Engineering exosomes from fibroblast growth factor 1 pre-conditioned adipose-derived stem cells promote ischemic skin flaps survival by activating autophagy

Background: The recovery of ischemic skin flaps is a major concern in clinical settings. The purpose of this study is to evaluate the effects of engineered exosomes derived from FGF1 pre-conditioned adipose-derived stem cells (FEXO) on ischemic skin flaps.

Method: 6 patients who suffered from pressure ulcer at stage 4 and underwent skin flaps surgery were recruited in this study to screen the potential targets of ischemic skin flaps in FGF family. FGF1 was co-incubated with adipose stem cells, and ultracentrifugation was applied to extract FEXO. Transcriptome sequencing analysis was used to determine the most effective microRNA in FEXO. Animal skin flaps models were established in our study to verify the effects of FEXO. Immunofluorescence (IF), western blotting (WB) and other molecular strategy were used to evaluate the effects and mechanism of FEXO.

Results: FGF1 was expected to be the therapeutic and diagnostic target of ischemic skin flaps, but there is still some deficiency in rescuing skin flaps. FEXO significantly improved the viability of RPSFs and endothelial cells by inhibiting oxidative stress and alleviating apoptosis and pyroptosis through augmenting autophagy flux. In addition, FEXO inhibited the over-activated inflammation responses. Transcriptome sequencing analysis showed that miR-183-5p was significantly elevated in FEXO, and inhibiting miR-183-5p resulted in impaired protective effects of autophagy in skin flaps. The exosomal miR-183-5p markedly enhanced cell viability, inhibited oxidative stress and alleviated apoptosis and pyroptosis in endothelial cells by targeting GPR137 through Pi3k/Akt/mTOR pathway, indicating that GPR137 could also be a therapeutic target of ischemic skin flap. It was also notabale that FGF1 increased the number of exosomes by upregulating VAMP3, which may be a promising strategy for clinical translation.

Conclusion: FEXO markedly improved the survivial rate of ischemic skin flaps through miR-183-5p/GPR137/Pi3k/Akt/mTOR axis, which would be a promising strategy to rescue ischemic skin flaps.