Hypoxic adipose stem cell‐derived exosomes carrying high‐abundant USP22 facilitate cutaneous wound healing through stabilizing HIF‐1α and upregulating lncRNA H19

Abstract Hypoxic preconditioning has been recognized as a promotive factor for accelerating cutaneous wound healing. Our previous study uncovered that exosomal lncRNA H19, derived from adipose‐derived stem cells (ADSCs), plays a crucial role in orchestrating cutaneous wound healing. Herein, we aimed to explore whether there is a connection between hypoxia and ADSC‐derived exosomes (ADSCs‐exos) in cutaneous wound healing. Exosomes extracted from ADSCs under normoxic and hypoxic conditions were identified using transmission electron microscope (TEM) and particle size analysis. The effects of ADSCs‐exos on the proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs) were evaluated by CCK‐8, EdU, wound healing, and tube formation assays. Expression patterns of H19, HIF‐1α, and USP22 were measured. Co‐immunoprecipitation, chromatin immunoprecipitation, ubiquitination, and luciferase reporter assays were conducted to confirm the USP22/HIF‐1α/H19 axis, which was further validated in a mice model of skin wound. Exosomes extracted from hypoxia‐treated ADSCs (termed as H‐ADSCs‐exos) significantly increased cell proliferation, migration, and angiogenesis in H 2 O 2 ‐exposed HUVECs, and promoted cutaneous wound healing in vivo. Moreover, H‐ADSCs and H‐ADSCs‐exos, which exhibited higher levels of H19, were found to be transcriptionally activated by HIF‐1α. Mechanically, H‐ADSCs carrying USP22 accounted for deubiquitinating and stabilizing HIF‐1α. Additionally, H‐ADSCs‐exos improved cell proliferation, migration, and angiogenesis in H 2 O 2 ‐triggered HUVECs by activating USP22/HIF‐1α axis and promoting H19 expression, which may provide a new clue for the clinical treatment of cutaneous wound healing.