Alveolar epithelial progenitor cells require Nkx2-1 to maintain progenitor-specific epigenomic state during lung homeostasis and regeneration

Andrea Toth, Paranthaman Kannan, John Snowball, Matthew Kofron, Joseph A. Wayman, James P. Bridges, Emily R. Miraldi, Daniel Swarr and William J. Zacharias ()
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Andrea Toth: Cincinnati Children’s Hospital Medical Center
Paranthaman Kannan: Cincinnati Children’s Hospital Medical Center
John Snowball: Cincinnati Children’s Hospital Medical Center
Matthew Kofron: Cincinnati Children’s Hospital Medical Center
Joseph A. Wayman: Cincinnati Children’s Hospital Medical Center
James P. Bridges: University of Colorado Anschutz Medical Campus
Emily R. Miraldi: University of Cincinnati College of Medicine
Daniel Swarr: Cincinnati Children’s Hospital Medical Center
William J. Zacharias: Cincinnati Children’s Hospital Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Lung epithelial regeneration after acute injury requires coordination cellular coordination to pattern the morphologically complex alveolar gas exchange surface. During adult lung regeneration, Wnt-responsive alveolar epithelial progenitor (AEP) cells, a subset of alveolar type 2 (AT2) cells, proliferate and transition to alveolar type 1 (AT1) cells. Here, we report a refined primary murine alveolar organoid, which recapitulates critical aspects of in vivo regeneration. Paired scRNAseq and scATACseq followed by transcriptional regulatory network (TRN) analysis identified two AT1 transition states driven by distinct regulatory networks controlled in part by differential activity of Nkx2-1. Genetic ablation of Nkx2-1 in AEP-derived organoids was sufficient to cause transition to a proliferative stressed Krt8+ state, and AEP-specific deletion of Nkx2-1 in adult mice led to rapid loss of progenitor state and uncontrolled growth of Krt8+ cells. Together, these data implicate dynamic epigenetic maintenance via Nkx2-1 as central to the control of facultative progenitor activity in AEPs.

Date: 2023
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DOI: 10.1038/s41467-023-44184-0

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