Extracellular Vesicles from Human Umbilical Cord Mesenchymal Stem Cells Facilitate Diabetic Wound Healing Through MiR-17-5p-mediated Enhancement of Angiogenesis
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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来自人脐带间充质干细胞的细胞外囊泡通过 MiR-17-5p 介导的血管生成增强促进糖尿病伤口愈合
DOI：
10.1007/s12015-021-10176-0
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发表时间：
2021-05-04
影响因子：
4.8
通讯作者：
Zhang, Cuiping
中科院分区：
文献类型：
--
作者：
Wei, Qian;Wang, Yaxi;Zhang, Cuiping
糖尿病持续高血糖引起的内皮功能障碍是糖尿病伤口血管生成受损的原因。细胞外载体（EV）被认为是促进糖尿病伤口愈合的潜在治疗工具。本研究旨在探讨高糖环境下人脐带间充质干细胞（human umbilical cord mesenchymal stem cells，hucMSC-EVs）分泌的EVs对血管生成的影响及其机制。在体内，hucMSC-EV的局部应用增强了伤口愈合和血管生成。在体外，hucMSC-EV通过抑制磷酸酶和张力蛋白同源物（PTEN）表达和激活AKT/HIF-1 α/VEGF通路促进增殖、迁移和管形成。发现miR-17- 5 p在hucMSC-EV中高度富集。在体外，miR-17- 5 p agomirs下调PTEN的表达，并激活AKT/HIF-1 α/VEGF通路，以促进HG处理的HUVEC的增殖、迁移和管形成。在体内，miR-17- 5 p agomir模拟了hucMSC-EV对伤口愈合和血管生成的作用，而miR-17- 5 p抑制剂逆转了它们的作用。我们的研究结果表明，hucMSC-EV通过转移靶向PTEN/ AKT/HIF-1 alpha/VEGF通路的miR-17- 5 p对HG诱导的内皮细胞具有再生和保护作用，从而加速糖尿病伤口愈合。因此，hucMSC-EV可能是改善糖尿病伤口血管生成的有希望的治疗候选物。
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-1 alpha/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-1 alpha/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-1 alpha/VEGF pathway, thereby accelerating diabetic wound healing. Thus, hucMSC-EVs may be promising therapeutic candidates for improving diabetic wound angiogenesis.