iPSC-derived sensory neurons for fate commitment of bone marrow-derived Schwann cells: Implication for re-myelination therapy

Abstract

This is a sequel to our effort of deriving Schwann cells from bone marrow stromal cells (BMSCs) as a resource for translational research. Earlier studies succeeded as far as generating neurospheres from BMSCs of adult rats and demonstrating competence of the neurosphere-derived cells for directed differentiation to Schwann cell-like cells; these however reverted to a myofibroblast-like phenotype upon withdrawal of the differentiation-inducing factors. We took an alternative approach and selected five small-molecule inhibitors of key signaling pathways in an 8-day program to induce differentiation of human iPSCs into sensory neurons, reaching ≥80% yield in terms of marker proteins. Continuing culture in maintenance medium then found neuronal networks which were electrically excitable, showing tetrodotoxin-sensitive action potentials in patch-clamp experiments. Co-culturing the human iPSC-derived sensory neurons with BMSC-derived Schwann cell-like cells mediated juxtacrine signaling that effected the cell-intrinsic switch to the Schwann cell fate. Henceforth, the cell progeny maintained the Schwann cell phenotype without need for exogenous differentiation-inducing factors or neurons. These derived Schwann cells were functionally capable of myelination and neurotrophic support of neurite growth in in vitro assays, similar to sciatic nerve-derived Schwann cells.