Modelling human hepato-biliary-pancreatic organogenesis from the foregut–midgut boundary
Open accessAbstract
Organogenesis is a complex and interconnected process that is orchestrated by multiple boundary tissue interactions 1-7. 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 vivo 8,9. 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.
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The engineer's approach is to pursue simpler reductionist models defined by minimal functional modules (MFMs) that drive a complex cellular or tissue FOI, to study mechanobiological causation or develop robust systems for high throughput screening.
“On the other hand, the engineer’s (cell as a machine) approach28,247 is to pursue simpler reductionist models defined by the minimal functional modules (MFMs) that drive a complex cellular or tissue FOI, to study the mechanobiological causation in development or repair, or to develop a robust system for high throughput screening.”
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- Authors
- Koike, H., Iwasawa, K., Ouchi, R., Maezawa, M., Giesbrecht, K., Saiki, N., Ferguson, A., Kimura, M., Thompson, W. L., Wells, J. M., Zorn, A. M., & Takebe, T.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- Tokyo Medical and Dental University (JP)
- Corresponding author
- Takebe, Takanori
- ORCID
- Venue
- Nature
- Published
- 2019-09-25
- Volume
- 574
- Issue
- 7776
- Pages
- 112-116
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7643931
- OpenAlex
- W2976549303
- Cited by
- 325
- References
- 35
- Citations by year
- 2026: 38 · 2025: 44 · 2024: 52 · 2023: 42 · 2022: 48 · 2021: 60 · 2020: 35 · 2019: 6
- FWCI
- 12.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (UL1TR001425)
- Japan Society for the Promotion of Science (18H02800, 19K22416)
- National Institute of Diabetes and Digestive and Kidney Diseases (UH3DK119982, P30DK078392)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD093363)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- human pluripotent stem cells, organoids, retinoic acid, Hes1, organ morphogenesis, invagination, branching morphogenesis
- MeSH terms
- Transcription Factor HES-1, Animals, Biliary Tract, Endoderm, Humans, Intestines, Liver, Male, Models, Biological, Morphogenesis, Organoids, Pancreas, Biomarkers, Spheroids, Cellular, Body Patterning, Mice, Induced Pluripotent Stem Cells
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