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Nat Commun. 2020 Jan 31;11(1):635. doi: 10.1038/s41467-020-14348-3.

The in vivo genetic program of murine primordial lung epithelial progenitors.

Author information

1
Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA, 02118, USA. laertis@bu.edu.
2
The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA. laertis@bu.edu.
3
Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA, 02118, USA.
4
The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA.
5
Department of Physics, Boston University, Boston, MA, 02215, USA.
6
Division of Pediatric Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
7
Department of Mathematics & Statistics, Boston University, Boston, MA, 02215, USA.
8
Chair of Bioinformatics Research Group, Boku University, 1190, Vienna, Austria.
9
Department of Biochemistry, Boston University School of Medicine, Boston, MA, 02118, USA.
10
Biogen Inc., 225 Binney St, Cambridge, MA, 02142, USA.
11
Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
12
Division of Pulmonary Biology, Cincinnati Children's Hospital, Cincinnati, OH, 45229, USA.
13
Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA, 02118, USA. dkotton@bu.edu.
14
The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA. dkotton@bu.edu.

Abstract

Multipotent Nkx2-1-positive lung epithelial primordial progenitors of the foregut endoderm are thought to be the developmental precursors to all adult lung epithelial lineages. However, little is known about the global transcriptomic programs or gene networks that regulate these gateway progenitors in vivo. Here we use bulk RNA-sequencing to describe the unique genetic program of in vivo murine lung primordial progenitors and computationally identify signaling pathways, such as Wnt and Tgf-β superfamily pathways, that are involved in their cell-fate determination from pre-specified embryonic foregut. We integrate this information in computational models to generate in vitro engineered lung primordial progenitors from mouse pluripotent stem cells, improving the fidelity of the resulting cells through unbiased, easy-to-interpret similarity scores and modulation of cell culture conditions, including substratum elastic modulus and extracellular matrix composition. The methodology proposed here can have wide applicability to the in vitro derivation of bona fide tissue progenitors of all germ layers.

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