Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 318, Issue 5, Pages C848-C856Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00041.2020
Keywords
adipose-derived mesenchymal stem cells; autophagy; diabetic; exosomes; mmu_circ_0000250
Categories
Funding
- Natural Science Foundation of Jiangsu Province of China [BK20180946]
- Natural Science Foundation of Nantong City Grant [MS12018068]
- Science Foundation of China Postdoctoral Grant [2019M651928]
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More and more evidence advises that circular RNAs (circRNAs) function critically in regulating different disease microenvironments. Our previous study found that autotransplantation of adipose-derived mesenchymal stem cells (ADSCs) promotes diabetes wound healing. Exosomes derived in ADSCs play an important regulatory role. This study aimed to characterize if mmu_circ_0000250 played a role in ADSC-exosome-mediated full-thickness skin wound repair in diabetic rats. Endothelial progenitor cells (EPCs) were selected to study the therapeutic mechanism of exosomes in high-glucose (HG)-induced cell damage and dysfunction. Analysis and luciferase reporter assay were utilized to explore the interaction among mmu_circ_0000250, miRNA (miR)-128-3p, and sirtuin (SIRT)1. The diabetic rats were used to confirm the therapeutic effect of mmu_circ_0000250 against exosome-mediated wound healing. Exosomes containing a high concentration of mmu_circ_0000250 had a greater therapeutic effect on restoration of the function of EPCs by promotion autophagy activation under HG conditions. Expression of mmu_circ_0000250 promoted SIRT1 expression by miR-128-3p adsorption, which was confirmed via luciferase reporter assay and bioinformatics analysis. In vivo, exosomes containing a high concentration of mmu_circ_0000250 had a more therapeutic effect on wound healing when compared with wild-type exosomes from ADSCs. Immunohistochemistry and immunofluorescence detection showed that mmu_circ_0000250 increased angiopoiesis with exosome treatment in wound skin and suppressed apoptosis by autophagy activation. In conclusion, we verified that mmu_circ_0000250 enhanced the therapeutic effect of ADSC-exosomes to promote wound healing in diabetes by absorption of miR-128-3p and upregulation of SIRT1. Therefore, these findings advocate targeting the mmu_circ_0000250/miR-128-3p/SIRT1 axis as a candidate therapeutic option for diabetic ulcers.
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