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

Hiroyuki Koike, Kentaro Iwasawa, Rie Ouchi, Mari Maezawa, Kirsten Giesbrecht, Norikazu Saiki, Autumn Ferguson, Masaki Kimura, Wendy L. Thompson, James M. Wells, Aaron M. Zorn and Takanori Takebe ()
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Hiroyuki Koike: Cincinnati Children’s Hospital Medical Center
Kentaro Iwasawa: Cincinnati Children’s Hospital Medical Center
Rie Ouchi: Cincinnati Children’s Hospital Medical Center
Mari Maezawa: Cincinnati Children’s Hospital Medical Center
Kirsten Giesbrecht: Cincinnati Children’s Hospital Medical Center
Norikazu Saiki: Tokyo Medical and Dental University (TMDU)
Autumn Ferguson: Cincinnati Children’s Hospital Medical Center
Masaki Kimura: Cincinnati Children’s Hospital Medical Center
Wendy L. Thompson: Cincinnati Children’s Hospital Medical Center
James M. Wells: Cincinnati Children’s Hospital Medical Center
Aaron M. Zorn: Cincinnati Children’s Hospital Medical Center
Takanori Takebe: Cincinnati Children’s Hospital Medical Center

Nature, 2019, vol. 574, issue 7776, 112-116

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1598-0

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