hUC-MSC-exosomes deliver Let-7b/7f-5p to dermal papilla cells for a multi-target synergistic treatment of androgenetic alopecia

BACKGROUND: Exosomes play pivotal roles in immunomodulation, tissue regeneration, and the treatment of diseases. However, their specific mechanisms of action remain unclear. Therefore, this study aimed to elucidate the therapeutic mechanisms of human umbilical cord mesenchymal stem cell-derived exosomes (hUC-MSC-exosomes) in androgenic alopecia (AGA). We established a modified AGA mouse model and found that hUC-MSC-Exosomes could be taken up by dermal papilla cells (DPCs), promoted the transition of hair follicles from telogen to anagen, ameliorated hair follicle miniaturization, and enhanced hair regeneration and thickening. RESULTS: Cytological experiments revealed that exosomes inhibited aging and apoptosis of DPCs, promoted their proliferation and migration, increased alkaline phosphatase (ALP) levels, stimulated the secretion of paracrine cytokines, and reduced the expression level of the androgen receptor (AR). Exosomal miRNA sequencing analysis revealed that the top 10 miRNAs were primarily from the Let-7 family. GO and Reactome functional enrichment analyses and dual-luciferase reporter experiments revealed that hUC-MSC-exosomes delivered Let-7b-5p to target the deubiquitinating enzyme USP12, thereby inhibiting AR deubiquitination and promoting AR ubiquitination and degradation. This process further activates the Wnt/β-catenin pathway and suppresses the TGF-β/Smad pathway. CONCLUSIONS: In summary, this study provides insights into the underlying mechanisms of action of hUC-MSC-exosomes in AGA, indicating their therapeutic potential. In-depth analysis revealed that Let-7b-5p simultaneously targets DKK3 to activate the Wnt/β-catenin pathway in multiple dimensions. Moreover, hUC-MSC-exosomes delivered Let-7f-5p to target Smad2, synergizing with Let-7b to inhibit the TGF-β/Smad pathway and suppress DHT-induced DPC apoptosis. Further exploratory clinical trial showed that hUC-MSC-exosomes increased hair density and average hair diameter in patients with AGA.