A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells.
A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells.
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DOI：
10.1016/j.celrep.2018.01.087
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发表时间：
2018-02-20
期刊：
影响因子：
8.8
通讯作者：
Lim B
中科院分区：
文献类型：
--
作者：
Ang LT;Tan AKY;Autio MI;Goh SH;Choo SH;Lee KL;Tan J;Pan B;Lee JJH;Lum JJ;Lim CYY;Yeo IKX;Wong CJY;Liu M;Oh JLL;Chia CPL;Loh CH;Chen A;Chen Q;Weissman IL;Loh KM;Lim B
密切相关的谱系，包括肝脏、胰腺和肠道，是如何从一个共同的内胚层起源分化出来的？在这里，我们应用从发育生物学中学到的原理，从人类多能干细胞（hPSCs）中快速重建肝祖细胞。绘制多个内胚层谱系的形成图揭示了内胚层的交替命运（如胰腺和肠道）在肝脏承托过程中是如何受到限制的。人类肝脏命运是由不同剂量的诱导和抑制细胞外信号组合编码的。然而，这些信号组合被暂时重新解释：细胞对类维甲酸、WNT、TGF-β和其他信号的反应能力在24小时内急剧改变。因此，细胞外信号的暂时动态操作是必要的，以抑制生产不需要的细胞命运跨越六个连续的发育节点。在hPSC分化第6天和第18天，分别高效生成94.1%±7.35%的TBX3+ HNF4A+人肝芽祖细胞和81.5%±3.2%的FAH+肝细胞样细胞；后者提高了Fah - / - Rag2 - / - Il2rg - / -肝衰竭小鼠模型的短期生存率。Ang等人描绘了人类肝祖细胞是如何从多能干细胞发育成六个发育步骤的，包括与肝脏形成相关的细胞外信号和表面标记。这一知识使肝芽祖细胞和随后的肝细胞样细胞能够有效地在体内和体外发挥作用。
How are closely related lineages, including liver, pancreas, and intestines, diversified from a common endodermal origin? Here, we apply principles learned from developmental biology to rapidly reconstitute liver progenitors from human pluripotent stem cells (hPSCs). Mapping the formation of multiple endodermal lineages revealed how alternate endodermal fates (e.g., pancreas and intestines) are restricted during liver commitment. Human liver fate was encoded by combinations of inductive and repressive extracellular signals at different doses. However, these signaling combinations were temporally re-interpreted: cellular competence to respond to retinoid, WNT, TGF-β, and other signals sharply changed within 24 hr. Consequently, temporally dynamic manipulation of extracellular signals was imperative to suppress the production of unwanted cell fates across six consecutive developmental junctures. This efficiently generated 94.1% ± 7.35% TBX3+ HNF4A+ human liver bud progenitors and 81.5% ± 3.2% FAH+ hepatocyte-like cells by days 6 and 18 of hPSC differentiation, respectively; the latter improved short-term survival in the Fah–/– Rag2–/– Il2rg–/– mouse model of liver failure. Ang et al. chart how human liver progenitors develop from pluripotent stem cells through six developmental steps, including extracellular signals and surface markers associated with liver formation. This knowledge enables efficient generation of liver bud progenitors and, subsequently, hepatocyte-like cells that could function in vivo and in vitro.
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