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Alveolar cell fate selection and lifelong maintenance of AT2 cells by FGF signaling

Author

Listed:
  • Douglas G. Brownfield

    (Stanford University School of Medicine
    Harvard T.H. Chan School of Public Health
    Mayo Clinic College of Medicine and Science)

  • Alex Diaz Arce

    (Stanford University School of Medicine)

  • Elisa Ghelfi

    (Harvard T.H. Chan School of Public Health)

  • Astrid Gillich

    (Stanford University School of Medicine)

  • Tushar J. Desai

    (Stanford University School of Medicine)

  • Mark A. Krasnow

    (Stanford University School of Medicine)

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.

Suggested Citation

  • Douglas G. Brownfield & Alex Diaz Arce & Elisa Ghelfi & Astrid Gillich & Tushar J. Desai & Mark A. Krasnow, 2022. "Alveolar cell fate selection and lifelong maintenance of AT2 cells by FGF signaling," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34059-1
    DOI: 10.1038/s41467-022-34059-1
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    References listed on IDEAS

    as
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    2. Daniel Lafkas & Amy Shelton & Cecilia Chiu & Gladys de Leon Boenig & Yongmei Chen & Scott S. Stawicki & Christian Siltanen & Mike Reichelt & Meijuan Zhou & Xiumin Wu & Jeffrey Eastham-Anderson & Heath, 2015. "Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung," Nature, Nature, vol. 528(7580), pages 127-131, December.
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