Human Embryonic Stem Cell-Derived Oligodendrocyte Progenitors Aid in Functional Recovery of Sensory Pathways following Contusive Spinal Cord Injury

Abstract

BackgroundTransplantations of human stem cell derivatives have been widely investigated in rodent models for the potential restoration of function of neural pathways after spinal cord injury (SCI). Studies have already demonstrated cells survival following transplantation in SCI. We sought to evaluate survival and potential therapeutic effects of transplanted human embryonic stem (hES) cell-derived oligodendrocyte progenitor cells (OPCs) in a contusive injury in rats. Bioluminescence imaging was utilized to verify survivability of cells up to 4 weeks, and somatosensory evoked potential (SSEPs) were recorded at the cortex to monitor function of sensory pathways throughout the 6-week recovery period.Principal FindingshES cells were transduced with the firefly luciferase gene and differentiated into OPCs. OPCs were transplanted into the lesion epicenter of rat spinal cords 2 hours after inducing a moderate contusive SCI. The hES-treatment group showed improved SSEPs, including increased amplitude and decreased latencies, compared to the control group. The bioluminescence of transplanted OPCs decreased by 97% in the injured spinal cord compared to only 80% when injected into an uninjured spinal cord. Bioluminescence increased in both experimental groups such that by week 3, no statistical difference was detected, signifying that the cells survived and proliferated independent of injury. Post-mortem histology of the spinal cords showed integration of human cells expressing mature oligodendrocyte markers and myelin basic protein without the expression of markers for astrocytes (GFAP) or pluripotent cells (OCT4).ConclusionshES-derived OPCs transplanted 2 hours after contusive SCI survive and differentiate into OLs that produce MBP. Treated rats demonstrated functional improvements in SSEP amplitudes and latencies compared to controls as early as 1 week post-injury. Finally, the hostile injury microenvironment at 2 hours post-injury initially caused increased cell death but did not affect the long-term cell proliferation or survival, indicating that cells can be transplanted sooner than conventionally accepted.

Inhibition of TROY Promotes OPC Differentiation and Increases Therapeutic Efficacy of OPC Graft for Spinal Cord Injury

“…OPC grafts contribute to remyelination and therefore aid in restoring normal conduction [5,38,48]. However, OPC graft therapy faces two main challenges, one of which is the lack of abundant purified cell source.…”

Repairing the ventral root is sufficient for simultaneous motor and sensory recovery in multiple complete cervical root transection injuries

“…The delayed P1 and N1 latencies could indicate slower conduction velocities in the regenerated fibers. Because P1 represents cortical activation elicited by myelinated, large-diameter afferent fibers, an extended P1 latency could indicate that axon regeneration and remyelination are still in progress (All et al, 2012). To elucidate the origin of sensory afferents, the regrown axons were re-transected, which resulted in the loss of sensory behavior and SSEPs.…”

The Effects of Local and General Hypothermia on Temperature Profiles of the Central Nervous System Following Spinal Cord Injury in Rats

“…Our SCI model has been previously described (Agrawal et al, 2008(Agrawal et al, , 2010a(Agrawal et al, , 2010bAl-Nashash et al, 2009;All et al, 2009All et al, , 2010All et al, , 2012Iyer et al, 2010;Kerr et al, 2010;Bazley et al, 2011Bazley et al, , 2012aBazley et al, , 2012b. A laminectomy was performed by removing the T8 thoracic vertebra to expose the dorsal surface of the spinal cord without opening the dura mater.…”