Department: Surgery, University of Toronto
Traumatic spinal cord injury (SCI) is a devastating neurological disorder that can affect anyone instantly. The mechanical insult of SCI rarely culminates in a complete transection of the cord. Rather, the majority of SCIs maintain a sub-population of demyelinated axons within the subpial rim of white matter. Moreover, the resulting secondary apoptotic loss of oligodendrocytes limits endogenous myelin repair and axonal conduction within the injured spinal cord. Our laboratory is interested in assessing the feasibility of transplanting adult brain-derived neural precursor cells (NPCs) as a regenerative medicine/cell replacement therapy to promote myelin repair and enhanced neurological recovery following experimental SCI. We have demonstrated that NPC survival and migration following sub-acute (2 weeks) post-SCI transplantation results in notable survival and migration in comparison to chronic NPC transplantation. Furthermore, surviving NPCs differentiate into oligodendrocytes that express myelin basic protein, ensheath axons and improved neurobehavioral recovery. Additional work in our laboratory has shown NPC transplantation promotes myelination of congenitally dysmyelinated axons, reconstruction of the nodes of Ranvier and enhancement axonal conduction. Currently we are actively investigating non-myelinating effects of NPC transplantation and examining combinatorial strategies using tissue engineering and neuroprotective strategies. Another promising and exciting area of research are induced Pluripotent Stem Cells (iPSCs). The promise of these is that sourcing from adults may be more feasible and have fewer ethical issues than using stem cells from embryonic or other sources. Furthermore, we have extended our research into Cerebral Palsy with a focus on remyelination. This work is linked to NeuroDevNet which is part of the Network of Centres of Excellence and also receives funding from the Ontario Brain Institute. In keeping with the team focus on translational medicine, we are leading international multicentre clinical trials in spinal cord injury
Recent Stem Cell Publications:
Salewski RP, Buttigieg J, Mitchell RA, van der Kooy D, Nagy A, Fehlings MG: The generation of definitive neural stem cells from piggyBac transposon induced pluripotent stem cells can be enhanced by induction of the NOTCH signaling pathway. Stem Cells and Development 2013: 22(3): pp 383-96.
Rowland JR, Lee JJ, Salewski RP, Eftekharpour E, van der Kooy D, Fehlings MG: Generation of neural stem cells from embryonic stem cells using the default mechanism: in vitro and in vivo characterization. Stem Cells and Development 2011: 20(11): pp 1829-45
Ruff CA, Ye H, Legasto JM, Stribbell NA, Wang J, Zhang L, Fehlings MG. Effects of adult neural precursor-derived myelination on axonal function in the perinatal congenitally dysmyelinated brain: optimizing time of intervention, developing accurate prediction models, and enhancing performance. J Neurosci. 2013 Jul 17;33(29):11899-915. doi: 10.1523/JNEUROSCI.1131-13.2013. PMID: 23864679