Enhanced Schwann cell differentiation of skin-derived neural crest-like stem cells through the synergistic action of SOX10 and immobilized NRG1 signaling

Human skin-derived neural crest (NC)-like stem cells present a highly accessible, autologous source of multipotent cells, with the potential to differentiate into a variety of cell types, including Schwann cells (SCs). However, these cells quickly lose their stem-like characteristics in vitro and eventually limit their ability to form functional SCs. To overcome this, we investigated SOX10 upregulation, the key regulator of NC formation and multipotency, using both small chemical (Forskolin and RepSox) treatment and genetic modification. Remarkably, SOX10 upregulation highly increased SC gene expression instead of NC markers, though Forskolin-RepSox also triggered melanocytic and smooth muscle gene markers alongside reduced NC genes. In contrast, genetic SOX10 upregulation enhanced both SOX10 and NC gene expression without inducing alternative lineages. Continuous SOX10 expression was necessary for increased SC protein markers, and differentiating SOX10-overexpressing cells on immobilized NRG1 further enhanced SC markers and induced a distinct, elongated morphology typical for myelinating SCs. Therefore, this study introduces a rapid, efficient method to derive SC-like cells from the skin-derived NCs, highlighting their potential in regenerative medicine for cell therapy and disease modeling applications.