Targeting the Thy-1 mechanotransduction regulator rescues regenerative wound healing and induces hair follicle neogenesis under high tension

Abstract

Abstract Mechanical tension is a critical driver of hypertrophic scar (HS) formation, primarily by inducing the differentiation of fibroblasts into pathological myofibroblasts. However, the upstream mechanotransduction regulators that initiate this fibrotic cell fate switch remain poorly understood. This study investigates the role of the glycoprotein Thy-1 (CD90) as a mechanotransduction regulator and its regulation of the p38MAPK signaling pathway under high-tension conditions. We established a murine high-tension scar model to simulate pathological scarring in vivo. Recombinant adeno-associated virus (rAAV) vectors were administered to locally knock down or overexpress Thy-1. Results demonstrated that Thy-1 was significantly upregulated and activated by high tension. Local knockdown of Thy-1 significantly reduced scar area and promoted orderly collagen arrangement. Crucially, Thy-1 silencing shifted the healing process toward functional regeneration, evidenced by the neogenesis of hair follicles and sebaceous glands. Mechanistically, silencing Thy-1 suppressed the downstream pro-fibrotic program, including p38MAPK phosphorylation, transforming growth factor-beta (TGF-β) expression, alpha-smooth muscle actin (α-SMA) levels, and excessive deposition of Collagen I and III. In vitro studies indicated that Thy-1 knockdown enhanced fibroblast proliferation and migration, suggesting its pathological role lies in driving terminal fibrotic differentiation. The Thy-1/p38MAPK axis acts as a crucial mechanotransduction pathway governing fibroblast-to-myofibroblast differentiation. Targeting this axis represents a promising therapeutic strategy to switch cell fate during healing, preventing pathological scarring and promoting functional skin regeneration.