PMID- 31918404 OWN - NLM STAT- MEDLINE DCOM- 20200930 LR - 20210110 IS - 2352-3964 (Electronic) IS - 2352-3964 (Linking) VI - 51 DP - 2020 Jan TI - Mesenchymal stem cells ameliorate beta cell dysfunction of human type 2 diabetic islets by reversing beta cell dedifferentiation. PG - 102615 LID - S2352-3964(19)30830-8 [pii] LID - 10.1016/j.ebiom.2019.102615 [doi] LID - 102615 AB - BACKGROUND: A physiological hallmark of patients with type 2 diabetes mellitus (T2DM) is beta cell dysfunction. Despite adequate treatment, it is an irreversible process that follows disease progression. Therefore, the development of novel therapies that restore beta cell function is of utmost importance. METHODS: This study aims to unveil the mechanistic action of mesenchymal stem cells (MSCs) by investigating its impact on isolated human T2DM islets ex vivo and in vivo. FINDINGS: We propose that MSCs can attenuate beta cell dysfunction by reversing beta cell dedifferentiation in an IL-1Ra-mediated manner. In response to the elevated expression of proinflammatory cytokines in human T2DM islet cells, we observed that MSCs was activated to secret IL-1R antagonist (IL-1Ra) which acted on the inflammed islets and reversed beta cell dedifferentiation, suggesting a crosstalk between MSCs and human T2DM islets. The co-transplantation of MSCs with human T2DM islets in diabetic SCID mice and intravenous infusion of MSCs in db/db mice revealed the reversal of beta cell dedifferentiation and improved glycaemic control in the latter. INTERPRETATION: This evidence highlights the potential of MSCs in future cell-based therapies regarding the amelioration of beta cell dysfunction. CI - Copyright (c) 2019 The Author(s). Published by Elsevier B.V. All rights reserved. FAU - Wang, Le AU - Wang L AD - Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China; NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China. FAU - Liu, Tengli AU - Liu T AD - NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China; Diabetes Research Institute Federation, Hollywood, FL 33021, USA. FAU - Liang, Rui AU - Liang R AD - NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China; Diabetes Research Institute Federation, Hollywood, FL 33021, USA. FAU - Wang, Guanqiao AU - Wang G AD - Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China. FAU - Liu, Yaojuan AU - Liu Y AD - NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China. FAU - Zou, Jiaqi AU - Zou J AD - NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China. FAU - Liu, Na AU - Liu N AD - NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China. FAU - Zhang, Boya AU - Zhang B AD - Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China. FAU - Liu, Yan AU - Liu Y AD - Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China. FAU - Ding, Xuejie AU - Ding X AD - Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China. FAU - Cai, Xiangheng AU - Cai X AD - The First Central Clinical College, Tianjin Medical University, Tianjin, 300192, China. FAU - Wang, Zhiping AU - Wang Z AD - Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China. FAU - Xu, Xiumin AU - Xu X AD - Diabetes Research Institute, Cell Transplant Centre; Department of Surgery; Department Medicine; Miller School of Medicine, University of Miami, Miami, FL 33136, USA; The Cure Alliance, Miami, FL 33137, USA; Diabetes Research Institute Federation, Hollywood, FL 33021, USA. FAU - Ricordi, Camillo AU - Ricordi C AD - Diabetes Research Institute, Cell Transplant Centre; Department of Surgery; Department Medicine; Miller School of Medicine, University of Miami, Miami, FL 33136, USA; The Cure Alliance, Miami, FL 33137, USA; Diabetes Research Institute Federation, Hollywood, FL 33021, USA. FAU - Wang, Shusen AU - Wang S AD - Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China; NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China; Diabetes Research Institute Federation, Hollywood, FL 33021, USA. Electronic address: shusen@vip.163.com. FAU - Shen, Zhongyang AU - Shen Z AD - Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China; Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China. Electronic address: zhongyangshen@vip.sina.com. LA - eng PT - Journal Article DEP - 20200106 PL - Netherlands TA - EBioMedicine JT - EBioMedicine JID - 101647039 RN - 0 (IL1RN protein, human) RN - 0 (Interleukin 1 Receptor Antagonist Protein) RN - 0 (Interleukin-1beta) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - Animals MH - *Cell Dedifferentiation MH - Diabetes Mellitus, Type 2/*pathology/therapy MH - Female MH - Humans MH - Insulin-Secreting Cells/*pathology MH - Interleukin 1 Receptor Antagonist Protein/metabolism MH - Interleukin-1beta/metabolism MH - Male MH - Mesenchymal Stem Cell Transplantation MH - Mesenchymal Stem Cells/*metabolism MH - Mice, SCID MH - Middle Aged MH - Tumor Necrosis Factor-alpha/metabolism PMC - PMC7000334 OTO - NOTNLM OT - Inflammation OT - Mesenchymal stem cells OT - Type 2 diabetes mellitus OT - beta cell dedifferentiation OT - beta cell dysfunction COIS- Declaration of Competing Interest No conflict of interest to disclose. EDAT- 2020/01/10 06:00 MHDA- 2020/10/02 06:00 PMCR- 2020/01/06 CRDT- 2020/01/10 06:00 PHST- 2019/09/11 00:00 [received] PHST- 2019/12/05 00:00 [revised] PHST- 2019/12/17 00:00 [accepted] PHST- 2020/01/10 06:00 [pubmed] PHST- 2020/10/02 06:00 [medline] PHST- 2020/01/10 06:00 [entrez] PHST- 2020/01/06 00:00 [pmc-release] AID - S2352-3964(19)30830-8 [pii] AID - 102615 [pii] AID - 10.1016/j.ebiom.2019.102615 [doi] PST - ppublish SO - EBioMedicine. 2020 Jan;51:102615. doi: 10.1016/j.ebiom.2019.102615. Epub 2020 Jan 6.