ZnT8 Loss-of-function Accelerates Functional Maturation of HESC-derived β Cells and Resists Metabolic Stress in Diabetes

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Jul 16

PMID 35842441

Authors

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

Zheng-Jun Chen

Zhejin Sheng

Mengyao Chai

Hong Wang

Weiyang Shi

Qiaolin Deng

Xin Cheng

Weida Li

Affiliations

Soon will be listed here.

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.

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