Pretreatment May Unlock the Regenerative Potential of Neural Stem Cells in Chronic Spinal Cord Injury

Michael G. Fehlings, MD, PhD, spoke with SpineUniverse about the study outcomes and potential clinical implications for patients with chronic spinal cord injury.

Pretreatment with the bacterial enzyme Chondroitinase ABC (ChABC) improves the regenerative outcome of neural stem cells (NSCs) in the chronically injured spinal cord, according to findings published in the August 3rd issue of PLoS One.

Chronic injury of the spinal cord results in the formation of a harsh injury microenvironment that is inhibitory to neural repair and regeneration; this is seen particularly with the creation of the glial scar formed by astrocytes surrounding the site of injury, explained senior author Michael G. Fehlings, MD, PhD, Professor of Neurosurgery and Co-Director of the Spine Program at the University of Toronto in Ontario, Canada. As part of the glial scarring process, inhibitory chondroitin sulfate proteoglycans (CSPGs) are deposited into the extracellular matrix, reducing the ability of axons to regenerate and repair following transplantation with exogenous NSCs Dr. Fehlings and colleagues noted in their paper.

“While stem cells show considerable promise as a potential therapeutic option for spinal cord injury, NSCs alone are not sufficient to enable repair and regeneration of the injured spinal cord unless one deals with these critical impediments to regeneration,” Dr. Fehlings told SpineUniverse.

“In this study, we showed that if we pre-treated the chronically injured spinal cord with an enzyme called ChABC, which degrades CSPGs in the extracellular matrix of the glial scar, it unlocks the potential for plasticity of the chronically injured spinal cord,” Dr. Fehlings explained.

One-Week Pretreatment Protocol Used
In the current study, a previously validated model of cervical spinal cord injury (SCI) was administered ChABC by intrathecal osmotic pump for 1 week, starting at 7 weeks after injury (ie, the chronic phase). Next, intraparenchymal-induced pluripotent stem cell-derived NSCs (iPS-NSC) were transplanted rostral and caudal to the injury epicenter. For comparison, other models of chronic cervical SCI were given ChABC only or iPS-NSCs only.

At 8 weeks post-transplant, the group pretreated with ChABC showed significantly increased survival of iPS-NSCs in the ChABC + iPS-NSC group compared with the group that received iPS-NSCs with no pretreatment: 7.88 ± 1.60% (15769 ± 3195 cells) vs 2.44 ± 1.04% (4876 ± 2079 cells; Figure). In addition, the neural cells differentiated along all three neuroglial lineages after transplantation in the pretreated group (ie, neurons, astrocytes, and oligodendrocytes).

Figure. Percent survival of transplanted iPSC-NSCs was significantly greater in chronic SCI models pretreated with ChABCFigure. Percent survival of transplanted iPSC-NSCs was significantly greater in chronic SCI models pretreated with ChABC. Reprinted from Suzuki H, Ahuja CS, Salewski RP, et al. Neural stem cell mediated recovery is enhanced by Chondroitinase ABC pretreatment in chronic cervical spinal cord injury. PLoS One. 2017;12(8):e0182339. *P<0.05.

In addition, the pretreatment group showed better recovery in key functional muscle groups, including forelimb grip strength and measures of forelimb/hindlimb locomotion assessed by Catwalk, compared with the other groups.

The findings indicate “a remarkable degree of regenerative potential of neural stem cells following ChABC pretreatment,” Dr. Fehlings said.

The 1-week pretreatment protocol was based on previous research by Dr. Fehlings and colleagues, showing that the use of ChABC over a 1-week period was sufficient to degrade glial scarring and to introduce plasticity into the injured cord, but was insufficient in and of itself to introduce functional benefit.1

Translation to Human Studies
“Our goal, ultimately, is to translate this research to human patients. However, we do feel that proof of concept studies in a number of diverse models of cervical spinal cord injury would be an essential next step,” Dr. Fehlings said.

The clinical implications of the findings could be “quite significant” for patients with chronic spinal cord injury, Dr. Fehlings told SpineUniverse. Current estimates suggest that more than 1.4 million people in the United States have a chronic spinal cord injury.2

“I would estimate that potentially a half-million Americans are living with severe chronic spinal cord injury in which a regenerative therapeutic approach could have substantial benefit if it were to work,” Dr. Fehlings said.

“In this setting of chronic severe spinal cord injury, while neural stem cells would appear to be quite attractive, they alone are insufficient to induce significant repair and regeneration,” Dr. Fehlings noted. “But, what if we could unlock the regenerative potential of the chronically injured central nervous system so that it resembled an acute or a sub-acute injury, and then introduce the neural stem cells and allow them to mediate their reparative or regenerative potential? That approach holds tremendous potential, and it has been shown that even relatively small functional benefits for people with a spinal cord injury can often have a significant improvement in quality of life and independence,” Dr. Fehlings concluded.

Updated on: 09/10/17
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