Human pluripotent stem cell fate trajectories toward lung and hepatocyte progenitors

Chaido Ori, Meshal Ansari, Ilias Angelidis, Ruth Olmer, Ulrich Martin, Fabian J. Theis, Herbert B. Schiller, Micha Drukker

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number108205
Issue number11
StatePublished - 17 Nov 2023


  • Cell biology
  • Developmental biology
  • Molecular biology


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