Alveolar Cell Fate Selection and Lifelong Maintenance of AT2 Cells by FGF Signaling

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Nov 22

PMID 36414616

Authors

Douglas G Brownfield

Alex Diaz de Arce

Elisa Ghelfi

Astrid Gillich

Tushar J Desai

Mark A Krasnow

Affiliations

Soon will be listed here.

Abstract

The lung's gas exchange surface is comprised of alveolar AT1 and AT2 cells that are corrupted in several common and deadly diseases. They arise from a bipotent progenitor whose differentiation is thought to be dictated by differential mechanical forces. Here we show the critical determinant is FGF signaling. Fgfr2 is expressed in the developing progenitors in mouse then restricts to nascent AT2 cells and remains on throughout life. Its ligands are expressed in surrounding mesenchyme and can, in the absence of exogenous mechanical cues, induce progenitors to form alveolospheres with intermingled AT2 and AT1 cells. FGF signaling directly and cell autonomously specifies AT2 fate; progenitors lacking Fgfr2 in vitro and in vivo exclusively acquire AT1 fate. Fgfr2 loss in AT2 cells perinatally results in reprogramming to AT1 identity, whereas loss or inhibition later in life triggers AT2 apoptosis and compensatory regeneration. We propose that Fgfr2 signaling selects AT2 fate during development, induces a cell non-autonomous AT1 differentiation signal, then continuously maintains AT2 identity and survival throughout life.

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References

Sinha M, Lowell C . Isolation of Highly Pure Primary Mouse Alveolar Epithelial Type II Cells by Flow Cytometric Cell Sorting. Bio Protoc. 2017; 6(22). PMC: 5293249. DOI: 10.21769/BioProtoc.2013. View

Shu W, Guttentag S, Wang Z, Andl T, Ballard P, Lu M . Wnt/beta-catenin signaling acts upstream of N-myc, BMP4, and FGF signaling to regulate proximal-distal patterning in the lung. Dev Biol. 2005; 283(1):226-39. DOI: 10.1016/j.ydbio.2005.04.014. View

Hokuto I, Perl A, Whitsett J . Prenatal, but not postnatal, inhibition of fibroblast growth factor receptor signaling causes emphysema. J Biol Chem. 2002; 278(1):415-21. DOI: 10.1074/jbc.M208328200. View

SCHANKER L, Hemberger J . Relation between molecular weight and pulmonary absorption rate of lipid-insoluble compounds in neonatal and adult rats. Biochem Pharmacol. 1983; 32(17):2599-601. DOI: 10.1016/0006-2952(83)90025-4. View

Borok Z, Lubman R, Danto S, Zhang X, Zabski S, King L . Keratinocyte growth factor modulates alveolar epithelial cell phenotype in vitro: expression of aquaporin 5. Am J Respir Cell Mol Biol. 1998; 18(4):554-61. DOI: 10.1165/ajrcmb.18.4.2838. View

Cohen M, Giladi A, Gorki A, Solodkin D, Zada M, Hladik A . Lung Single-Cell Signaling Interaction Map Reveals Basophil Role in Macrophage Imprinting. Cell. 2018; 175(4):1031-1044.e18. DOI: 10.1016/j.cell.2018.09.009. View

Liu Y, Jiang H, Crawford H, Hogan B . Role for ETS domain transcription factors Pea3/Erm in mouse lung development. Dev Biol. 2003; 261(1):10-24. DOI: 10.1016/s0012-1606(03)00359-2. View

Hokuto I, Perl A, Whitsett J . FGF signaling is required for pulmonary homeostasis following hyperoxia. Am J Physiol Lung Cell Mol Physiol. 2003; 286(3):L580-7. DOI: 10.1152/ajplung.00278.2003. View

Pan Y, Woodbury A, Esko J, Grobe K, Zhang X . Heparan sulfate biosynthetic gene Ndst1 is required for FGF signaling in early lens development. Development. 2006; 133(24):4933-44. DOI: 10.1242/dev.02679. View

10.

Bellusci S, Grindley J, EMOTO H, Itoh N, Hogan B . Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung. Development. 1998; 124(23):4867-78. DOI: 10.1242/dev.124.23.4867. View

11.

Frank D, Penkala I, Zepp J, Sivakumar A, Linares-Saldana R, Zacharias W . Early lineage specification defines alveolar epithelial ontogeny in the murine lung. Proc Natl Acad Sci U S A. 2019; 116(10):4362-4371. PMC: 6410851. DOI: 10.1073/pnas.1813952116. View

12.

Metzger R, Klein O, Martin G, Krasnow M . The branching programme of mouse lung development. Nature. 2008; 453(7196):745-50. PMC: 2892995. DOI: 10.1038/nature07005. View

13.

Hwang D, Chamberlain D, Poutanen S, Low D, Asa S, Butany J . Pulmonary pathology of severe acute respiratory syndrome in Toronto. Mod Pathol. 2004; 18(1):1-10. PMC: 7100506. DOI: 10.1038/modpathol.3800247. View

14.

Barnes P, Burney P, Silverman E, Celli B, Vestbo J, Wedzicha J . Chronic obstructive pulmonary disease. Nat Rev Dis Primers. 2016; 1:15076. DOI: 10.1038/nrdp.2015.76. View

15.

Yuan T, Volckaert T, Redente E, Hopkins S, Klinkhammer K, Wasnick R . FGF10-FGFR2B Signaling Generates Basal Cells and Drives Alveolar Epithelial Regeneration by Bronchial Epithelial Stem Cells after Lung Injury. Stem Cell Reports. 2019; 12(5):1041-1055. PMC: 6524168. DOI: 10.1016/j.stemcr.2019.04.003. View

16.

Tippimanchai D, Nolan K, Poczobutt J, Verzosa G, Li H, Scarborough H . Adenoviral vectors transduce alveolar macrophages in lung cancer models. Oncoimmunology. 2018; 7(6):e1438105. PMC: 5980415. DOI: 10.1080/2162402X.2018.1438105. View

17.

Fujino N, Kubo H, Ota C, Suzuki T, Suzuki S, Yamada M . A novel method for isolating individual cellular components from the adult human distal lung. Am J Respir Cell Mol Biol. 2011; 46(4):422-30. DOI: 10.1165/rcmb.2011-0172OC. View

18.

Zhou W, Hur W, McDermott U, Dutt A, Xian W, Ficarro S . A structure-guided approach to creating covalent FGFR inhibitors. Chem Biol. 2010; 17(3):285-95. PMC: 2920453. DOI: 10.1016/j.chembiol.2010.02.007. View

19.

Herriges J, Verheyden J, Zhang Z, Sui P, Zhang Y, Anderson M . FGF-Regulated ETV Transcription Factors Control FGF-SHH Feedback Loop in Lung Branching. Dev Cell. 2015; 35(3):322-32. PMC: 4763945. DOI: 10.1016/j.devcel.2015.10.006. View

20.

Nagaraj A, Lahtela J, Hemmes A, Pellinen T, Blom S, Devlin J . Cell of Origin Links Histotype Spectrum to Immune Microenvironment Diversity in Non-small-Cell Lung Cancer Driven by Mutant Kras and Loss of Lkb1. Cell Rep. 2017; 18(3):673-684. DOI: 10.1016/j.celrep.2016.12.059. View