Mef2c Promotes Peripheral Nerve Regeneration Through the Regulation of Schwann Cell Phenotype

Abstract

Schwann cells (SCs) play a crucial core role in peripheral nerve regeneration. The combination of peripheral nerve scaffolds and SCs for repairing nerve defects is a promising strategy. The conversion of SCs into repair SCs (rSCs) can promote axonal regeneration and tissue homeostasis, which is important for combination with peripheral nerve scaffolds to repair long segment defects. Autologous nerve grafts (ANGs) are the gold standard for the treatment of peripheral nerve defects and studying the phenotypic characteristics of SCs in nerve scaffolds. We employed single-nucleus RNA sequencing (snRNA-seq) and identified increased Mef2c expression in rSCs. Immunofluorescence staining of ANGs revealed significant upregulation of Mef2c during peripheral nerve regeneration. In vitro, Mef2c negatively regulated rat primary SC proliferation and migration. Transcriptomic analysis demonstrated the direct impact of Mef2c on key myelination factors such as Sox10, Egr2, and Stat3. In vivo, Mef2c suppression via Mef2c-siRNA hindered nerve regeneration, suggesting its role in restraining SC proliferation and migration while promoting myelination. These findings highlight the role of Mef2c in regulating remyelination after peripheral nerve injuries, making it a promising target to enhance peripheral nerve scaffold and SC-based therapies for long segment defect repair.

Keywords: Mef2c, Schwann cells, repair Schwann cells, Peripheral nerve regeneration, long segment defects, snRNA-seq