Towards remyelination therapy using human bone marrow stromal cell-derived Schwann cells in rats after traumatic neural injury

Abstract

An ultimate goal of in vitro derivation of Schwann cells from human bone marrow stromal cells (hBMSCs) is such that they may be used autologously to assist post-traumatic nerve regeneration. Towards this end, Cai et al. (2017) selectively expanded neuro-ectodermal progenitor cells among the hBMSCs for cytokine induction into Schwann cell-like cells which, via contact-mediated signaling (Shea et al., 2020) with human iPSC-derived sensory neurons in co-culture, were switched into lineage-committed Schwann cells. Schwann cells so derived could be stored under liquid nitrogen for extended periods and thawed for use on demand.

One set of hBMSC-derived-Schwann cells (hBMSC-dSCs) was used to seed chitosan-based nerve guidance channels for bridging a critical gap in the rat model of sciatic nerve injury. By 12 weeks post-transplantation, electrophysiological studies revealed the success in signal conduction of evoked signals across the bridged nerves. Z-stacking of images captured under confocal microscopy revealed uni-axially aligned regrowing fibers positive for rat TUJ1; the fibers were associated with longitudinal, MBP-positive myelin layers that extended from the proximal to distal stump. Schwann cells doubly immunopositive for MBP and the human nucleus marker, HuN were identifiable in the nerve bridge. Thus, the hBMSC-dSCs remained functionally viable both in guiding axonal regrowth and mediating myelination of regrowing axons.

Another set of hBMSC-derived SCs was introduced into the contused thoracic cord together with chondroitinase ABC (ChABC). By 12 weeks post-transplantation, confocal microscopy revealed 2B6-positive epitopes indicative of ChABC cleavage of chondroitin sulfate proteoglycans (CSPGs). Cells were doubly positive for HuN and MBP detectable within the lesion site, indicated that the transplanted hBMSC-dSCs in the injured site with capacity for myelination. Behavioral assessments showed that the rats that received combined treatment have better prognosis and motor function recovery than rats that received single treatment or the vehicle control. Taken together, the combinatorial treatment with hBMSC-dSCs and ChABC promised post-traumatic axonal regrowth and remyelination, with prospects of motor recovery in a rat model of spinal cord injury.

Our results support translation into a protocol whereby hBMSC-dSCs become available for autologous transplantation and remyelination therapy in injuries of both the peripheral and central nervous systems. (347 words)