P-MSC-derived extracellular vesicles facilitate diabetic wound healing via miR-145-5p/ CDKN1A-mediated functional improvements of high glucose-induced senescent fibroblasts

Jianlong Su; Qian Wei; Kui Ma; Yaxi Wang; Wenzhi Hu; Hao Meng; Qiankun Li; Yuehou Zhang; Wenhua Zhang; Haihong Li; Xiaobing Fu; Cuiping Zhang

doi:10.1093/burnst/tkad010

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P-MSC-derived extracellular vesicles facilitate diabetic wound healing via miR-145-5p/ CDKN1A-mediated functional improvements of high glucose-induced senescent fibroblasts

更新时间：2024-02-04

- P-MSC-derived extracellular vesicles facilitate diabetic wound healing via miR-145-5p/ CDKN1A-mediated functional improvements of high glucose-induced senescent fibroblasts
- Burns & Trauma Vol. 11, Issue 1, (2023)
- 作者机构：
  
  1. Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese PLA General Hospital
  2. School of Medicine, NanKai University
  3. Research Unit of Trauma Care
  4. Chinese Academy of Medical Sciences
  5. Burn and Plastic Surgery, Zhongda Hospital Affiliated Southeast University
  6. Department of Wound Repair
  7. Southern University of Science and Technology School of Medicine
  8. PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration
- 作者简介：
- 基金信息：
- DOI：10.1093/burnst/tkad010
  CLC：
- Published：2023，
  
  Published Online：18 October 2023，
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Jianlong Su, Qian Wei, Kui Ma, Yaxi Wang, Wenzhi Hu, Hao Meng, Qiankun Li, Yuehou Zhang, Wenhua Zhang, Haihong Li, Xiaobing Fu, Cuiping Zhang, P-MSC-derived extracellular vesicles facilitate diabetic wound healing via miR-145-5p/ CDKN1A-mediated functional improvements of high glucose-induced senescent fibroblasts, Burns & Trauma, Volume 11, 2023, tkad010, https://doi.org/10.1093/burnst/tkad010
DOI：

Jianlong Su, Qian Wei, Kui Ma, Yaxi Wang, Wenzhi Hu, Hao Meng, Qiankun Li, Yuehou Zhang, Wenhua Zhang, Haihong Li, Xiaobing Fu, Cuiping Zhang, P-MSC-derived extracellular vesicles facilitate diabetic wound healing via miR-145-5p/ CDKN1A-mediated functional improvements of high glucose-induced senescent fibroblasts, Burns & Trauma, Volume 11, 2023, tkad010, https://doi.org/10.1093/burnst/tkad010 DOI：

摘要

Abstract

BackgroundPersistent hyperglycaemia in diabetes causes functional abnormalities of human dermal fibroblasts (HDFs)

partially leading to delayed skin wound healing. Extracellular vesicles (EVs) containing multiple pro-healing microRNAs (miRNAs) have been shown to exert therapeutic effects on diabetic wound healing. The present study aimed to observe the effects of EVs derived from placental mesenchymal stem cells (P-MSC-EVs) on diabetic wound healing and high glucose (HG)-induced senescent fibroblasts and to explore the underlying mechanisms.MethodsP-MSC-EVs were isolated by differential ultracentrifugation and locally injected into the full-thickness skin wounds of diabetic mice

to observe the beneficial effects on wound healing in vivo by measuring wound closure rates and histological analysis. Next

a series of assays were conducted to evaluate the effects of low (2.28 x 1010 particles/ml) and high (4.56 x 1010 particles/ml) concentrations of P-MSC-EVs on the senescence

proliferation

migration

and apoptosis of HG-induced senescent HDFs in vitro. Then

miRNA microarrays and real-time quantitative PCR (RT–qPCR) were carried out to detect the differentially expressed miRNAs in HDFs after EVs treatment. Specific RNA inhibitors

miRNA mimics

and small interfering RNA (siRNA) were used to evaluate the role of a candidate miRNA and its target genes in P-MSC-EV-induced improvements in the function of HG-induced senescent HDFs.ResultsLocal injection of P-MSC-EVs into diabetic wounds accelerated wound closure and reduced scar widths

with better-organized collagen deposition and decreased p16INK4a expression. In vitro

P-MSC-EVs enhanced the antisenescence

proliferation

migration

and antiapoptotic abilities of HG-induced senescent fibroblasts in a dose-dependent manner. MiR-145-5p was found to be highly enriched in P-MSC-EVs. MiR-145-5p inhibitors effectively attenuated the P-MSC-EV-induced functional improvements of senescent fibroblasts. MiR-145-5p mimics simulated the effects of P-MSC-EVs on functional improvements of fibroblasts by suppressing the expression of cyclin-dependent kinase inhibitor 1A and activating the extracellular signal regulated kinase (Erk)/protein kinase B (Akt) signaling pathway. Furthermore

local application of miR-145-5p agomir mimicked the effects of P-MSC-EVs on wound healing.ConclusionsThese results suggest that P-MSC-EVs accelerate diabetic wound healing by improving the function of senescent fibroblasts through the transfer of miR-145-5p

which targets cyclin-dependent kinase inhibitor 1A to activate the Erk/Akt signaling pathway. P-MSC-EVs are promising therapeutic candidates for diabetic wound treatment.

关键词

Keywords

Diabetic woundsMesenchymal stem cellsExtracellular vesiclesmiR-145-5pCDKN1ASenescenceFibroblastglucose

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