Multilineage communication regulates human liver bud development from pluripotency
Abstract
Conventional two-dimensional differentiation from pluripotency fails to recapitulate cell interactions occurring during organogenesis. Three-dimensional organoids generate complex organ-like tissues; however, it is unclear how heterotypic interactions affect lineage identity. Here we use single-cell RNA sequencing to reconstruct hepatocyte-like lineage progression from pluripotency in two-dimensional culture. We then derive three-dimensional liver bud organoids by reconstituting hepatic, stromal, and endothelial interactions, and deconstruct heterogeneity during liver bud development. We find that liver bud hepatoblasts diverge from the two-dimensional lineage, and express epithelial migration signatures characteristic of organ budding. We benchmark three-dimensional liver buds against fetal and adult human liver single-cell RNA sequencing data, and find a striking correspondence between the three-dimensional liver bud and fetal liver cells. We use a receptor-ligand pairing analysis and a high-throughput inhibitor assay to interrogate signalling in liver buds, and show that vascular endothelial growth factor (VEGF) crosstalk potentiates endothelial network formation and hepatoblast differentiation. Our molecular dissection reveals interlineage communication regulating organoid development, and illuminates previously inaccessible aspects of human liver development.
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These liver progenitors provide a fertile venue for subsequent liver maturation efforts and, perhaps, the assembly of enhanced 3D liver "organoids".
“Thus, these liver progenitors provide a fertile venue for subsequent liver maturation efforts and, perhaps, the assembly of enhanced 3D liver “organoids” (Camp et al., 2017; Ogawa et al., 2013; Takebe et al., 2013).”
From A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells (2018) · cites this paper as Camp et al., 2017
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- Authors
- Camp, J. G., Sekine, K., Gerber, T., Loeffler-Wirth, H., Binder, H., Gac, M., Kanton, S., Kageyama, J., Damm, G., Seehofer, D., Belicova, L., Bickle, M., Barsacchi, R., Okuda, R., Yoshizawa, E., Kimura, M., Ayabe, H., Taniguchi, H., Takebe, T., & Treutlein, B.
- Affiliations
- Max Planck Institute for Evolutionary Anthropology (DE)
- Yokohama City University (JP)
- Leipzig University (DE)
- University Hospital Leipzig (DE)
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Sekine, Keisuke
- Takebe, Takanori
- Treutlein, Barbara
- ORCID
- Venue
- Nature
- Published
- 2017-06
- Volume
- 546
- Issue
- 7659
- Pages
- 533-538
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2626990934
- Cited by
- 621
- References
- 10
- Citations by year
- 2026: 51 · 2025: 73 · 2024: 63 · 2023: 68 · 2022: 79 · 2021: 68 · 2020: 83 · 2019: 65 · 2018: 57 · 2017: 12
- FWCI
- 24.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (15KK0314, 15H05677, 16K15597, 16KT0073, 15H04922)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- hepatoblast differentiation, pluripotency, endothelial network formation, VEGF signaling, hepatic stroma, fetal liver, organogenesis
- MeSH terms
- Aged, Cell Communication, Cell Differentiation, Cell Movement, Endothelium, Epithelial Cells, Extracellular Matrix, Female, Fetus, Humans, Liver, Male, Middle Aged, Organoids, Signal Transduction, Cell Hypoxia, Sequence Analysis, RNA, Cell Lineage, Hepatocytes, Organogenesis, Pluripotent Stem Cells, Vascular Endothelial Growth Factor A, Tissue Culture Techniques, Young Adult, Single-Cell Analysis
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