IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-31829-9.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-31829-9
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-31829-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Jason Flannick & Josep M. Mercader & Christian Fuchsberger & Miriam S. Udler & Anubha Mahajan & Jennifer Wessel & Tanya M. Teslovich & Lizz Caulkins & Ryan Koesterer & Francisco Barajas-Olmos & Thomas, 2019. "Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls," Nature, Nature, vol. 570(7759), pages 71-76, June.
    2. Robert Sladek & Ghislain Rocheleau & Johan Rung & Christian Dina & Lishuang Shen & David Serre & Philippe Boutin & Daniel Vincent & Alexandre Belisle & Samy Hadjadj & Beverley Balkau & Barbara Heude &, 2007. "A genome-wide association study identifies novel risk loci for type 2 diabetes," Nature, Nature, vol. 445(7130), pages 881-885, February.
    3. Zaniar Ghazizadeh & Der-I Kao & Sadaf Amin & Brandoch Cook & Sahana Rao & Ting Zhou & Tuo Zhang & Zhaoying Xiang & Reyn Kenyon & Omer Kaymakcalan & Chengyang Liu & Todd Evans & Shuibing Chen, 2017. "ROCKII inhibition promotes the maturation of human pancreatic beta-like cells," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    4. Adrian Veres & Aubrey L. Faust & Henry L. Bushnell & Elise N. Engquist & Jennifer Hyoje-Ryu Kenty & George Harb & Yeh-Chuin Poh & Elad Sintov & Mads Gürtler & Felicia W. Pagliuca & Quinn P. Peterson &, 2019. "Charting cellular identity during human in vitro β-cell differentiation," Nature, Nature, vol. 569(7756), pages 368-373, May.
    5. Liam Drew, 2021. "How stem cells could fix type 1 diabetes," Nature, Nature, vol. 595(7867), pages 64-66, July.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Sarah Meulebrouck & Judith Merrheim & Gurvan Queniat & Cyril Bourouh & Mehdi Derhourhi & Mathilde Boissel & Xiaoyan Yi & Alaa Badreddine & Raphaël Boutry & Audrey Leloire & Bénédicte Toussaint & Souhi, 2024. "Functional genetics reveals the contribution of delta opioid receptor to type 2 diabetes and beta-cell function," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Ping Rao & Hao Wang & Honghong Fang & Qing Gao & Jie Zhang & Manshu Song & Yong Zhou & Youxin Wang & Wei Wang, 2016. "Association between IGF2BP2 Polymorphisms and Type 2 Diabetes Mellitus: A Case–Control Study and Meta-Analysis," IJERPH, MDPI, vol. 13(6), pages 1-13, June.
    3. Vikash Chandra & Hazem Ibrahim & Clémentine Halliez & Rashmi B. Prasad & Federica Vecchio & Om Prakash Dwivedi & Jouni Kvist & Diego Balboa & Jonna Saarimäki-Vire & Hossam Montaser & Tom Barsby & Väin, 2022. "The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. Paul F O’Reilly & Clive J Hoggart & Yotsawat Pomyen & Federico C F Calboli & Paul Elliott & Marjo-Riitta Jarvelin & Lachlan J M Coin, 2012. "MultiPhen: Joint Model of Multiple Phenotypes Can Increase Discovery in GWAS," PLOS ONE, Public Library of Science, vol. 7(5), pages 1-1, May.
    5. Jiajin Li & Brandon Jew & Lingyu Zhan & Sungoo Hwang & Giovanni Coppola & Nelson B Freimer & Jae Hoon Sul, 2019. "ForestQC: Quality control on genetic variants from next-generation sequencing data using random forest," PLOS Computational Biology, Public Library of Science, vol. 15(12), pages 1-30, December.
    6. Hongyan Mao & Qin Li & Shujun Gao, 2012. "Meta-Analysis of the Relationship between Common Type 2 Diabetes Risk Gene Variants with Gestational Diabetes Mellitus," PLOS ONE, Public Library of Science, vol. 7(9), pages 1-7, September.
    7. Ren Matsuba & Minako Imamura & Yasushi Tanaka & Minoru Iwata & Hiroshi Hirose & Kohei Kaku & Hiroshi Maegawa & Hirotaka Watada & Kazuyuki Tobe & Atsunori Kashiwagi & Ryuzo Kawamori & Shiro Maeda, 2016. "Replication Study in a Japanese Population of Six Susceptibility Loci for Type 2 Diabetes Originally Identified by a Transethnic Meta-Analysis of Genome-Wide Association Studies," PLOS ONE, Public Library of Science, vol. 11(4), pages 1-9, April.
    8. Stephanie O. Erjavec & Sahar Gelfman & Alexa R. Abdelaziz & Eunice Y. Lee & Isha Monga & Anna Alkelai & Iuliana Ionita-Laza & Lynn Petukhova & Angela M. Christiano, 2022. "Whole exome sequencing in Alopecia Areata identifies rare variants in KRT82," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    9. Nicholette D Palmer & Caitrin W McDonough & Pamela J Hicks & Bong H Roh & Maria R Wing & S Sandy An & Jessica M Hester & Jessica N Cooke & Meredith A Bostrom & Megan E Rudock & Matthew E Talbert & Jos, 2012. "A Genome-Wide Association Search for Type 2 Diabetes Genes in African Americans," PLOS ONE, Public Library of Science, vol. 7(1), pages 1-14, January.
