GATA6 Plays an Important Role in the Induction of Human Definitive Endoderm, Development of the Pancreas, and Functionality of Pancreatic β Cells.
GATA6 Plays an Important Role in the Induction of Human Definitive Endoderm, Development of the Pancreas, and Functionality of Pancreatic β Cells.
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DOI：
10.1016/j.stemcr.2016.12.026
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发表时间：
2017-03-14
影响因子：
5.9
通讯作者：
Gadue P
中科院分区：
文献类型：
--
作者：
Tiyaboonchai A;Cardenas-Diaz FL;Ying L;Maguire JA;Sim X;Jobaliya C;Gagne AL;Kishore S;Stanescu DE;Hughes N;De Leon DD;French DL;Gadue P
诱导多能干细胞是从一名患有 GATA6 突变的胰腺发育不全患者身上产生的。使用基因组编辑技术，生成了两个 GATA6 等位基因均发生突变的其他干细胞系，并证明定形内胚层诱导受到严重阻碍，这可以通过重新表达几个不同的 GATA 家族成员来挽救。使用内胚层祖干细胞培养系统绕过内胚层阶段的发育障碍，一个或两个 GATA6 等位基因突变的细胞系可以分化为 β 样细胞，但效率降低。在胰腺规范过程中使用次优剂量的视黄酸显示出更严重的表型，更接近于患者的疾病。 GATA6 突变型 β 样细胞在葡萄糖刺激下无法分泌胰岛素，并表现出胰岛素加工缺陷。这些数据表明，GATA6 在人类内胚层和胰腺规范以及 β 样细胞功能中发挥着关键作用。 GATA6 是人类 ES/iPS 细胞定形内胚层规范所必需的 绕过内胚层缺陷使 GATA6 突变体能够生成 β 样细胞 次优视黄酸信号传导阻断 GATA6 突变体中的胰腺规范 GATA6 对于体外人类 β 细胞功能至关重要 在这项研究中，Gadue 及其同事研究了 GATA6 突变体多能干细胞，并证明 GATA6 对于人类定形内胚层规范是必需的。 GATA6 在胰腺规范中也发挥着重要作用，视黄酸信号传导可以部分绕过这一作用。此外，衍生的 β 细胞在体外缺乏葡萄糖反应性，这表明 GATA6 对于人类胰腺的适当发育至关重要。
Induced pluripotent stem cells were created from a pancreas agenesis patient with a mutation in GATA6. Using genome-editing technology, additional stem cell lines with mutations in both GATA6 alleles were generated and demonstrated a severe block in definitive endoderm induction, which could be rescued by re-expression of several different GATA family members. Using the endodermal progenitor stem cell culture system to bypass the developmental block at the endoderm stage, cell lines with mutations in one or both GATA6 alleles could be differentiated into β-like cells but with reduced efficiency. Use of suboptimal doses of retinoic acid during pancreas specification revealed a more severe phenotype, more closely mimicking the patient’s disease. GATA6 mutant β-like cells fail to secrete insulin upon glucose stimulation and demonstrate defective insulin processing. These data show that GATA6 plays a critical role in endoderm and pancreas specification and β-like cell functionality in humans. GATA6 is required for definitive endoderm specification in human ES/iPS cells Bypassing the endoderm defect allows GATA6 mutants to generate β-like cells Suboptimal retinoic acid signaling blocks pancreas specification in GATA6 mutants GATA6 is critical for human β cell function in vitro In this study, Gadue and colleagues studied GATA6 mutant pluripotent stem cells and demonstrate that GATA6 is necessary for human definitive endoderm specification. GATA6 also plays an important role in pancreas specification which could be partially bypassed by retinoic acid signaling. Furthermore, derivative β cells lacked glucose responsiveness in vitro, showing that GATA6 is vital for appropriate human pancreas development.