Regulation of epithelial transitional states in murine and human pulmonary fibrosis

Fa Wang, Christopher Ting, Kent A Riemondy, Michael Douglas, Kendall Foster, Nisha Patel, Norihito Kaku, Alexander Linsalata, Jean Nemzek, Brian M Varisco, Erez Cohen, Jasmine A Wilson, David Wh Riches, Elizabeth F Redente, Diana M Toivola, Xiaofeng Zhou, Bethany B Moore, Pierre A Coulombe, M Bishr Omary, Rachel L Zemans

Research output: Contribution to journalArticleScientificpeer-review

14 Citations (Scopus)
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Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease arising from impaired regeneration of the alveolar epithelium after injury. During regeneration, type 2 alveolar epithelial cells (AEC2s) assume a transitional state that upregulates multiple keratins and ultimately differentiate into AEC1s. In IPF, transitional AECs accumulate with ineffectual AEC1 differentiation. However, whether and how transitional cells cause fibrosis, whether keratins regulate transitional cell accumulation and fibrosis, and why transitional AECs and fibrosis resolve in mouse models but accumulate in IPF are unclear. Here, we show that human keratin 8 (KRT8) genetic variants were associated with IPF. Krt8-/- mice were protected from fibrosis and accumulation of the transitional state. Keratin 8 (K8) regulated the expression of macrophage chemokines and macrophage recruitment. Profibrotic macrophages and myofibroblasts promoted the accumulation of transitional AECs, establishing a K8-dependent positive feedback loop driving fibrogenesis. Finally, rare murine transitional AECs were highly senescent and basaloid and may not differentiate into AEC1s, recapitulating the aberrant basaloid state in human IPF. We conclude that transitional AECs induced and were maintained by fibrosis in a K8-dependent manner; in mice, most transitional cells and fibrosis resolved, whereas in human IPF, transitional AECs evolved into an aberrant basaloid state that persisted with progressive fibrosis.

Original languageEnglish
Article numbere165612
Number of pages18
JournalJournal of Clinical Investigation
Volume133
Issue number22
DOIs
Publication statusPublished - 15 Nov 2023
MoE publication typeA1 Journal article-refereed

Keywords

  • Humans
  • Animals
  • Mice
  • Keratin-8/metabolism
  • Alveolar Epithelial Cells
  • Idiopathic Pulmonary Fibrosis/metabolism
  • Epithelial Cells/metabolism
  • Cell Differentiation

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