VEGF-A promotes the proliferation and myelination of induced oligodendrocyte progenitor cells in rat spinal cord injury lesions

Abstract

Oligodendrocyte precursor cells (OPCs) transplantation represents a promising strategy for promoting spinal cord injury (SCI) recovery, However, the acquisition of allogeneic OPCs from human donors remains challenging due to resource limitation and ethical concerns. Induced OPCs (iOPCs) derived from human Wharton’s jelly cells (h-WJCs) offer a potential alternative for cell transplantation, however, their therapeutic efficacy is hindered by limited cell numbers and in vivo apoptosis. In this study, we identified vascular endothelial growth factor (VEGF-A) as a key factor promoting the proliferation and survival of h-WJC-derived iOPC, as demonstrated by CCK-8 and EdU assay. We further showed that activated T cell supernatant promotes iOPCs proliferation, which is blocked by VEGF-A receptor 2 inhibitor 5408. Transcriptomic analysis revealed the involvement of the MAPK/ERK signaling pathway and phosphorylated protein analysis showed that VEGF-A promotes the phosphorylation of Erk2, effects that attenuated by SU5408. However, transplantation of h-WJCs, iNSCs, and iOPCs alone yielded suboptimal recovery. To address this limitation, we engineered h-WJCs, iNSCs and iOPCs to express exogenous VEGF-A. Among these cells, only h-WJCs exhibited sustained VEGF-A secretion, whereas iNSCs and iOPCs produced low levels of VEGF-A, iOPCs underwent apoptosis, and iNSCs differentiated into GFAP-positive astrocytes. We then co-transplanted iOPCs with h-WJCs expressing VEGF-A into rat SCI. This mixed cell transplantation significantly enhanced cell survival and myelin-binding protein expression. Neuroelectrophysiological recording showed somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) even though no improvement in motor behaviour according to Basso, Beatie, and Bresnahan (BBB) Locomotor Rating Scale. In conclusion, VEGF-A promotes the proliferation and viability of iOPCs in injured spinal cord repair; a transplantation strategy involving mixed-cell grafts supplemented with VEGF-A holds a potential for improving SCI treatment outcomes.