Title: The in vivo genetic program of murine primordial lung epithelial progenitors.
Authors: Ikonomou, Laertis; Herriges, Michael J; Lewandowski, Sara L; Marsland 3rd, Robert; Villacorta-Martin, Carlos; Caballero, Ignacio S; Frank, David B; Sanghrajka, Reeti M; Dame, Keri; Kańduła, Maciej M; Hicks-Berthet, Julia; Lawton, Matthew L; Christodoulou, Constantina; Fabian, Attila J; Kolaczyk, Eric; Varelas, Xaralabos; Morrisey, Edward E; Shannon, John M; Mehta, Pankaj; Kotton, Darrell N
Published In Nat Commun, (2020 Jan 31)
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.
PubMed ID: 32005814
MeSH Terms: Animals; Cell Culture Techniques; Cell Differentiation; Epithelial Cells/cytology*; Epithelial Cells/metabolism; Extracellular Matrix/genetics; Extracellular Matrix/metabolism; Female; Germ Layers/embryology; Germ Layers/metabolism; Lung/cytology*; Lung/embryology; Lung/metabolism; Male; Mice, Inbred C57BL; Mice, Transgenic; Mice/embryology; Mice/genetics*; Mice/metabolism; Pluripotent Stem Cells/cytology*; Pluripotent Stem Cells/metabolism; Signal Transduction; Thyroid Nuclear Factor 1/genetics; Thyroid Nuclear Factor 1/metabolism; Transcriptome; Transforming Growth Factor beta/genetics; Transforming Growth Factor beta/metabolism