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.
Tsingtao Advanced Research Institute, Tongji University, Qingdao, 266073, China.
Nat Commun. 2022 Jul 16;13(1):4142. doi: 10.1038/s41467-022-31829-9.
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.
人类胚胎干细胞衍生的β 细胞（SC-β 细胞）在治疗糖尿病方面具有巨大的应用前景，然而如何实现其功能成熟并保护其免受代谢应激（如糖毒性和脂毒性）的影响仍然难以捉摸。我们的单细胞 RNA 测序分析表明，ZnT8 功能丧失（LOF）加速了 SC-β 细胞的功能成熟。其结果是，ZnT8 LOF 通过释放锌对胰岛素分泌的抑制作用的负反馈，改善了葡萄糖刺激的胰岛素分泌（GSIS）。此外，我们证明，ZnT8 LOF 突变通过调节锌水平减轻内质网（ER）应激，赋予 SC-β 细胞对脂毒性/糖毒性诱导的细胞死亡的抵抗能力。重要的是，将具有 ZnT8 LOF 的 SC-β 细胞移植到患有糖尿病的小鼠体内，可显著改善血糖恢复和葡萄糖耐量。这些发现强调了 ZnT8 LOF 对 SC-β 细胞功能成熟和存活的有益影响，为细胞替代治疗提供了一种有潜力的来源。
