학술논문
Lung extracellular matrix modulates KRT5+ basal cell activity in pulmonary fibrosis
Document Type
Original Paper
Author
Hewitt, Richard J.; Puttur, Franz; Gaboriau, David C. A.; Fercoq, Frédéric; Fresquet, Maryline; Traves, William J.; Yates, Laura L.; Walker, Simone A.; Molyneaux, Philip L.; Kemp, Samuel V.; Nicholson, Andrew G.; Rice, Alexandra; Roberts, Edward; Lennon, Rachel; Carlin, Leo M.; Byrne, Adam J.; Maher, Toby M.; Lloyd, Clare M.
Source
Nature Communications. 14(1)
Subject
Language
English
ISSN
2041-1723
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.
Idiopathic pulmonary fibrosis has been associated with aberrant expansion of KRT5-expressing basal cells. Here the authors show how changes in the ECM glycoprotein SPARC restrict the movement of KRT5+ cells, affecting their retention within fibrotic tissue.
Idiopathic pulmonary fibrosis has been associated with aberrant expansion of KRT5-expressing basal cells. Here the authors show how changes in the ECM glycoprotein SPARC restrict the movement of KRT5+ cells, affecting their retention within fibrotic tissue.