Significance of Remyelination by Neural Stem/Progenitor Cells Transplanted into the Injured Spinal Cord

Abstract

Previous reports of functional recovery from spinal cord injury (SCI) in rodents and monkeys after the delayed transplantation of neural stem/progenitor cells (NS/PCs) have raised hopes that stem cell therapy could be used to treat SCI in humans. More research is needed, however, to understand the mechanism of functional recovery. Oligodendrocytes derived from grafted NS/PCs remyelinate spared axons in the injured spinal cord. Here, we studied the extent of this remyelination's contribution to functional recovery following contusive SCI in mice. To isolate the effect of remyelination from other possible regenerative benefits of the grafted cells, NS/PCs obtained from myelin-deficient shiverer mutant mice (shi-NS/PCs) were used in this work alongside wild-type NS/PCs (wt-NS/PCs). shi-NS/PCs behaved like wt-NS/PCs in vitro and in vivo, with the exception of their myelinating potential. shi-NS/ PC-derived oligodendrocytes did not express myelin basic protein in vitro and formed much thinner myelin sheaths in vivo compared with wt-NS/PC-derived oligodendrocytes. The transplantation of shi-NS/PCs promoted some locomotor and electrophysiological functional recovery but significantly less than that afforded by wt-NS/PCs. These findings establish the biological importance of remyelination by graft-derived cells for functional recovery after the transplantation of NS/PCs into the injured spinal cord.

Allogeneic Neural Stem/Progenitor Cells Derived From Embryonic Stem Cells Promote Functional Recovery After Transplantation Into Injured Spinal Cord of Nonhuman Primates

“…Previous studies have demonstrated that NS/PC transplantation for SCI affects histological and/or functional outcomes in several processes, including neurotrophic support [32,33], angiogenesis [34,35], axonal regrowth [24,36], neural circuit reconstruction [37][38][39], and remyelination [40,41]. Most of these previous studies involved the use of rodent SCI models.…”

“…In contrast, remyelination is one of the potential mechanisms for functional recovery, especially at the late phase after NS/PC transplantation [40,41,57,58]. However, it is difficult to obtain oligodendrocytes derived from human NS/PCs [12] and human iPSC-NS/PCs [33] in vitro.…”

“…Remyelination does not occur easily at the early phase after transplantation. For example, Yasuda et al reported that remyelination only starts 6 weeks after transplantation [41]. It probably takes longer for marmoset ESC-NS/PCs to differentiate into mature oligodendrocytes than for mouse NS/PCs.…”

Translational Medicine of Stem Cells: Central Nervous System Regeneration and Modeling Neurological Diseases

“…In our previous studies [25][26][27][28][29][30] , we found that transplanted neural stem cells (NSCs) survived and differentiated into neurons, astrocytes, and oligodendrocytes, which are three major cellular components of the CNS. Graft-derived neurons formed synapses with host neurons and integrated with host neuronal circuits.…”

“…Graft-derived neurons formed synapses with host neurons and integrated with host neuronal circuits. Graft-derived oligodendrocytes were shown to participate in re-myelination of host axons in SCI models [ 28,30 ] , which signi fi cantly contributes to functional recovery after SCI [ 30 ] . It is possible that graft-derived astrocytes and undifferentiated NSCs produce various trophic factors that support angiogenesis [27][28][29] , cellular survival, and axonal regeneration of host axons including 5-HT-positive raphe-spinal tracts involved in the locomotive functions of hindlimbs [27][28][29] .…”