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Human pluripotent stem cell fate trajectories toward lung and hepatocyte progenitors

In this study, we interrogate molecular mechanisms underlying the specification of lung progenitors from human pluripotent stem cells (hPSCs). We employ single-cell RNA-sequencing with high temporal precision, alongside an optimized differentiation protocol, to elucidate the transcriptional hierarch...

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Autores principales: Ori, Chaido, Ansari, Meshal, Angelidis, Ilias, Olmer, Ruth, Martin, Ulrich, Theis, Fabian J., Schiller, Herbert B., Drukker, Micha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10663741/
https://www.ncbi.nlm.nih.gov/pubmed/38026193
http://dx.doi.org/10.1016/j.isci.2023.108205
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author Ori, Chaido
Ansari, Meshal
Angelidis, Ilias
Olmer, Ruth
Martin, Ulrich
Theis, Fabian J.
Schiller, Herbert B.
Drukker, Micha
author_facet Ori, Chaido
Ansari, Meshal
Angelidis, Ilias
Olmer, Ruth
Martin, Ulrich
Theis, Fabian J.
Schiller, Herbert B.
Drukker, Micha
author_sort Ori, Chaido
collection PubMed
description In this study, we interrogate molecular mechanisms underlying the specification of lung progenitors from human pluripotent stem cells (hPSCs). We employ single-cell RNA-sequencing with high temporal precision, alongside an optimized differentiation protocol, to elucidate the transcriptional hierarchy of lung specification to chart the associated single-cell trajectories. Our findings indicate that Sonic hedgehog, TGF-β, and Notch activation are essential within an ISL1/NKX2-1 trajectory, leading to the emergence of lung progenitors during the foregut endoderm phase. Additionally, the induction of HHEX delineates an alternate trajectory at the early definitive endoderm stage, preceding the lung pathway and giving rise to a significant hepatoblast population. Intriguingly, neither KDR+ nor mesendoderm progenitors manifest as intermediate stages in the lung and hepatic lineage development. Our multistep model offers insights into lung organogenesis and provides a foundation for in-depth study of early human lung development and modeling using hPSCs.
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spelling pubmed-106637412023-10-14 Human pluripotent stem cell fate trajectories toward lung and hepatocyte progenitors Ori, Chaido Ansari, Meshal Angelidis, Ilias Olmer, Ruth Martin, Ulrich Theis, Fabian J. Schiller, Herbert B. Drukker, Micha iScience Article In this study, we interrogate molecular mechanisms underlying the specification of lung progenitors from human pluripotent stem cells (hPSCs). We employ single-cell RNA-sequencing with high temporal precision, alongside an optimized differentiation protocol, to elucidate the transcriptional hierarchy of lung specification to chart the associated single-cell trajectories. Our findings indicate that Sonic hedgehog, TGF-β, and Notch activation are essential within an ISL1/NKX2-1 trajectory, leading to the emergence of lung progenitors during the foregut endoderm phase. Additionally, the induction of HHEX delineates an alternate trajectory at the early definitive endoderm stage, preceding the lung pathway and giving rise to a significant hepatoblast population. Intriguingly, neither KDR+ nor mesendoderm progenitors manifest as intermediate stages in the lung and hepatic lineage development. Our multistep model offers insights into lung organogenesis and provides a foundation for in-depth study of early human lung development and modeling using hPSCs. Elsevier 2023-10-14 /pmc/articles/PMC10663741/ /pubmed/38026193 http://dx.doi.org/10.1016/j.isci.2023.108205 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ori, Chaido
Ansari, Meshal
Angelidis, Ilias
Olmer, Ruth
Martin, Ulrich
Theis, Fabian J.
Schiller, Herbert B.
Drukker, Micha
Human pluripotent stem cell fate trajectories toward lung and hepatocyte progenitors
title Human pluripotent stem cell fate trajectories toward lung and hepatocyte progenitors
title_full Human pluripotent stem cell fate trajectories toward lung and hepatocyte progenitors
title_fullStr Human pluripotent stem cell fate trajectories toward lung and hepatocyte progenitors
title_full_unstemmed Human pluripotent stem cell fate trajectories toward lung and hepatocyte progenitors
title_short Human pluripotent stem cell fate trajectories toward lung and hepatocyte progenitors
title_sort human pluripotent stem cell fate trajectories toward lung and hepatocyte progenitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10663741/
https://www.ncbi.nlm.nih.gov/pubmed/38026193
http://dx.doi.org/10.1016/j.isci.2023.108205
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