Bone morphogenetic proteins prevent bone marrow stromal cell-mediated oligodendroglial differentiation of transplanted adult neural progenitor cells in the injured spinal cord

Abstract

The loss of oligodendroglia and demyelination contributes to the lack of functional recovery after spinal cord injury. The transplantation of adult neural progenitor cells (NPCs) might be a promising strategy to replace oligodendroglia lost after injury, however only a very small proportion of grafted NPCs differentiate into oligodendroglia. The present study aimed to investigate whether co-transplantation of subventricular zone-derived NPCs with bone marrow stromal cells (BMSCs) will enhance oligodendroglial differentiation of NPCs. In vitro, oligodendroglial differentiation was strongly enhanced by co-cultivation of NPCs with BMSCs or BMSC-conditioned medium. For in vivo experiments, adult Fischer 344 rats underwent cervical dorsal funiculus transections, immediately followed by grafting of 5-bromo-2′-deoxyuridine (BrdU) pre-labeled syngeneic NPCs mixed with BMSCs isolated from adult bone marrow. Six weeks post-injury and grafting, BMSC-containing grafts filled the lesion cavity but did not enhance oligodendroglial differentiation of co-grafted NPCs. The failure of BMSCs to induce oligodendroglial differentiation in vivo coincided with a rapid upregulation of bone morphogenetic protein 2/4 (BMP2/4) around the injury site and in vitro data demonstrated that BMP2/4 can override the oligodendrogenic effects of BMSCs. Moreover, blocking BMP activity can rescue the effect of BMSCs on NPCs. Thus, neutralization of BMP or BMP signaling might be required to allow for BMSC-induced oligodendroglial differentiation of grafted NPCs in the injured spinal cord.