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

ABSTRACT: Aberrant 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 migration in 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.

SUBMITTER: Hewitt RJ

PROVIDER: S-EPMC10533905 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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

Hewitt Richard J RJ Puttur Franz F Gaboriau David C A DCA Fercoq Frédéric F Fresquet Maryline M Traves William J WJ Yates Laura L LL Walker Simone A SA Molyneaux Philip L PL Kemp Samuel V SV Nicholson Andrew G AG Rice Alexandra A Roberts Edward E Lennon Rachel R Carlin Leo M LM Byrne Adam J AJ Maher Toby M TM Lloyd Clare M CM

Nature communications 20230927 1

Aberrant 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 migrat ...[more]

PMID: 37758700

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Project description:Fibrotic disease is characterized by the pathological accumulation of extracellular matrix (ECM) proteins. Surprisingly, very little is known about the synthesis and degradation rates of the many proteins and proteoglycans that constitute healthy or pathological extracellular matrix. A comprehensive understanding of altered ECM protein synthesis and degradation during the onset and progression of fibrotic disease would be immensely valuable. We have developed a dynamic proteomics platform that quantifies the fractional synthesis rates of large numbers of proteins via stable isotope labeling and LC/MS-based mass isotopomer analysis. Here, we present the first broad analysis of ECM protein kinetics during the onset of experimental pulmonary fibrosis. Mice were labeled with heavy water for up to 21 days following the induction of lung fibrosis with bleomycin. Lung tissue was subjected to sequential protein extraction to fractionate cellular, guanidine-soluble ECM proteins and residual insoluble ECM proteins. Fractional synthesis rates were calculated for 34 ECM proteins or protein subunits, including collagens, proteoglycans, and microfibrillar proteins. Overall, fractional synthesis rates of guanidine-soluble ECM proteins were faster than those of insoluble ECM proteins, suggesting that the insoluble fraction reflected older, more mature matrix components. This was confirmed through the quantitation of pyridinoline cross-links in each protein fraction. In fibrotic lung tissue, there was a significant increase in the fractional synthesis of unique sets of matrix proteins during early (pre-1 week) and late (post-1 week) fibrotic response. Furthermore, we isolated fast turnover subpopulations of several ECM proteins (e.g. type I collagen) based on guanidine solubility, allowing for accelerated detection of increased synthesis of typically slow-turnover protein populations. This establishes the presence of multiple kinetic pools of pulmonary collagen in vivo with altered turnover rates during evolving fibrosis. These data demonstrate the utility of dynamic proteomics in analyzing changes in ECM protein turnover associated with the onset and progression of fibrotic disease.

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

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Lung extracellular matrix modulates KRT5<sup>+</sup> basal cell activity in pulmonary fibrosis.

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Dataset Information

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

Publications

Lung extracellular matrix modulates KRT5&lt;sup&gt;+&lt;/sup&gt; basal cell activity in pulmonary fibrosis.

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OmicsDI is part of the ELIXIR infrastructure

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

Lung extracellular matrix modulates KRT5<sup>+</sup> basal cell activity in pulmonary fibrosis.