ArticleNature communications2022
ZnT8 loss-of-function accelerates functional maturation of hESC-derived β cells and resists metabolic stress in diabetes.
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Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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32citing papers in PubMed
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32 citing papers in PubMed, 42 citations in OpenAlex.
- Article
- Endocrine-Metabolic Crosstalk Between Diabetes Mellitus and Hypothyroidism: From Network Mechanisms to Translational Stratification.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Review
- Metal-dependent regulated cell death: Molecular architecture and translational frontiers.iMeta · 2026Review
- Zinc accumulation-induced integrated stress response triggers β-cell identity loss.Cell research · 2026Article
- To β or not to β: think zinc (again)!Cell research · 2026Article
- A loss of function variant inmedRxiv : the preprint server for health sciences · 2026Article
- Zinc dynamics in the pluripotent stem cells during maintenance of pluripotency and pancreatic differentiation.Scientific reports · 2026Article
- Diabetes and its complications: molecular mechanisms, prevention and treatment.Signal transduction and targeted therapy · 2026Review
- Type 2 diabetes mellitus and zinc dysregulation: From basic and epidemiological evidence to interventions.Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) · 2025Review
- Identifying Combinatorial Regulatory Genes for Cell Fate Decision via Reparameterizable Subset Explanations.KDD : proceedings. International Conference on Knowledge Discovery & Data Mining · 2025Article
- Zrt-Irt-like Proteins (ZIP) Family Zinc Transporters: Emerging Players in Pancreatic β Cell Function and Insulin Regulation.The Journal of nutrition · 2025Review
- A Compound Screen Based on Isogenic hESC-Derived β Cell Reveals an Inhibitor Targeting ZnT8-Mediated Zinc Transportation to Protect Pancreatic β Cell from Stress-Induced Cell Death.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Molecular puzzle of insulin: structural assembly pathways and their role in diabetes.Frontiers in cell and developmental biology · 2025Review
- A double knockout for zinc transporter 8 and somatostatin in mice reveals their distinct roles in regulation of insulin secretion and obesity.Genes & nutrition · 2024Article
- PARN Maintains RNA Stability to Regulate Insulin Maturation and GSIS in Pancreatic β Cells.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Alpha- to Beta-Cell Transdifferentiation in Neonatal Compared with Adult Mouse Pancreas in Response to a Modest Reduction in Beta-Cells Using Streptozotocin.International journal of molecular sciences · 2024Article
- Review
- Electrophysiological Characterization of Inducible Pluripotent Stem Cell-Derived Human β-Like Cells and an SLC30A8 Disease Model.Diabetes · 2024Article
- Organoid-guided precision hepatology for metabolic liver disease.Journal of hepatology · 2024Review
- Scaling Insulin-Producing Cells by Multiple Strategies.Endocrinology and metabolism (Seoul, Korea) · 2024Review
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Authors and funding
24 authors at 6 institutions in 2 countries.
Qing Ma *Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
Yini Xiao *State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, 200031, Shanghai, China.
Wenjun Xu *Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.ORCID 0000-0002-5931-7948
Menghan WangDepartment of Physiology and Pharmacology, Karolinska Institute, 17177, Solna, Sweden.
Sheng LiTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
Zhihao YangTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.ORCID 0000-0002-2006-279X
Minglu XuTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
Tengjiao ZhangTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
Zhen-Ning ZhangTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
Rui HuTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
Qiang SuTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.ORCID 0000-0002-7622-5711
Fei YuanTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.ORCID 0000-0002-4977-1872
Tinghui XiaoTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.ORCID 0000-0002-1660-5384
Xuan WangTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
Qing HeTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.ORCID 0000-0002-8869-3109
Jiaxu ZhaoState Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, 200031, Shanghai, China.
Zheng-Jun ChenState Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, 200031, Shanghai, China.ORCID 0000-0002-1748-5273
Zhejin ShengTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
Mengyao ChaiTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
Hong WangTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
Weiyang ShiMinistry of Education Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Tsingtao, 266003, China.
Qiaolin DengDepartment of Physiology and Pharmacology, Karolinska Institute, 17177, Solna, Sweden. qiaolin.deng@ki.se.ORCID 0000-0001-5934-7816
Xin ChengState Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, 200031, Shanghai, China. xcheng@sibcb.ac.cn.ORCID 0000-0002-6649-7959
Weida LiTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China. liweida@tongji.edu.cn.ORCID 0000-0001-8970-0633
Tongji University · CNCenter for Excellence in Molecular Cell Science · CNKarolinska Institutet · SEShanghai East Hospital · CNOcean University of China · CNShanghaiTech University · CN
Funding
No grant is acknowledged in the PubMed record.
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.
Indexed as
Cation Transport ProteinsDiabetes MellitusHuman Embryonic Stem CellsInsulin-Secreting CellsAnimalsGlucoseHumansInsulinMiceStress, PhysiologicalZincCation Transport ProteinsGlucoseInsulinZinc
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