ZnT8 loss-of-function accelerates functional maturation of hESC-derived β cells and resists metabolic stress in diabetes.
ZnT8 loss-of-function accelerates functional maturation of hESC-derived β cells and resists metabolic stress in diabetes.
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锌T8功能丧失可加速人胚胎干细胞来源的β细胞的功能成熟，并抵抗糖尿病时的代谢应激。
DOI：
10.1038/s41467-022-31829-9
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发表时间：
2022-07-16
影响因子：
16.6
通讯作者：
Li, Weida
中科院分区：
文献类型：
--
作者：
Ma, Qing;Xiao, Yini;Xu, Wenjun;Wang, Menghan;Li, Sheng;Yang, Zhihao;Xu, Minglu;Zhang, Tengjiao;Zhang, Zhen-Ning;Hu, Rui;Su, Qiang;Yuan, Fei;Xiao, Tinghui;Wang, Xuan;He, Qing;Zhao, Jiaxu;Chen, Zheng-jun;Sheng, Zhejin;Chai, Mengyao;Wang, Hong;Shi, Weiyang;Deng, Qiaolin;Cheng, Xin;Li, Weida
人胚胎干细胞来源的β细胞(SC-β细胞)在治疗糖尿病方面前景看好，但如何实现功能成熟并保护它们免受糖毒性和脂毒性等代谢应激的影响仍是个未知数。我们的单细胞RNA-SEQ分析表明，锌的功能丧失(LOF)加速了SC-β细胞的功能成熟。因此，通过释放锌抑制胰岛素分泌的负反馈，锌LOF改善了葡萄糖刺激的胰岛素分泌(GSIS)。此外，我们还证明，通过调节锌水平来减轻内质网(ER)应激，锌锌LOF突变赋予SC-β细胞对脂毒性/糖毒性引起的细胞死亡的抵抗力。重要的是，将带有ZnT8LOF的SC-β细胞移植到先前存在糖尿病的小鼠体内，显著改善了血糖恢复和葡萄糖耐量。这些发现突出了锌低氧对SC-β细胞功能成熟和存活的有益影响，这是一种潜在的细胞替代治疗来源。人胚胎干细胞来源的β细胞(SC-β细胞)的功能不成熟和脆性阻碍了其在糖尿病细胞治疗中的应用。在此，作者认为锌是一个基因编辑靶点，可以通过取消SC-β细胞的锌转运来促进胰岛素的分泌和代谢应激下的细胞存活。
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. Immature function and fragility hinder application of hESC-derived β cells (SC-β cell) for diabetes cell therapy. Here, the authors identify ZnT8 as a gene editing target to enhance the insulin secretion and cell survival under metabolic stress by abolishing zinc transport in SC-β cells.
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影响因子：
30.8
作者：
Flannick, Jason;Thorleifsson, Gudmar;Beer, Nicola L.;Jacobs, Suzanne B. R.;Grarup, Niels;Burtt, Noel P.;Mahajan, Anubha;Fuchsberger, Christian;Atzmon, Gil;Benediktsson, Rafn;Blangero, John;Bowden, Don W.;Brandslund, Ivan;Brosnan, Julia;Burslem, Frank;Chambers, John;Cho, Yoon Shin;Christensen, Cramer;Douglas, Desiree A.;Duggirala, Ravindranath;Dymek, Zachary;Farjoun, Yossi;Fennell, Timothy;Fontanillas, Pierre;Forsen, Tom;Gabriel, Stacey;Glaser, Benjamin;Gudbjartsson, Daniel F.;Hanis, Craig;Hansen, Torben;Hreidarsson, Astradur B.;Hveem, Kristian;Ingelsson, Erik;Isomaa, Bo;Johansson, Stefan;Jorgensen, Torben;Jorgensen, Marit Eika;Kathiresan, Sekar;Kong, Augustine;Kooner, Jaspal;Kravic, Jasmina;Laakso, Markku;Lee, Jong-Young;Lind, Lars;Lindgren, Cecilia M.;Linneberg, Allan;Masson, Gisli;Meitinger, Thomas;Mohlke, Karen L.;Molven, Anders;Morris, Andrew P.;Potluri, Shobha;Rauramaa, Rainer;Ribel-Madsen, Rasmus;Richard, Ann-Marie;Rolph, Tim;Salomaa, Veikko;Segre, Ayellet V.;Skaerstrand, Hanna;Steinthorsdottir, Valgerdur;Stringham, Heather M.;Sulem, Patrick;Tai, E. Shyong;Teo, Yik Ying;Teslovich, Tanya;Thorsteinsdottir, Unnur;Trimmer, Jeff K.;Tuomi, Tiinamaija;Tuomilehto, Jaakko;Vaziri-Sani, Fariba;Voight, Benjamin F.;Wilson, James G.;Boehnke, Michael;McCarthy, Mark I.;Njolstad, Pal R.;Pedersen, Oluf;Groop, Leif;Cox, David R.;Stefansson, Kari;Altshuler, David
通讯作者：
Altshuler, David
影响因子：
8.2
作者：
Chang, I;Cho, N;Lee, MS
通讯作者：
Lee, MS
影响因子：
46.9
作者：
Butler A;Hoffman P;Smibert P;Papalexi E;Satija R
通讯作者：
Satija R
影响因子：
29
作者：
Arruda AP;Hotamisligil GS
通讯作者：
Hotamisligil GS
DOI：
10.1111/j.1432-1033.1990.tb15495.x
发表时间：
1990-04-30
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
BRODERSEN, R;ANDERSEN, S;PEDERSEN, AO
通讯作者：
PEDERSEN, AO