Single-Cell RNA Sequencing Highlights a Contribution of Human Amniotic Mesenchymal Stem Cells-Derived Exosomes to Androgenetic Alopecia.

Androgenetic alopecia (AGA) is a prevalent disorder caused by dihydrotestosterone (DHT), characterized by hair follicle (HF) miniaturization and hair sparsity. Human amniotic mesenchymal stem cells (hAMSC) have been reported as promising stem cells for clinical therapy due to their no tumorigenicity, low immunogenicity, no ethical concerns, potent proliferative potential, and tissue repair. At present, the effects and underlying mechanism of exosomes derived from hAMSC (hAMSC-exo) on AGA are still not explored. Here, we reported that hAMSC-exo accelerated hair growth in AGA mice. Then, single-cell RNA sequencing was performed to analyze the cellular landscape of mouse dorsal skin, identifying 15 cell types and determining the differentiation trajectory of HF during hAMSC-exo-induced hair growth. It was found that hAMSC-exo strengthened crosstalk between cycling HF cells and niche-resident DPC, providing critical signaling for orchestrating hair follicle stem cells (HFSC) differentiation. Focusing on DPC, we further demonstrated that hAMSC-exo alleviated DHT-induced mitochondrial dysfunction and exerted protection against DHT-induced DPC damage via Wnt/β-catenin signaling, which may reset the HFSC niche to a favorable environment for HF regeneration. These results revealed the protective effect and molecular mechanisms of hAMSC-exo against hair loss at the single-cell level and provided a novel therapy combating AGA.