Modelling human hepato-biliary-pancreatic organogenesis from the foregut-midgut boundary.
Modelling human hepato-biliary-pancreatic organogenesis from the foregut-midgut boundary.
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DOI：
10.1038/s41586-019-1598-0
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发表时间：
2019-10
期刊：
影响因子：
64.8
通讯作者：
Takebe T
中科院分区：
文献类型：
--
作者：
Koike H;Iwasawa K;Ouchi R;Maezawa M;Giesbrecht K;Saiki N;Ferguson A;Kimura M;Thompson WL;Wells JM;Zorn AM;Takebe T
器官发生是一个复杂且相互关联的过程，由多个边界组织相互作用协调。然而，目前尚不清楚单个相邻组件如何协调以建立完整的多器官结构。在这里，我们报告的连续图案和动态形态发生的肝脏，胆道和胰腺结构，从三维培养的人多能干细胞（PSC）的内陷。从人PSC分化的前肠球状体和后肠球状体之间的边界相互作用使得在不存在外源因子供应的情况下，在前肠-中肠边界类器官处指定的肝胆胰（HBP）器官域能够自主出现。而移植衍生的组织主要由中肠衍生物，长期培养的微解剖HBP类器官发展成一个分离的肝-胰-胆原基，随后是早期形态发生事件的重演，包括三个不同的和相互连接的器官结构的内陷和分支，让人想起来自小鼠前肠-中肠培养的组织。如在体内所见，由HES 1中的基因突变引起的多器官结构域的误分离消除了培养物中的胆汁特异性潜力。总之，我们表明，实验多器官集成模型可以建立前肠和中肠组织的并列，并可能作为一个易于处理的，可操作的和易于访问的模型，在人类复杂的内胚层器官发生的研究。
Organogenesis is a complex and inter-connected process, orchestrated by multiple boundary tissue interactions. However, it is currently unclear how individual, neighboring components coordinate to establish an integral multi-organ structure. Here, we report the continuous patterning and dynamic morphogenesis of hepatic, biliary and pancreatic structures, invaginating from a three-dimensional culture of human pluripotent stem cell (PSC). The boundary interactions between anterior and posterior gut spheroids differentiated from human PSCs enables autonomous emergence of hepato-biliary-pancreatic (HBP) organ domains specified at the foregut-midgut boundary organoids in the absence of extrinsic factor supply. Whereas transplant-derived tissues were dominated by midgut derivatives, long-term culture of micro dissected HBP organoids develop into a segregated hepato-pancreato-biliary anlage, followed by the recapitulation of early morphogenetic events including the invagination and branching of three different and inter-connected organ structures, reminiscent of tissues derived from mouse explanted foregut-midgut culture. Missegregation of multi-organ domains incurred by a genetic mutation in HES1 abolishes the biliary specification potential in culture, as seen in vivo. Together, we demonstrate that the experimental multi-organ integrated model can be established by the juxta-positioning of foregut and midgut tissues, and potentially serves as a tractable, manipulatable and easily-accessible model for the study of complicated endoderm organogenesis in human.
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