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

Su, Jianlong1,2,3; Wei, Qian1,2; Ma, Kui1,2,4; Wang, Yaxi1,2; Hu, Wenzhi1,2; Meng, Hao1,2; Li, Qiankun1,2; Zhang, Yuehou5; Zhang, Wenhua1,2; Li, Haihong6; Fu, Xiaobing1,2,3,4,7,8; Zhang, Cuiping1,2,4,7,8

2023

10.1093/burnst/tkad010

BURNS & TRAUMA   影响因子和分区

2321-3868

2321-3876

["Background: Persistent 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.","Methods: P-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 10(10) particles/ml) and high (4.56 x 10(10) 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.","Results: Local 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.","Conclusions: These 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.","[GRAPHICS]","."]

Diabetic wounds Mesenchymal stem cells Extracellular vesicles miR-145-5p CDKN1A Senescence Fibroblast Glucose

SCI

英语

通讯

National Nature Science Foundation of China["82172211","81830064","82172231","81901971"] ; National Key Research and Development Programs of China[2022YFA1104303] ; CAMS Innovation Fund for Medical Sciences(CIFMS)[2019-I2M-5-059] ; Military Medical Research and Development Projects["AWS17J005","2019-126"] ; Military Medical Science and Technology Youth Training Program[21QNPY128]

Emergency Medicine ; Dermatology ; Surgery

Emergency Medicine ; Dermatology ; Surgery

WOS:001187779600001

OXFORD UNIV PRESS

Web of Science

1.Chinese Peoples Liberat Army Gen Hosp, Res Ctr Tissue Repair & Regenerat, Med Innovat Res Div, 51 Fucheng Rd, Beijing 100048, Peoples R China
2.Chinese Peoples Liberat Army Gen Hosp, Med Ctr 4, 51 Fucheng Rd, Beijing 100048, Peoples R China
3.NanKai Univ, Sch Med, 94 Weijin Rd, Tianjin 300071, Peoples R China
4.Chinese Acad Med Sci, Res Unit Trauma Care Tissue Repair & Regenerat, 2019RU051,51 Fucheng Rd, Beijing 100048, Peoples R China
5.Southeast Univ, Zhongda Hosp, Burn & Plast Surg, Dingjiaqiao 87, Nanjing 210009, Peoples R China
6.Southern Univ Sci & Technol, Southern Univ Sci & Technol Hosp, Sch Med, Dept Wound Repair,Inst Wound Repair & Regenerat M, 6019 Xililiuxian Rd, Shenzhen 518055, Peoples R China
7.PLA Key Lab Tissue Repair & Regenerat Med, 51 Fucheng Rd, Beijing 100048, Peoples R China
8.Beijing Key Res Lab Skin Injury Repair & Regenera, 51 Fucheng Rd, Beijing 100048, Peoples R China

Su, Jianlong,Wei, Qian,Ma, Kui,et al. P-MSC-derived extracellular vesicles facilitate diabetic wound healing via miR-145-5p/CDKN1A-mediated functional improvements of high glucose-induced senescent fibroblasts[J]. BURNS & TRAUMA,2023,11.

Su, Jianlong.,Wei, Qian.,Ma, Kui.,Wang, Yaxi.,Hu, Wenzhi.,...&Zhang, Cuiping.(2023).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,11.

Su, Jianlong,et al."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 11(2023).