ZnT8 loss-of-function accelerates functional maturation of hESC-derived β cells and resists metabolic stress in diabetes

• Published in: Nature communications Vol. 13; no. 1; pp. 4142 - 16
• Main Authors: Ma, Qing, Xiao, Yini, Xu, Wenjun, Wang, Menghan, Li, Sheng, Yang, Zhihao, Xu, Minglu, Zhang, Tengjiao, Zhang, Zhen-Ning, Hu, Rui, Su, Qiang, Yuan, Fei, Xiao, Tinghui, Wang, Xuan, He, Qing, Zhao, Jiaxu, Chen, Zheng-jun, Sheng, Zhejin, Chai, Mengyao, Wang, Hong, Shi, Weiyang, Deng, Qiaolin, Cheng, Xin, Li, Weida
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.07.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 13/2; 13/31; 14/1; 14/19; 631/532/2117; 631/80/82; 64/60; 692/163/2743/137; Beta cells; Blood glucose; Cell death; Cell survival; Cell therapy; Diabetes; Diabetes mellitus; Endoplasmic reticulum; Fragility; Genetic modification; Genome editing; Glucose; Glucose tolerance; Humanities and Social Sciences; Immunological tolerance; Insulin; Insulin secretion; Maturation; Metabolism; multidisciplinary; Mutation; Negative feedback; Science; Science (multidisciplinary); Secretion; Stem cells; Survival; Transplantation; Zinc
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31829-9

Human embryonic stem cell-derived β cells (SC-β cells) hold great promise for treatment of diabetes, yet how to achieve functional maturation and protect them against metabolic stresses such as glucotoxicity and lipotoxicity remains elusive. Our single-cell RNA-seq analysis reveals that ZnT8 loss of function (LOF) accelerates the functional maturation of SC-β cells. As a result, ZnT8 LOF improves glucose-stimulated insulin secretion (GSIS) by releasing the negative feedback of zinc inhibition on insulin secretion. Furthermore, we demonstrate that ZnT8 LOF mutations endow SC-β cells with resistance to lipotoxicity/glucotoxicity-triggered cell death by alleviating endoplasmic reticulum (ER) stress through modulation of zinc levels. Importantly, transplantation of SC-β cells with ZnT8 LOF into mice with preexisting diabetes significantly improves glycemia restoration and glucose tolerance. These findings highlight the beneficial effect of ZnT8 LOF on the functional maturation and survival of SC-β cells that are useful as a potential source for cell replacement therapies. Immature function and fragility hinder application of hESC-derived β cells (SC-β cell) for diabetes cell therapy. Here, the authors identify ZnT8 as a gene editing target to enhance the insulin secretion and cell survival under metabolic stress by abolishing zinc transport in SC-β cells.