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

Amitoj S. Sawhney, Brian J. Deskin, Junming Cai, Daniel Gibbard, Gibran Ali, Annika Utoft, Xianmei Qi, Aaron Olson, Hannah Hausman, Liberty Sabol, Shannon Holmberg, Ria Shah, Rachel Warren, Stijn Langhe, Zintis Inde, Kristopher A. Sarosiek, Evan Lemire, Adam Haber, Liu Wang, Zong Wei, Rui Benedito and Douglas G. Brownfield ()
Additional contact information
Amitoj S. Sawhney: Mayo Clinic College of Medicine and Science
Brian J. Deskin: Harvard T.H. Chan School of Public Health
Junming Cai: Mayo Clinic College of Medicine and Science
Daniel Gibbard: Mayo Clinic College of Medicine and Science
Gibran Ali: Mayo Clinic College of Medicine and Science
Annika Utoft: Mayo Clinic College of Medicine and Science
Xianmei Qi: Mayo Clinic College of Medicine and Science
Aaron Olson: Mayo Clinic College of Medicine and Science
Hannah Hausman: Mayo Clinic College of Medicine and Science
Liberty Sabol: Mayo Clinic College of Medicine and Science
Shannon Holmberg: Mayo Clinic College of Medicine and Science
Ria Shah: Mayo Clinic College of Medicine and Science
Rachel Warren: Mayo Clinic College of Medicine and Science
Stijn Langhe: Mayo Clinic College of Medicine and Science
Zintis Inde: Harvard T.H. Chan School of Public Health
Kristopher A. Sarosiek: Harvard T.H. Chan School of Public Health
Evan Lemire: Harvard T.H. Chan School of Public Health
Adam Haber: Harvard T.H. Chan School of Public Health
Liu Wang: Mayo Clinic College of Medicine and Science
Zong Wei: Mayo Clinic College of Medicine and Science
Rui Benedito: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Douglas G. Brownfield: Mayo Clinic College of Medicine and Science

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-64224-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64224-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-64224-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().