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

Author

Listed:
  • Qing Ma

    (Tongji University
    Tongji University)

  • Yini Xiao

    (University of Chinese Academy of Sciences)

  • Wenjun Xu

    (Tongji University
    Tongji University)

  • Menghan Wang

    (Karolinska Institute)

  • Sheng Li

    (Tongji University
    Tongji University)

  • Zhihao Yang

    (Tongji University
    Tongji University)

  • Minglu Xu

    (Tongji University
    Tongji University)

  • Tengjiao Zhang

    (Tongji University
    Tongji University)

  • Zhen-Ning Zhang

    (Tongji University
    Tongji University)

  • Rui Hu

    (Tongji University
    Tongji University)

  • Qiang Su

    (Tongji University
    Tongji University)

  • Fei Yuan

    (Tongji University
    Tongji University)

  • Tinghui Xiao

    (Tongji University
    Tongji University)

  • Xuan Wang

    (Tongji University
    Tongji University)

  • Qing He

    (Tongji University
    Tongji University)

  • Jiaxu Zhao

    (University of Chinese Academy of Sciences
    Fudan University)

  • Zheng-jun Chen

    (University of Chinese Academy of Sciences
    ShanghaiTech University)

  • Zhejin Sheng

    (Tongji University)

  • Mengyao Chai

    (Tongji University
    Tongji University)

  • Hong Wang

    (Tongji University)

  • Weiyang Shi

    (Ocean University of China)

  • Qiaolin Deng

    (Karolinska Institute)

  • Xin Cheng

    (University of Chinese Academy of Sciences)

  • Weida Li

    (Tongji University
    Tongji University)

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.

Suggested Citation

  • 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 , 2022. "ZnT8 loss-of-function accelerates functional maturation of hESC-derived β cells and resists metabolic stress in diabetes," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31829-9
    DOI: 10.1038/s41467-022-31829-9
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