Lung extracellular matrix modulates KRT5<sup>+</sup>basal cell activity in pulmonary fibrosis-Reference-Cited by-同舟云学术

Lung extracellular matrix modulates KRT5⁺basal cell activity in pulmonary fibrosis

Published:2022-12-18 Issue: Volume: Page:
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Hewitt Richard J.^ORCID,Puttur Franz,Gaboriau David C. A.,Fercoq Frédéric,Fresquet Maryline,Traves William J.,Yates Laura L.,Walker Simone A.,Molyneaux Philip L.^ORCID,Kemp Samuel V.,Nicholson Andrew G.,Rice Alexandra,Lennon Rachel^ORCID,Carlin Leo M.^ORCID,Byrne Adam J.,Maher Toby M.,Lloyd Clare M.

Abstract

AbstractAberrant expansion of KRT5+basal cells in the distal lung accompanies progressive alveolar epithelial cell loss and tissue remodelling during fibrogenesis in idiopathic pulmonary fibrosis (IPF). The mechanisms determining activity of KRT5+cells in IPF have not been delineated. Here, we reveal a potential mechanism by which KRT5+cells migrate within the fibrotic lung, navigating regional differences in collagen topography.In vitro, KRT5+cell migratory characteristics and expression of remodelling genes are modulated by extracellular matrix (ECM) composition and organisation. Mass spectrometry-based proteomics revealed compositional differences in ECM components secreted by primary human lung fibroblasts (HLF) from IPF patients compared to controls. Over-expression of ECM glycoprotein, Secreted Protein Acidic and Cysteine Rich (SPARC) in the IPF HLF matrix restricts KRT5+cell migrationin vitro. Together, our findings demonstrate how changes to the ECM in IPF directly influence KRT5+cell behaviour and function contributing to remodelling events in the fibrotic niche.

Publisher

Cold Spring Harbor Laboratory

Reference78 articles.

1. Adams, T.S. et al. Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis. Science Advances 6, eaba1983 (2020).

2. Habermann, A.C. et al. Single-cell RNA sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis. Science Advances 6, eaba1972 (2020).

3. Reyfman, P.A. et al. Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis. American journal of respiratory and critical care medicine (2018).

4. Seibold, M.A. et al. The idiopathic pulmonary fibrosis honeycomb cyst contains a mucocilary pseudostratified epithelium. PloS one 8, e58658 (2013).

5. Ectopic respiratory epithelial cell differentiation in bronchiolised distal airspaces in idiopathic pulmonary fibrosis