Transplantation of Pro-Oligodendroblasts, Preconditioned by LPS-Stimulated Microglia, Promotes Recovery After Acute Contusive Spinal Cord Injury.

Abstract

Spinal cord injury (SCI) is a significant clinical challenge, and to date no effective treatment is available. Oligodendrocyte progenitor cell (OPC) transplantation has been a promising strategy for SCI repair. However, the poor posttransplantation survival and deficiency in differentiation into myelinating oligodendrocytes (OLs) are two major challenges that limit the use of OPCs as donor cells. Here we report the generation of an OL lineage population [i.e., pro-oligodendroblasts (proOLs)] that is relatively more mature than OPCs for transplantation after SCI. We found that proOLs responded to lipopolysaccharide (LPS)-stimulated microglia conditioned medium (L+M) by preserving toll-like receptor 4 (TLR4) expression, improving cell viability, and enhancing the expression of a myelinating OL marker myelin basic protein (MBP), compared to other OL lineage cells exposed to either LPS-stimulated (L+M) or nonstimulated microglia conditioned medium (LM). When L+M-stimulated proOLs were intrathecally delivered through a lumbar puncture after a T10 thoracic contusive SCI, they promoted behavioral recovery, as assessed by the BassoBeattieBresnahan (BBB) locomotor rating scale, stride length, and slips on the grid tests. Histologically, transplantation of L+M proOLs caused a considerable increase in intralesional axon numbers and myelination, and less accumulation of invading macrophages when compared with the vehicle control or OPC transplantation. Thus, transplantation of proOLs, preconditioned by L+M, may offer a better therapeutic potential for SCI than OPCs since the former may have initiated the differentiation process toward OLs prior to transplantation.