PMID- 37726853 OWN - NLM STAT- MEDLINE DCOM- 20230921 LR - 20231121 IS - 1757-6512 (Electronic) IS - 1757-6512 (Linking) VI - 14 IP - 1 DP - 2023 Sep 19 TI - Umbilical cord mesenchymal stem cell-derived apoptotic extracellular vesicles ameliorate cutaneous wound healing in type 2 diabetic mice via macrophage pyroptosis inhibition. PG - 257 LID - 10.1186/s13287-023-03490-6 [doi] LID - 257 AB - BACKGROUND: Delayed healing of diabetic cutaneous wounds is one of the most common complications of type 2 diabetes mellitus (T2DM), which can bring great distress to patients. In diabetic patients, macrophages accumulate around skin wounds and produce NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasomes, which in turn undergo pyroptosis and produce inflammatory factors such as interleukin-1beta that affect wound healing. Although our previous study revealed that apoptotic extracellular vesicles (ApoEVs) produced from mesenchymal stem cells (MSCs) improve cutaneous wound healing in normal C57BL/6 mice, whether ApoEVs can also improve diabetic wound healing remains unclear. METHODS: Umbilical cord mesenchymal stem cells (UCMSCs) were cultured in vitro and apoptosis was induced. ApoEVs were extracted and identified and used in a T2DM mouse cutaneous wound model to evaluate the efficacy. The inhibitory effect of ApoEVs on macrophage pyroptosis was verified in vivo and in vitro, and the level of oxidative stress in macrophages was assessed to explore the mechanism by which ApoEVs play a role. RESULTS: UCMSC-derived ApoEVs improved skin defect healing in T2DM mice. Moreover, UCMSC-derived ApoEVs inhibited macrophage pyroptosis in T2DM mice in vivo as well as in vitro under high-glucose culture conditions. In addition, we demonstrated that ApoEVs reduce oxidative stress levels, which is a possible mechanism by which they inhibit macrophage pyroptosis. CONCLUSIONS: Our study confirmed that local application of UCMSC-derived ApoEVs improved cutaneous wound healing in T2DM mice. ApoEVs, as products of MSC apoptosis, can inhibit macrophage pyroptosis and regulate the death process by decreasing the level of oxidative stress. CI - (c) 2023. BioMed Central Ltd., part of Springer Nature. FAU - Wang, Yiming AU - Wang Y AD - State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Oral Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China. AD - State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China. FAU - Jing, Lin AU - Jing L AD - State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China. FAU - Lei, Xiao AU - Lei X AD - State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China. AD - State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China. FAU - Ma, Zhen AU - Ma Z AD - State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Oral Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China. FAU - Li, Bei AU - Li B AD - State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China. AD - State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China. FAU - Shi, Yuanyuan AU - Shi Y AD - State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China. AD - The College of Life Sciences and Medicine, Northwest University, Xi'an, 710069, Shaanxi, China. FAU - Zhang, Wuyang AU - Zhang W AD - State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Oral Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China. FAU - Li, Yuan AU - Li Y AD - State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Oral Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China. FAU - Zhou, Hongzhi AU - Zhou H AD - State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Oral Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China. FAU - Hu, Kaijin AU - Hu K AD - State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Oral Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China. hukaijin2015@126.com. FAU - Xue, Yang AU - Xue Y AD - State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Oral Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China. xueyangfmmu@163.com. FAU - Jin, Yan AU - Jin Y AUID- ORCID: 0000-0002-2586-1152 AD - State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China. yanjin@fmmu.edu.cn. AD - State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China. yanjin@fmmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230919 PL - England TA - Stem Cell Res Ther JT - Stem cell research & therapy JID - 101527581 SB - IM MH - Animals MH - Mice MH - Mice, Inbred C57BL MH - Mice, Inbred NOD MH - Pyroptosis MH - *Diabetes Mellitus, Type 2/therapy MH - *Diabetes Mellitus, Experimental/therapy MH - Apoptosis MH - Disease Models, Animal MH - *Extracellular Vesicles MH - Macrophages MH - *Mesenchymal Stem Cells MH - Umbilical Cord MH - Wound Healing PMC - PMC10510296 OTO - NOTNLM OT - Apoptotic extracellular vesicles OT - Cell death regulation OT - Diabetic cutaneous wound OT - Oxidative stress OT - Pyroptosis COIS- The authors declare that they have no competing interests. EDAT- 2023/09/20 00:43 MHDA- 2023/09/21 06:42 PMCR- 2023/09/19 CRDT- 2023/09/19 23:55 PHST- 2022/12/12 00:00 [received] PHST- 2023/09/04 00:00 [accepted] PHST- 2023/09/21 06:42 [medline] PHST- 2023/09/20 00:43 [pubmed] PHST- 2023/09/19 23:55 [entrez] PHST- 2023/09/19 00:00 [pmc-release] AID - 10.1186/s13287-023-03490-6 [pii] AID - 3490 [pii] AID - 10.1186/s13287-023-03490-6 [doi] PST - epublish SO - Stem Cell Res Ther. 2023 Sep 19;14(1):257. doi: 10.1186/s13287-023-03490-6.