Crosstalk between Immune Microenvironment and Hair Follicle Cells Underlies Sexual Dimorphism in Androgenetic Alopecia

Abstract Androgenetic alopecia (AGA), also known as female pattern hair loss (FPHL) in women, is the most prevalent form of hair loss. It is characterized by progressive miniaturization of hair follicles and shortening of the anagen phase. The condition is widely attributed to genetic predisposition and androgen-mediated activation of androgen receptors. Other factors, such as the immune microenvironment, could also contribute to the pathogenesis. However, the specific mechanisms involved are still poorly understood. This study aimed to investigate the potential role of skin-resident myeloid cells in interacting with hair follicle cells under androgen stimulation, and to elucidate the sex-specific differences in dihydrotestosterone (DHT)-induced hair loss. Both female and male mice received DHT treatment, and histological examination was performed to assess DHT-induced alterations in skin morphology. Single-cell RNA sequencing (scRNA-seq) was utilized to profile skin cell populations and explore underlying mechanisms. Our results demonstrated that DHT inhibited hair regrowth in both sexes, altered skin thickness, and induced hair follicle miniaturization. scRNA-seq analysis revealed enhanced interactions between myeloid and fibroblast subpopulations, with more robust crosstalk observed in female mice. An in vitro experiment demonstrated that DHT promoted apoptosis of dermal papilla cells (DPCs) in the presence of macrophages. Treatment with polypeptides Y001 and Y002 effectively promoted hair regrowth by suppressing apoptosis signaling pathways. Our findings underscore the interactions between immune cells and hair follicular cells, particularly mediated by skin-resident myeloid cells, in the sexual dimorphism of androgenetic alopecia. The polypeptides Y001 and Y002 exhibit promising therapeutic potential by targeting apoptotic pathways, offering novel avenues for AGA treatment.