Exosomes derived from adipose tissues accelerate fibroblasts and keratinocytes proliferation and cutaneous wound healing via miR-92a/Hippo-YAP axis.

ABSTRACT

Delayed wound healing is an urgent clinical issue. Cellular communication involving exosome-borne cargo such as miRNA is a critical mechanism involved in wound healing. This study isolated and identified human adipose tissue-derived exosomes (Exo-ATs). The specific effects of Exo-ATs on keratinocytes and fibroblasts were examined. Enriched miRNAs in Exo-ATs were analyzed, and miR-92a-3p was selected. The transfer of Exo-ATs-derived miR-92a-3p to keratinocytes and fibroblasts was verified. miR-92a-3p binding to LATS2 was examined and the dynamic effects of the miR-92a-3p/LATS2 axis were investigated. In a dorsal skin wound model, the in vivo effects of Exo-ATs on wound healing were examined. Exo-AT incubation increased keratinocytes and fibroblast proliferation, migration, and extracellular matrix (ECM) accumulation. miR-92a-3p, enriched in Exo-ATs, could be transferred to keratinocytes and fibroblasts, resulting in enhanced proliferation, migration, and ECM accumulation. Large tumor suppressor kinase 2 (LATS2) was a direct target of miR-92a-3p. miR-92a-3p inhibitor effects on keratinocytes and fibroblasts could be partially reversed by LATS2 knockdown. In a dorsal skin wound model, Exo-ATs accelerated wound healing through enhanced cell proliferation, collagen deposition, re-epithelialization, and YAP/TAZ activation. In conclusion, Exo-ATs improve skin wound healing by promoting keratinocyte and fibroblast migration and proliferation and collagen production by fibroblast, which could be partially eliminated by miR-92a inhibition through its downstream target LATS2 and the YAP/TAZ signaling.