Platelet‐derived growth factor‐responsive neural precursors give rise to myelinating oligodendrocytes after transplantation into the spinal cords of contused rats and dysmyelinated mice

Abstract

Spinal cord injury (SCI) results in substantial oligodendrocyte death and subsequent demyelination leading to white-matter defects. Cell replacement strategies to promote remyelination are under intense investigation; however, the optimal cell for transplantation remains to be determined. We previously isolated a platelet-derived growth factor (PDGF)-responsive neural precursor (PRP) from the ventral forebrain of fetal mice that primarily generates oligodendrocytes, but also astrocytes and neurons. Importantly, human PRPs were found to possess a greater capacity for oligodendrogenesis than human epidermal growth factor- and/or fibroblast growth factor-responsive neural stem cells. Therefore, we tested the potential of PRPs isolated from green fluorescent protein (GFP)-expressing transgenic mice to remyelinate axons in the injured rat spinal cord. PRPs were transplanted 1 week after a moderate thoracic (T9) spinal cord contusion in adult male rats. After initial losses, PRP numbers remained stable from 2 weeks posttransplantation onward and those surviving cells integrated into host tissue. Approximately one-third of the surviving cells developed the typical branched phenotype of mature oligodendrocytes, expressing the marker APC-CC1. The close association of GFP cells with myelin basic protein as well as with Kv1.2 and Caspr in the paranodal and juxtaparanodal regions of nodes of Ranvier indicated that the transplanted cells successfully formed mature myelin sheaths. Transplantation of PRPs into dysmyelinated Shiverer mice confirmed the ability of PRP-derived cells to produce compact myelin sheaths with normal periodicity. These findings indicate that PRPs are a novel candidate for CNS myelin repair, although PRP-derived myelinating oligodendrocytes were insufficient to produce behavioral improvements in our model of SCI.

Long-Distance Axonal Growth from Human Induced Pluripotent Stem Cells after Spinal Cord Injury

“…These cells form functional relays across sites of complete spinal cord transection to restore conductivity across a lesion site and improve functional outcomes (Lu et al, 2012b). Grafts of neural progenitor cells can also remyelinate spared axons surrounding sites of partial spinal cord injury, and may have neuroprotective properties (Cummings et al, 2005; Keirstead et al, 2005; Plemel et al, 2011). …”

Human Embryonic Stem Cell-Derived Oligodendrocytes: Protocols and Perspectives

“…EGF is a mitogen, which was shown to increase the pool of OPCs in rodents [79,80] and may well be able to replace PDGF in protocols used for oligodendrocyte differentiation from hESCs [20,21]. However, the addition of PDGF appears important in promoting differentiation to OPCs but not necessarily to mature oligodendrocytes [81], and so would seem an important inclusion during the early stages of hESCdifferentiation. Supporting this contention is the evidence through careful dissection of developmental pathways, which established that PDGF could prevent premature differentiation and enhance proliferation by controlling the timing of oligodendrocyte maturation [82][83][84].…”

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

“…In addition, PDGF induces the remyelination of NS/PCs into oligodendrocytes [55]. Finally, VEGF facilitates angiogenesis at the lesion site by inhibiting cell death [56].…”