Smurf2-induced degradation of SMAD2 causes inhibition of hair follicle stem cell differentiation

Abstract

Hair follicle stem cells (HFSCs) are implicated in the formation of hair follicles and epidermis. This study aims to clarify the role of SMAD2 in regulating the differentiation of HFSCs, which is involved with Smurf2. Functional assays were carried out in human HFSCs to assess the effect of SMAD2 and Smurf2 with altered expression on growth dynamics of HFSCs. Ubiquitination of SMAD2 and its protein stability were assessed. The binding relationship between NANOG and DNMT1 was assessed. A mouse skin wound model was induced to verify the effects of Smurf2/SMAD2/NANOG/DNMT1 on wound healing. SMAD2 overexpression was observed in HFSCs during differentiation and its ectopic expression contributed to promotion of differentiation and apoptosis of HFSCs while arresting cell proliferation. Mechanistic investigations indicated that Smurf2 promoted the ubiquitination and degradation of SMAD2, thus causing downregulation of SMAD2 expression. By this mechanism, NANOG expression was reduced and the subsequent DNMT1 transcriptional expression was also diminished, leading to suppression of differentiation and apoptosis of HFSCs while stimulating cell proliferation. Moreover, in vivo data showed that Smurf2 upregulation limited epidermal wound healing in mice by inhibiting the SMAD2/NANOG/DNMT1 axis. Our work proposed a potential target regarding SMAD2 restoration in promoting HFSC differentiation and skin wound healing.