Mesenchymal stem cells ameliorate β cell dysfunction of human type 2 diabetic islets by reversing β cell dedifferentiation
Le Wang,
Tengli Liu,
Rui Liang,
Guanqiao Wang,
Yaojuan Liu,
Jiaqi Zou,
Na Liu,
Boya Zhang,
Yan Liu,
Xuejie Ding,
Xiangheng Cai,
Zhiping Wang,
Xiumin Xu,
Camillo Ricordi,
Shusen Wang,
Zhongyang Shen
Affiliations
Le Wang
Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China; NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China
Tengli Liu
NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China; Diabetes Research Institute Federation, Hollywood, FL 33021, USA
Rui Liang
NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China; Diabetes Research Institute Federation, Hollywood, FL 33021, USA
Guanqiao Wang
Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
Yaojuan Liu
NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China
Jiaqi Zou
NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China
Na Liu
NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China
Boya Zhang
Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
Yan Liu
Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
Xuejie Ding
Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
Xiangheng Cai
The First Central Clinical College, Tianjin Medical University, Tianjin, 300192, China
Zhiping Wang
Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
Xiumin Xu
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
Camillo Ricordi
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
Shusen Wang
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; Corresponding authors.
Zhongyang Shen
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; Corresponding authors.
Background: A physiological hallmark of patients with type 2 diabetes mellitus (T2DM) is β cell dysfunction. Despite adequate treatment, it is an irreversible process that follows disease progression. Therefore, the development of novel therapies that restore β 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 β cell dysfunction by reversing β 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 β 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 β 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 β cell dysfunction. Keywords: Mesenchymal stem cells, Type 2 diabetes mellitus, β cell dysfunction, Inflammation, β cell dedifferentiation
