A molecular circuit regulates fate plasticity in emerging and adult AT2 cells

Alveolar Type 1 and Type 2 cells are vital for lung gas exchange and become compromised in several diseases. While key differentiation signals are known, their emergence and fate plasticity are unclear. Here we show in the embryonic lung that single AT2s emerge at intermediate zones, extrude, and connect with nearby epithelium via interlumenal junctioning. We observe AT2s retain fate plasticity until the bZIP transcription factor C/EBPα suppresses Notch signaling at a novel Dlk1 enhancer. Both Dlk1 and Cebpa are regulated by the polycomb repressive complex (PRC2), which together form a "pulse generator" circuit that times Dlk1 expression and thus Notch activation, resulting in a "salt and pepper" pattern of AT1 and AT2 fate. In injured adult lungs, C/EBPα downregulation is required to re-access AT2 fate plasticity and is mediated by the dominant negative C/EBP family member CHOP. Finally, Cebpa loss also activates a "defender" AT2 state, distinct from its reparative state, and we propose AT2s toggle between either state following infection to protect and repair alveoli.

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Publication Details

Journal
Nature Communications
Published
2025-10-14
DOI
https://doi.org/10.1038/s41467-025-64224-1
Citations
3
Primary Topic
Phagocytosis and Immune Regulation
Type
article
Field-Weighted Citation Impact
2.39
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article

A molecular circuit regulates fate plasticity in emerging and adult AT2 cells

Stijn De Langhe, Rahul Shah, Adam L. Haber, Xianmei Qi et al.
3 citations
Nature Communications
Phagocytosis and Immune Regulation
2.39
article

A molecular circuit regulates fate plasticity in emerging and adult AT2 cells

Stijn De Langhe, Rahul Shah, Adam L. Haber, Xianmei Qi, Kristopher A. Sarosiek, Evan Lemire, Zintis Inde, Steen Holmberg, Hannah Hausman, Douglas Brownfield, Rui Benedito, D. Gibbard, Amitoj Singh Sawhney, Zong Wei, Rachel Warren, Aaron Olson, B. Deskin, Liu Wang, Gibran Ali, Junming Cai, Annika Utoft, Liberty Sabol
article en
3 citations

Abstract

Alveolar Type 1 and Type 2 cells are vital for lung gas exchange and become compromised in several diseases. While key differentiation signals are known, their emergence and fate plasticity are unclear. Here we show in the embryonic lung that single AT2s emerge at intermediate zones, extrude, and connect with nearby epithelium via interlumenal junctioning. We observe AT2s retain fate plasticity until the bZIP transcription factor C/EBPα suppresses Notch signaling at a novel Dlk1 enhancer. Both Dlk1 and Cebpa are regulated by the polycomb repressive complex (PRC2), which together form a "pulse generator" circuit that times Dlk1 expression and thus Notch activation, resulting in a "salt and pepper" pattern of AT1 and AT2 fate. In injured adult lungs, C/EBPα downregulation is required to re-access AT2 fate plasticity and is mediated by the dominant negative C/EBP family member CHOP. Finally, Cebpa loss also activates a "defender" AT2 state, distinct from its reparative state, and we propose AT2s toggle between either state following infection to protect and repair alveoli.

Nature CommunicationsVol. 16(1)
Mayo Clinic (US), Spanish National Centre for Cardiovascular Research (ES), Department of Physiological Sciences (RU), Mayo Clinic in Arizona (US), Mayo Clinic in Florida (US)
Openalex Percentile: Top 10%
Phagocytosis and Immune Regulation
2.39
DOIOpen Access PDFOpenAlex
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