The androgen-THY1 axis mediates sexual dimorphism in dermal adipogenesis and fibrosis

Summary: Abstract Body: Sexual dimorphism manifests in human development and diseases, with the skin being one of the most sexually differentiated tissues. Dermal white adipose tissue (dWAT, also known as dermal fat) plays a crucial role in various skin processes including hair cycling, tissue regeneration and defense against bacterial infection. However, the sex differences in dermal fat and the underlying mechanism remain poorly understood. In this study, we analyzed the dynamic changes in dWAT during skin maturation and found that male dWAT volume were rapidly lost by 2 months of age, whereas female dWAT was relatively resistant to these age-dependent changes. Single-cell RNA sequencing identified dermal fibroblasts (dFBs) as the most sex-biased cell type. Specifically, female dFBs expressed elevated level of Thy1, while male dFBs exhibited increased expression of fibrotic-associated genes. Gonadectomy surgeries and fibroblast-specific androgen receptor (AR) knockout mice revealed that activation of AR signaling in dFBs contributed to the sexual dimorphism in dermal fat and downregulation of THY1 expression in dFBs. Next, we generated Thy1 knockout (KO) mice, and found that Thy1-KO skin exhibited a thinner fat layer and extensive collagen deposition compared to control skin. Mechanistically, Thy1 deficiency in dFBs led to increased susceptibility to TNF-mediated P38 phosphorylation and upregulation of fibrotic genes. In a large wound-induced skin fibrosis mouse model, deletion of Thy1 blocked the regeneration of dWAT layer and promoted ECM accumulation, whereas inhibiting AR signaling in dFBs restored THY1 expression and promoted skin regeneration in male mice. Together, our results show that androgen-driven loss of THY1 in dermal fibroblasts inhibits adipogenesis, promotes skin fibrosis, and prevents regeneration, providing a better understanding of skin sexual dimorphism under homeostatic and fibrotic conditions. Xiaowei Zhang¹, Xinyuan Zhang¹, Xiaoxuan Ji¹, Jiacheng Li¹, Lixiang Sun^{2, 1}, Ling-juan Zhang*¹ 1. School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen, China. 2. Central Laboratory, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. Stem Cell Biology, Tissue Regeneration and Wound Healing