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Nature. 2019 Oct;574(7776):112-116. doi: 10.1038/s41586-019-1598-0. Epub 2019 Sep 25.

Modelling human hepato-biliary-pancreatic organogenesis from the foregut-midgut boundary.

Koike H1,2, Iwasawa K1,2, Ouchi R1,2, Maezawa M1,2, Giesbrecht K1,2, Saiki N3, Ferguson A1,2, Kimura M1,2, Thompson WL1,2, Wells JM2,4,5,6, Zorn AM2,4,6, Takebe T7,8,9,10,11.

Author information

1
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
2
Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
3
Institute of Research, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
4
Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
5
Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
6
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
7
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. takanori.takebe@cchmc.org.
8
Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. takanori.takebe@cchmc.org.
9
Institute of Research, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. takanori.takebe@cchmc.org.
10
Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. takanori.takebe@cchmc.org.
11
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. takanori.takebe@cchmc.org.

Abstract

Organogenesis is a complex and interconnected process that is orchestrated by multiple boundary tissue interactions1-7. However, it remains unclear how individual, neighbouring 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 cells. The boundary interactions between anterior and posterior gut spheroids differentiated from human pluripotent stem cells enables retinoic acid-dependent emergence of hepato-biliary-pancreatic organ domains specified at the foregut-midgut boundary organoids in the absence of extrinsic factors. Whereas transplant-derived tissues are dominated by midgut derivatives, long-term-cultured microdissected hepato-biliary-pancreatic organoids develop into segregated multi-organ anlages, which then recapitulate early morphogenetic events including the invagination and branching of three different and interconnected organ structures, reminiscent of tissues derived from mouse explanted foregut-midgut culture. Mis-segregation of multi-organ domains caused by a genetic mutation in HES1 abolishes the biliary specification potential in culture, as seen in vivo8,9. In sum, we demonstrate that the experimental multi-organ integrated model can be established by the juxtapositioning of foregut and midgut tissues, and potentially serves as a tractable, manipulatable and easily accessible model for the study of complex human endoderm organogenesis.

PMID:
31554966
DOI:
10.1038/s41586-019-1598-0
[Indexed for MEDLINE]

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