ZnT8 loss-of-function accelerates functional maturation of hESC-derived β cells and resists metabolic stress in diabetes
Qing Ma, Yini Xiao, Wenjun Xu, Menghan Wang, Sheng Li, Zhihao Yang, Minglu Xu, Tengjiao Zhang, Zhen‐Ning Zhang, Rui Hu, Qiang Su, Fei Yuan, Tinghui Xiao, Xuan Wang, Qing He, Jiaxu Zhao, Zhengjun Chen, Zhejin Sheng, Mengyao Chai, Hong Wang, Weiyang Shi, Qiaolin Deng, Xin Cheng, Weida Li
Abstract
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.