Combinatorial expression of glial transcription factors induces Schwann cell-specific gene expression in mouse...

Schwann cells provide peripheral nerve trophic support, myelinate axons, and assist in repair. However, Schwann cell repair capacity is limited by chronic injury, disease, and aging. Schwann cell reprogramming is a cellular conversion strategy that could provide a renewable cell supply to repair injured nerves. Here, we developed a plasmid-based approach to test the Schwann cell conversion potential of four glial transcription factors.

We employed four transcription factors implicated in Schwann cell differentiation and repair: Sox10, Sox2, Jun, and Pax3. Expression vectors were generated for Sox10 alone and two triple transcription factor combinations: Jun-Pax3-Sox2 (triple 1, T1) and Sox10-Jun-Sox2 (triple 2, T2). Mouse embryonic fibroblasts (MEFs) were transfected with these vectors, transferred to glial inductive media, and Schwann cell-marker expression was in assessed by immunostaining, flow cytometry, and qPCR. All expression vectors repressed fibroblast-specific gene expression. However, T2 was most efficient at generating O4⁺ Schwann cell-like cells, which had some capacity to myelinate denervated axons from explanted dorsal root ganglia. In comparison, T1 more efficiently induced repair Schwann cell-marker expression in converted O4⁺ cells.

T1 and T2 convert MEFs to Schwann cells with different efficacies and gene expression profiles, and may provide cell-based therapies for peripheral nerve repair.