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Extracellular Vesicles from Human Umbilical Cord Mesenchymal Stem Cells Facilitate Diabetic Wound Healing Through MiR-17-5p-mediated Enhancement of Angiogenesis

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Abstract

Endothelial dysfunction caused by persistent hyperglycemia in diabetes is responsible for impaired angiogenesis in diabetic wounds. Extracellular vehicles (EVs) are considered potential therapeutic tools to promote diabetic wound healing. The aim of this study was to investigate the effects of EVs secreted by human umbilical cord mesenchymal stem cells (hucMSC-EVs) on angiogenesis under high glucose (HG) conditions in vivo and in vitro and to explore the underlying mechanisms. In vivo, local application of hucMSC-EVs enhanced wound healing and angiogenesis. In vitro, hucMSC-EVs promoted proliferation, migration, and tube formation by inhibiting phosphatase and tensin homolog (PTEN) expression and activating the AKT/HIF-1α/VEGF pathways. MiR-17-5p was found to be highly enriched in hucMSC-EVs. In vitro, MiR-17-5p agomirs downregulated the expression of PTEN and activated the AKT/HIF-1α/VEGF pathway to promote proliferation, migration, and tube formation in HG-treated HUVECs. In vivo, miR-17-5p agomirs mimicked the effects of hucMSC-EVs on wound healing and angiogenesis, whereas miR-17-5p inhibitors reversed their effects. Our findings suggest that hucMSC-EVs have regenerative and protective effects on HG-induced endothelial cells via transfer of miR-17-5p targeting PTEN/ AKT/HIF-1α/VEGF pathway, thereby accelerating diabetic wound healing. Thus, hucMSC-EVs may be promising therapeutic candidates for improving diabetic wound angiogenesis.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the National Nature Science Foundation of China (81830064, 81721092, 81901971); the National Key Research Development Plan (2017YFC1103304); the CAMS Innovation Fund for Medical Sciences (CIFMS, 2019-I2M-5-059); the Military Medical Research and Development Projects (AWS17J005, 2019 − 126) and the Beijing Municipal Natural Science Foundation (7202197, 7194316).

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QW: design and performance of the in vivo and in vitro studies, result analysis and writing original manuscript draft; YW: in vivo transplantation and imaging studies; KM: preparation of the cells and in vitro studies; XB: EV studies and imaging; QL: RNA interference; BL: blood perfusion evaluation; WH: cell function evaluation; XF and CZ: design, result analysis, manuscript writing and editing, and funding acquisition. All authors have read and approved the final manuscript draft.

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Correspondence to Xiaobing Fu or Cuiping Zhang.

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Wei, Q., Wang, Y., Ma, K. et al. Extracellular Vesicles from Human Umbilical Cord Mesenchymal Stem Cells Facilitate Diabetic Wound Healing Through MiR-17-5p-mediated Enhancement of Angiogenesis. Stem Cell Rev and Rep 18, 1025–1040 (2022). https://doi.org/10.1007/s12015-021-10176-0

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