Alveolar and airway progenitors converge on an epigenetically encoded profibrotic state

During organ regeneration, epithelial transitional states arise from progenitors and instruct the mesenchyme to remodel the extracellular matrix. However, the identity of the progenitors, the mechanisms underlying this transition, and why these states persist in tissue fibrosis often remain elusive. Here, using lineage tracing in mice, we show that the profibrotic KRT5−/KRT17+ state in pulmonary fibrosis arises convergently from alveolar type (AT) 2 and airway secretory cells. AT1 cells generate neither KRT5−/KRT17+ nor AT2 cells. TGF−β/SMAD3 acts through KMT2A and p300 to epigenetically reprogram human AT2 cells into the KRT5−/KRT17+ state. In human pulmonary fibrosis, KRT5−/KRT17+ cells slough off, and transitional cells re-epithelialize the denuded basement membrane. Transcriptionally convergent states arise in injured kidney, skin, and intestine. This work reframes fibrogenesis as the accumulation of a conserved profibrotic transitional state via ongoing turnover, not persistence alone, and nominates the state transition and its epigenetic regulators as therapeutic targets.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-11-10
DOI
https://doi.org/10.64898/2026.11.08.765110
Primary Topic
Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
Type
preprint
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preprint

Alveolar and airway progenitors converge on an epigenetically encoded profibrotic state

Tristan Frum, Nicole R. Falkowski, Cheng‐Yu Lee, Rachel L. Zemans et al.
bioRxiv (Cold Spring Harbor Laboratory)
Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
preprint

Alveolar and airway progenitors converge on an epigenetically encoded profibrotic state

Tristan Frum, Nicole R. Falkowski, Cheng‐Yu Lee, Rachel L. Zemans, Qinxue Shen, Haichun Pan, Jason R. Spence, Kristine E. Konopka, Darrell N. Kotton, Jessica Liang, Rubin M. Tuder, Robert P. Dickson, Lars Knudsen, Joshua Franzen, Lauren J. Ayers, Kendall Foster, Christopher Ting, Cole Weber, Rachel Genova, Anuradha Basyal, Xulun Zhang, Cyrina Ostgaard
preprint en

Abstract

During organ regeneration, epithelial transitional states arise from progenitors and instruct the mesenchyme to remodel the extracellular matrix. However, the identity of the progenitors, the mechanisms underlying this transition, and why these states persist in tissue fibrosis often remain elusive. Here, using lineage tracing in mice, we show that the profibrotic KRT5−/KRT17+ state in pulmonary fibrosis arises convergently from alveolar type (AT) 2 and airway secretory cells. AT1 cells generate neither KRT5−/KRT17+ nor AT2 cells. TGF−β/SMAD3 acts through KMT2A and p300 to epigenetically reprogram human AT2 cells into the KRT5−/KRT17+ state. In human pulmonary fibrosis, KRT5−/KRT17+ cells slough off, and transitional cells re-epithelialize the denuded basement membrane. Transcriptionally convergent states arise in injured kidney, skin, and intestine. This work reframes fibrogenesis as the accumulation of a conserved profibrotic transitional state via ongoing turnover, not persistence alone, and nominates the state transition and its epigenetic regulators as therapeutic targets.

bioRxiv (Cold Spring Harbor Laboratory)
Boston University (US), Boston Medical Center (US), University of Michigan (US), University of Colorado System (US), Medizinische Hochschule Hannover (DE)
Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
DOIOpen Access PDFOpenAlex
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