The extracellular matrix to bind them all: interactions between ECM and cells in lung fibrosis and influences thereof

Lung fibrosis includes a group of devastating rare diseases with poor prognosis and very low survival rates. Among these, idiopathic pulmonary fibrosis (IPF) is the most common form with a poorly understood origin.  Deposition of excessive extracellular matrix (ECM), the bioactive network of proteins providing structural support to all tissues and organs, is one of the main characteristics of IPF. Recruitment of (myo)fibroblasts, major producers of ECM, induced by epithelial cells as a part of the abnormal wound repair response is currently though as the disease underlying mechanism. This fibrotic ECM can influence cells through its aberrant composition, altered biomechanics or disorganized fibers to guide them towards abnormal behavior. Therefore, this thesis aimed to investigate the interactions between fibrotic ECM and cells in the context of perpetuation of fibrotic responses. By utilizing native lung tissue, primary cells and ECM isolated from IPF and non-IPF donors, a series of characterizations were performed both in whole lung tissue and using advanced in vitro models such as lung organoids and lung ECM-derived hydrogels. These characterizations of cell:matrix interactions included ECM organization, epithelial cell regenerative responses, biomechanical profiling of ECM-derived hydrogels (i.e. stiffness and viscoelastic relaxation), myofibroblast activation and fibroblast-driven ECM remodeling responses. Overall, this thesis, through its elucidation of new mechanisms through which fibrotic ECM directs cell responses, or by providing innovative and advanced methodologies to recreate the lung microenvironment in vitro, furthers our understanding of complex cell:matrix interactions and illustrates the overruling capacity of fibrotic ECM in the context of lung fibrosis.

Dissertation: https://hdl.handle.net/11370/c215d316-e44f-4fa9-87ef-fcd763b336c3