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Nature. 2017 Jun 22;546(7659):533-538. doi: 10.1038/nature22796. Epub 2017 Jun 14.

Multilineage communication regulates human liver bud development from pluripotency.

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Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, Leipzig 04103, Germany.
Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
Interdisciplinary Centre for Bioinformatics, Leipzig University, 16 Härtelstrasse, Leipzig 04107, Germany.
Department of Hepatobiliary and Transplantation Surgery, University Hospital of Leipzig, Liebigstrasse 20, Leipzig 04103, Germany.
Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, 55 Philipp-Rosenthal-Strasse, Leipzig 04103, Germany.
Max Planck Institute of Molecular Cell Biology and Genetics, 108 Pfotenhauerstrasse, Dresden 01307, Germany.
Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA.


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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