Adipose-derived mesenchymal stem cell-loaded β-chitin nanofiber hydrogel activates the AldoA/HIF-1α pathway to promote diabetic wound healing

Objectives: To identify the effect of adipose-derived mesenchymal stem cell-loaded beta-chitin nanofiber (ADSC-loaded beta-ChNF) hydrogel on diabetic wound healing and clarify its mechanism of action. Methods: We prepared the ADSC-loaded beta-ChNF hydrogel to repair wounds of db/db diabetic mice. Wound healing rate, histopathology, enzyme-linked immunosorbent assay, and western blot were used to confirm its role and mechanism in promoting diabetic wound healing. Results: The ADSC-loaded beta-ChNF hydrogel accelerated wound healing in db/db diabetic mice, as indicated by increased cell proliferation, epithelization, and tissue granulation in the skin. Moreover, expression of vascular endothelial growth factor (VEGF) and its receptor (VEGFR), matrix metalloproteinase 9 (MMP9), and TIMP metallopeptidase inhibitor 1 (TIMP1) were upregulated. These results demonstrate the beneficial effects of this ADSC-loaded beta-ChNF hydrogel on diabetic wound healing. Furthermore, we show that the ADSC-loaded beta-ChNF hydrogel activated aldolase A (AldoA)/hypoxia-inducible factor 1 alpha (HIF-1 alpha) signaling. An inhibitor of HIF-1 alpha markedly decreased the promotive effects of the ADSC-loaded beta-ChNF hydrogel on wound healing and reduced expression of VEGF, VEGFR, MMP9, and TIMP1. Conclusions: Our findings suggest that the ADSC-loaded beta-ChNF hydrogel activated the HIF-1 alpha/MMP9 axis through AldoA feedback to promote diabetic wound healing.