Neural Progenitor Cell Transplantation in Spinal Cord Injury

Michael G. Fehlings, MD, explains the potential clinical implications of this research.

Peer Reviewed

Researchers from the Fehlings Laboratory for Neural Repair and Regeneration at the University of Toronto have developed an experimental therapy to redirect transplanted neural progenitor cells to differentiate into neurons that improved motor function after injury in rodents, rather than into astrocytes as is common in the hostile microenvironment of spinal cord injury. It is theorized that this therapy may improve graft survival, integration, and function recovery in spinal cord injury. SpineUniverse spoke with Michael G. Fehlings, MD, PhD, FRCSC, FACS, to understand the potential clinical implications of this research.

nerve cellsNerve cells. Photo Source: iStock.com.

What should SpineUniverse know about translational medicine as a driver for new SCI interventions?

Dr. Fehlings: Current treatment options for spinal cord injury (SCI) are limited and we are desperately in need of new approaches that can lead to significant gains in function. Translational medicine provides us the opportunity to transfer knowledge from “bench to bedside,” where promising discoveries in preclinical research labs are advanced to clinical practice. Using clinically-relevant animal models of SCI we can test therapies in the research lab, and if findings from these proof-of-concept studies are encouraging, this provides us with the evidence needed to advance therapies to the clinical trial stage. Typically, findings published in the journal Science Translational Medicine are exciting new discoveries that have the potential to advance medicine in a certain field.

Your research demonstrated that “Notch ligands are up-regulated in the spinal cord microenvironment after injury, which biases differentiation of transplanted NPCs toward more astrocytes.” Can you explain what this means and why manipulating the transplanted cells to bias differentiation toward a neuronal lineage may be helpful in SCI?

Dr. Fehlings: After a SCI there are changes in the expression of different proteins. Inflammatory proteins are upregulated, signalling pathways are modified, and growth factor expression is also altered. One of the pathways that becomes upregulated after a SCI is the Notch signalling pathway, and this increase corresponds to a decrease in neurogenesis and neuronal differentiation. Additionally, Notch signalling is found to enhance the proliferation and activation of astrocytes—the neural cell type involved in gliosis and scarring in the spinal cord after injury.

Importantly, in our research, we have found that upregulation of the Notch signalling pathway changes the differentiation profile of transplanted cells toward producing more astrocytes and fewer neurons. This is an unfavourable change, since neurons are critical for repairing the injured cord. We used qPCR gene expression analysis to better understand what factors contributed to Notch signalling and we discovered that the neurotrophic factor GDNF can attenuate Notch signalling, making the spinal cord microenvironment more hospitable for the transplanted cells.

Utilizing our novel bioengineering method, we generated glial cell–derived neurotrophic factor (GDNF) over-expressing cells that differentiated to more neurons when transplanted into the injured spinal cord, which included more excitatory interneurons and motor neurons. Additionally, these cells made more synaptic connections with the endogenous network, which allows for better signal relay across the injury site. We hypothesize that these new connections allow the body to more effectively produce the electrical signals needed for successful movement and sensation.

What are the potential clinical implications of these findings for the care of patients with SCI?

Dr. Fehlings: To date, there are no proven stem cell-based regenerative therapies available. Stem cell therapy has been slow to reach the clinic for a number of reasons, including ethical concerns surrounding the origin of the cells, host rejection, reduced integration of transplanted cells into the endogenous neural network, and the SCI environment that is hostile to cell survival and differentiation. Our approach bypasses ethical concerns and host rejection, since we are using a patient’s own cells to generate our GDNF over-expressing cells. Additionally, the over-expression of GDNF targets the Notch signalling pathway and makes the microenvironment more favourable for the cells, allowing them to differentiate to neurons and integrate into the endogenous neural network.

How does this study complement other SCI research inside the Fehlings Laboratory for Neural Repair and Regeneration and outside?

Dr. Fehlings: I have been studying stem cell therapies for the past 15 years due to their exciting potential to improve outcomes for those living with spinal cord injury. The condition is a complex problem and it is going to take a multifaceted approach to tackle the diverse pathology of SCI in order to produce meaningful improvements in function for patients. In my lab, I am working on approaches that tackle these problems, such as the use of stem cells, anti-inflammatory drugs, rehabilitation, electrical stimulation, biomaterials, and neuroprotective drugs. I believe this combinatorial approach will be the key to unlocking repair and regeneration of the injured spinal cord – and I hope this approach will soon have a major impact on the lives of patients and their families.

Is there anything else you would like to tell our readers about this research or topic?

Dr. Fehlings: Our next step is to refine this technology and move these cells toward the clinic by obtaining regulatory approval followed by a phase I clinical trial.

Importantly, this research was a team effort. Lead author Mohamad Khazaei, PhD, is a Scientific Associate at Fehlings Laboratory for Neural Repair and Regeneration and recently won the prestigious Stem Cells Translational Medicine Young Investigator Award.

Disclosures
Dr. Fehlings has no relevant disclosures.

Updated on: 02/05/20
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Effective Value-Based Initiatives for Complex Spine Surgery
Michael G. Fehlings, MD, PhD, FRCSC, FACS
Professor of Neurosurgery
Vice Chair Research, Department of Surgery
University of Toronto
Toronto, ON
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