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Single cell trajectory analysis of human pluripotent stem cells differentiating towards lung and hepatocyte progenitors

Chaido Ori, Meshal Ansari, Ilias Angelidis, Fabian J. Theis, Herbert B. Schiller, Micha Drukker
doi: https://doi.org/10.1101/2021.02.23.432413
Chaido Ori
1Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Munich, Germany
2Institute of Lung Biology and Disease (ILBD), Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
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Meshal Ansari
2Institute of Lung Biology and Disease (ILBD), Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
3Institute of Computational Biology, Neuherberg, Munich, Germany
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Ilias Angelidis
2Institute of Lung Biology and Disease (ILBD), Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
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Fabian J. Theis
3Institute of Computational Biology, Neuherberg, Munich, Germany
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Herbert B. Schiller
2Institute of Lung Biology and Disease (ILBD), Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
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  • For correspondence: herbert.schiller@helmholtz-muenchen.de micha.drukker@helmholtz-muenchen.de m.drukker@lacdr.leidenuniv.nl
Micha Drukker
1Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Munich, Germany
4Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands
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  • For correspondence: herbert.schiller@helmholtz-muenchen.de micha.drukker@helmholtz-muenchen.de m.drukker@lacdr.leidenuniv.nl
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ABSTRACT

Understanding the development of human respiratory tissues is crucial for modeling and treating lung disorders. The molecular details for the specification of lung progenitors from human pluripotent stem cells (hPSCs) are unclear. Here, we use single cell RNA-sequencing with high temporal resolution along an optimized differentiation protocol to determine the transcriptional hierarchy of lung specification from human hPSCs and map out the underlying single cell trajectories. We show that Sonic hedgehog, TGF-β and Notch activation are required in an ISL1/NKX2-1 trajectory that gives rise to lung progenitors during the foregut endoderm stage. Induction of HHEX marks an alternative trajectory at the early definitive endoderm stage, which precedes the lung trajectory and generates a major hepatoblast population. Moreover, neither KDR+ nor mesendoderm progenitors are apparent intermediate states of lung and hepatic lineages. Our hierarchical multistep model predicts mechanisms leading to lung organogenesis, and creates a basis for studying early human lung development, as well as hPSC based disease and drug research.

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Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 23, 2021.
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Single cell trajectory analysis of human pluripotent stem cells differentiating towards lung and hepatocyte progenitors
Chaido Ori, Meshal Ansari, Ilias Angelidis, Fabian J. Theis, Herbert B. Schiller, Micha Drukker
bioRxiv 2021.02.23.432413; doi: https://doi.org/10.1101/2021.02.23.432413
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Single cell trajectory analysis of human pluripotent stem cells differentiating towards lung and hepatocyte progenitors
Chaido Ori, Meshal Ansari, Ilias Angelidis, Fabian J. Theis, Herbert B. Schiller, Micha Drukker
bioRxiv 2021.02.23.432413; doi: https://doi.org/10.1101/2021.02.23.432413

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