    10. Jennifer P. Nguyen & Timothy D. Arthur & Kyohei Fujita & Bianca M. Salgado & Margaret K. R. Donovan & Hiroko Matsui & Ji Hyun Kim & Agnieszka D’Antonio-Chronowska & Matteo D’Antonio & Kelly A. Frazer, 2023. "eQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    11. Inga Prokopenko & Wenny Poon & Reedik Mägi & Rashmi Prasad B & S Albert Salehi & Peter Almgren & Peter Osmark & Nabila Bouatia-Naji & Nils Wierup & Tove Fall & Alena Stančáková & Adam Barker & Vasilik, 2014. "A Central Role for GRB10 in Regulation of Islet Function in Man," PLOS Genetics, Public Library of Science, vol. 10(4), pages 1-13, April.
    12. Trine Welløv Boesgaard & Anette Prior Gjesing & Niels Grarup & Jarno Rutanen & Per-Anders Jansson & Marta Letizia Hribal & Giorgio Sesti & Andreas Fritsche & Norbert Stefan & Harald Staiger & Hans Här, 2009. "Variant near ADAMTS9 Known to Associate with Type 2 Diabetes Is Related to Insulin Resistance in Offspring of Type 2 Diabetes Patients—EUGENE2 Study," PLOS ONE, Public Library of Science, vol. 4(9), pages 1-7, September.
    13. Artak Labadzhyan & Jinrui Cui & Miklós Péterfy & Xiuqing Guo & Yii-Der I Chen & Willa A Hsueh & Jerome I Rotter & Mark O Goodarzi, 2016. "Insulin Clearance Is Associated with Hepatic Lipase Activity and Lipid and Adiposity Traits in Mexican Americans," PLOS ONE, Public Library of Science, vol. 11(11), pages 1-11, November.
    14. Ching-Yu Cheng & David Reich & Christopher A Haiman & Arti Tandon & Nick Patterson & Selvin Elizabeth & Ermeg L Akylbekova & Frederick L Brancati & Josef Coresh & Eric Boerwinkle & David Altshuler & H, 2012. "African Ancestry and Its Correlation to Type 2 Diabetes in African Americans: A Genetic Admixture Analysis in Three U.S. Population Cohorts," PLOS ONE, Public Library of Science, vol. 7(3), pages 1-9, March.
    15. Xueling Sim & Rick Twee-Hee Ong & Chen Suo & Wan-Ting Tay & Jianjun Liu & Daniel Peng-Keat Ng & Michael Boehnke & Kee-Seng Chia & Tien-Yin Wong & Mark Seielstad & Yik-Ying Teo & E-Shyong Tai, 2011. "Transferability of Type 2 Diabetes Implicated Loci in Multi-Ethnic Cohorts from Southeast Asia," PLOS Genetics, Public Library of Science, vol. 7(4), pages 1-12, April.
    16. Pasi J Eskola & Susanna Lemmelä & Per Kjaer & Svetlana Solovieva & Minna Männikkö & Niels Tommerup & Allan Lind-Thomsen & Kirsti Husgafvel-Pursiainen & Kenneth M C Cheung & Danny Chan & Dino Samartzis, 2012. "Genetic Association Studies in Lumbar Disc Degeneration: A Systematic Review," PLOS ONE, Public Library of Science, vol. 7(11), pages 1-10, November.
    17. Mengling Tang & Kun Chen & Fangxing Yang & Weiping Liu, 2014. "Exposure to Organochlorine Pollutants and Type 2 Diabetes: A Systematic Review and Meta-Analysis," PLOS ONE, Public Library of Science, vol. 9(10), pages 1-12, October.
    18. Sun, Yan V. & Jacobsen, Douglas M. & Turner, Stephen T. & Boerwinkle, Eric & Kardia, Sharon L.R., 2009. "Fast implementation of a scan statistic for identifying chromosomal patterns of genome wide association studies," Computational Statistics & Data Analysis, Elsevier, vol. 53(5), pages 1794-1801, March.
    19. Florian Mittag & Michael Römer & Andreas Zell, 2015. "Influence of Feature Encoding and Choice of Classifier on Disease Risk Prediction in Genome-Wide Association Studies," PLOS ONE, Public Library of Science, vol. 10(8), pages 1-18, August.
    20. Jing Yan & Yuemei Zhang & Hairong Yu & Yicen Zong & Daixi Wang & Jiangfei Zheng & Li Jin & Xiangtian Yu & Caizhi Liu & Yi Zhang & Feng Jiang & Rong Zhang & Xiangnan Fang & Ting Xu & Mingyu Li & Jianzh, 2022. "GPSM1 impairs metabolic homeostasis by controlling a pro-inflammatory pathway in macrophages," Nature Communications, Nature, vol. 13(1), pages 1-22, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31829-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.