Anatomically and functionally distinct lung mesenchymal populations marked by Lgr5 and Lgr6
Hofree M, M
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Lee, J., Tammela, T., Hofree M, M., Choi, J., Marjanovic, N., Han, S., Canner, D., et al. (2017). Anatomically and functionally distinct lung mesenchymal populations marked by Lgr5 and Lgr6. Cell, 170 (6), 1149-1163. https://doi.org/10.1016/j.cell.2017.07.028
The diversity of mesenchymal cell types in the lung that influence epithelial homeostasis and regeneration is poorly defined. We used genetic lineage tracing, single-cell RNA sequencing, and organoid culture approaches to show that Lgr5 and Lgr6, well-known markers of stem cells in epithelial tissues, are markers of mesenchymal cells in the adult lung. Lgr6+ cells comprise a subpopulation of smooth muscle cells surrounding airway epithelia and promote airway differentiation of epithelial progenitors via Wnt-Fgf10 cooperation. Genetic ablation of Lgr6+ cells impairs airway injury repair in vivo. Distinct Lgr5+ cells are located in alveolar compartments and are sufficient to promote alveolar differentiation of epithelial progenitors through Wnt activation. Modulating Wnt activity altered differentiation outcomes specified by mesenchymal cells. This identification of region- and lineage-specific crosstalk between epithelium and their neighboring mesenchymal partners provides new understanding of how different cell types are maintained in the adult lung.
mesenchymal cells, bronchiolar epithelium, alveolar epithelium, lung stem cells, lung, differentiation, niche, Wnt signaling
This work was supported by (J.-H.L. and J.C.) Wellcome Trust and the Royal Society (107633/Z/15/Z), European Research Council Starting Grant (679411), and the Cambridge Stem Cell Institute Core grant (07922/Z/11/Z) from Wellcome Trust and Medical Research Council; (J.-H.L.) the Hope Funds for Cancer Research; (M.P.) American Lung Association (400553); (A.R.) Howard Hughes Medical Institute, the Klarman Cell Observatory, and NCI grant 1U24CA180922; (A.R., T.T., and T.J.) the Koch Institute Core grant P30-CA14051 from the NCI; (T.T.) the National Cancer InstituteK99 CA187317, the Sigrid Juselius Foundation, the Hope Funds for Cancer Research; (T.J.) a Howard Hughes Medical Institute Investigator, a David H. Koch Professor of Biology and a Daniel K. Ludwig Scholar; and (C.F.K.) R01 HL090136, R01 HL132266, R01 HL125821, U01 HL100402, Harvard Stem Cell Institute, Alfred and Gilda Slifka, Gail and Adam Slifka, and the CFMS Fund.
ECH2020 EUROPEAN RESEARCH COUNCIL (ERC) (679411)
WELLCOME TRUST (107633/Z/15/Z)
External DOI: https://doi.org/10.1016/j.cell.2017.07.028
This record's URL: https://www.repository.cam.ac.uk/handle/1810/265759
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International