Walk Symposium. The conference is a unique opportunity for spinal cord injury advocates, scientists, clinicians, and investors to meet and share the latest news & strategies, and form partnerships that will accelerate progress toward curative therapies.

Working 2 Walk Symposium Registration
October 13-14, 2017 – Miami, Florida

Register HERE for early bird rates!

Working 2 Walk 2017 Agenda LINK

Working 2 Walk Speaker List HERE

Venue Lodging LINK

Posted in Chronic Spinal Cord Injury Research, Regenerative Medicine, Spinal Research, Unite 2 Fight Paralysis, Working 2 Walk Science & Advocacy Symposium | 1 Comment

Airline lobby wins another big delay on reporting data for wheelchair damages and losses *January 2019*

By Russ Choma

Dodson’s story seems to be fairly common. His chair has also been repeatedly broken by airlines, and as the national secretary of Paralyzed Veterans of America, he hears about airlines breaking or losing wheelchairs on a regular basis. Still, no one knows just how common it is or which airlines are the worst offenders. There is literally no transparency when it comes to how airlines handle wheelchairs—they are not required to keep or publicly release data on the chairs and motorized scooters they carry.

A new federal rule written by the Obama administration was supposed to change that. Beginning on January 1, 2018, the rule would have required airlines to track, and report on a monthly basis, how many wheelchairs and motorized scooters each airline carries and how many they break or mishandle. That would allow disabled travelers to easily assess which airlines to use and which to avoid.

But then Donald Trump’s administration stepped in. Just weeks after Trump took office, the Department of Transportation bowed to pressure from airline industry lobbyists and abruptly delayed the new rule—with no input from the public.

There had been no public comment, no notice given to any of the stakeholders who had participated in the five-year rulemaking process, and only limited explanation of why the rule had been delayed.

Read the Full Article HERE from Mother Jones

Posted in Advocacy, Chronic Spinal Cord Injury Research | 1 Comment

An injectable hydrogel enhances tissue repair after spinal cord injury by promoting extracellular matrix remodeling

Nature Communications 8, Article number: 533 (2017)

The cystic cavity that develops following injuries to brain or spinal cord is a major obstacle for tissue repair in central nervous system (CNS). Here we report that injection of imidazole-poly(organophosphazenes) (I-5), a hydrogel with thermosensitive sol–gel transition behavior, almost completely eliminates cystic cavities in a clinically relevant rat spinal cord injury model. Cystic cavities are bridged by fibronectin-rich extracellular matrix. The fibrotic extracellular matrix remodeling is mediated by matrix metalloproteinase-9 expressed in macrophages within the fibrotic extracellular matrix. A poly(organophosphazenes) hydrogel lacking the imidazole moiety, which physically interacts with macrophages via histamine receptors, exhibits substantially diminished bridging effects. I-5 injection improves coordinated locomotion, and this functional recovery is accompanied by preservation of myelinated white matter and motor neurons and an increase in axonal reinnervation of the lumbar motor neurons. Our study demonstrates that dynamic interactions between inflammatory cells and injectable biomaterials can induce beneficial extracellular matrix remodeling to stimulate tissue repair following CNS injuries.

Le Thi Anh Hong, Young-Min Kim, Hee Hwan Park, Dong Hoon Hwang, Yuexian Cui, Eun Mi Lee, Stephanie Yahn, Jae K. Lee, Soo-Chang Song & Byung Gon Kim

Read the Full Publication HERE

Posted in Chronic Spinal Cord Injury Research, Regenerative Medicine, Spinal Research, Stem Cell Research

17th International Symposium on Neural Regeneration

Asilomar

The ISNR is a forum for the presentation and discussion of important research progress, insights and controversies important to advancing the understanding of injury responses and potential therapeutics targeting both peripheral nerve and central nervous system injuries. This year marks the 17th bi-annual meeting and the last time that we will be holding ISNR at the Asilomar conference grounds. I know that this is a meeting that many of you look forward to and I hope to see you again for this year’s meeting.

If you have already registered, thank you. If not, then please register and spread the word to your colleagues. Also, encourage your students and trainees to register. This is a perfect meeting for them!

The ISNR meeting will take place November 27-December 1, 2017 at the Asilomar Conference Grounds in Pacific Grove, CA.

Please visit http://theisnr.org/ to see this years agenda and to register.

Phillip Popovich, Ph.D., Director
International Symposium on Neural Regeneration
694 Biomedical Research Tower
460 W. 12th Ave
Columbus, Ohio 43210 USA
Phone: 614-688-8576 | Email: ISNR@osumc.edu

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Spinal Research | Tagged

Combinatory repair strategy to promote axon regeneration and functional recovery after chronic spinal cord injury

Marc A. DePaul

Eight weeks post contusive spinal cord injury, we built a peripheral nerve graft bridge (PNG) through the cystic cavity and treated the graft/host interface with acidic fibroblast growth factor (aFGF) and chondroitinase ABC (ChABC). This combinatorial strategy remarkably enhanced integration between host astrocytes and graft Schwann cells, allowing for robust growth, especially of catecholaminergic axons, through the graft and back into the distal spinal cord. In the absence of aFGF+ChABC fewer catecholaminergic axons entered the graft, no axons exited, and Schwann cells and astrocytes failed to integrate. In sharp contrast with the acutely bridge-repaired cord, in the chronically repaired cord only low levels of serotonergic axons regenerated into the graft, with no evidence of re-entry back into the spinal cord. The failure of axons to regenerate was strongly correlated with a dramatic increase of SOCS3 expression. While regeneration was more limited overall than at acute stages, our combinatorial strategy in the chronically injured animals prevented a decline in locomotor behavior and bladder physiology outcomes associated with an invasive repair strategy. These results indicate that PNG+aFGF+ChABC treatment of the chronically contused spinal cord can provide a permissive substrate for the regeneration of certain neuronal populations that retain a growth potential over time, and lead to functional improvements.

Authors: Marc A. DePaul, Ching-Yi Lin, Jerry Silver, Yu-Shang Lee

See the Full Publication at Nature Scientific Reports: LINK

Posted in Chronic Spinal Cord Injury Research, Spinal Research | Tagged , , , | 1 Comment

Gait Rehabilitation with a Neurologically Controlled Exoskeleton

Gait Rehabilitation with a Neurologically Controlled Exoskeleton
Ziadee Cambier, PT, MSPT, DPT

Ziadee Cambier Physical Therapist Swedish Medical Center


Seattle Science Foundation is a non-profit organization dedicated to the international collaboration among physicians, scientists, technologists, engineers and educators. The Foundation’s training facilities and extensive internet connectivity have been designed to foster improvements in health care through professional medical education, training, creative dialogue and innovation.

http://www.seattlesciencefoundation.org

NOTE: All archived recorded lectures are available for informational purposes only and are only eligible for self-claimed Category II credit. They are not intended to serve as, or be the basis of a medical opinion, diagnosis, prognosis, or treatment for any particular patient.

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