Adipose-derived stem cells-derived exosomes facilitate cutaneous wound healing by delivering XIST and restoring discoidin domain receptor 2

Background: Adipose-derived stem cells (ADSCs) and their derived exosomes (ADSC-Exos) have shown potential functions in tissue repair. This study focuses on the effects of ADSCs-Exos on cutaneous wound healing and the potential involvement of the long non-coding RNA (lncRNA) XIST/microRNA-96-5p (miR-96-5p)/discoidin domain receptor 2 (DDR2) axis. Methods: Exos were isolated from the ADSCs and identified. A mouse model of full-thickness skin wounds was established. The mice were treated with ADSC-Exos to evaluate the function of ADSC-Exos in wound healing. Mouse dermal fibroblasts (MDFs) were co-cultured with the ADSC-Exos for in vitro experiments. The most differentially expressed lncRNAs in mouse skin tissues after ADSC-Exo treatment were screened by microarray analysis. The downstream molecules were analyzed by bioinformatics tools. Gain-and loss-of-function studies were performed to examine the functions of the XIST/miR-96-5p/DDR2 axis in wound healing. Results: ADSC-Exos facilitated wound healing in mice, reduced inflammatory infiltration, and increased collagen deposition in the wound skin tissues. In vitro, the ADSC-Exos promoted proliferation, migration of the MDFs. XIST was the most upregulated lncRNA in MDFs after ADSC-Exo treatment. Downregulation of XIST suppressed the promoting role of ADSC-Exos in wound healing. XIST bound to miR-96-5p to restore the expression of DDR2 mRNA. Either silencing of miR-96-5p or overexpression of DDR2 restored the promoting functions of ADSC-Exos in proliferation and migration of MDFs. Conclusion: This study demonstrates that ADSC-Exos-carried XIST accelerates cutaneous wound healing through suppressing miR-96-5p and restoring the DDR2 expression.