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Stem Cell Reports. 2018 Jan 9;10(1):101-119. doi: 10.1016/j.stemcr.2017.11.012. Epub 2017 Dec 14.

In Vitro Induction and In Vivo Engraftment of Lung Bud Tip Progenitor Cells Derived from Human Pluripotent Stem Cells.

Author information

1
Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
2
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
3
Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
4
Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI 48109, USA.
5
Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: spencejr@umich.edu.

Abstract

The current study aimed to understand the developmental mechanisms regulating bud tip progenitor cells in the human fetal lung, which are present during branching morphogenesis, and to use this information to induce a bud tip progenitor-like population from human pluripotent stem cells (hPSCs) in vitro. We identified cues that maintained isolated human fetal lung epithelial bud tip progenitor cells in vitro and induced three-dimensional hPSC-derived organoids with bud tip-like domains. Bud tip-like domains could be isolated, expanded, and maintained as a nearly homogeneous population. Molecular and cellular comparisons revealed that hPSC-derived bud tip-like cells are highly similar to native lung bud tip progenitors. hPSC-derived epithelial bud tip-like structures survived in vitro for over 16 weeks, could be easily frozen and thawed, maintained multilineage potential, and successfully engrafted into the airways of immunocompromised mouse lungs, where they persisted for up to 6 weeks and gave rise to several lung epithelial lineages.

KEYWORDS:

SOX2; SOX9; branching morphogenesis; bud tip; directed differentiation; human pluripotent stem cell; lung; lung organoid; organoid; progenitor

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