Lung extracellular matrix modulates KRT5+ basal cell activity in pulmonary fibrosis
Richard Hewitt, Franz Puttur, David C. A. Gaboriau, Frédéric Fercoq, Maryline Fresquet, William J. Traves, Laura L. Yates, Simone A. Walker, Philip L. Molyneaux, Samuel V. Kemp, Andrew G. Nicholson, Alexandra Rice, Edward W. Roberts, Rachel Lennon, Leo M. Carlin, Adam J. Byrne, Toby M. Maher, Clare M. Lloyd
Abstract
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.