A guide to building the matrisome interactome: from computational predictions to experimental validation

The extracellular matrix (ECM) is a complex meshwork of proteins and polysaccharides found in all multicellular organisms, that provides structural support to cells and organize them into tissues and organs. In addition to its architectural role, the ECM conveys key mechanical and biochemical signals to cells via cell surface receptors that activate biological pathways controlling a plethora of cellular behaviors, including proliferation, stemness, adhesion, migration, or differentiation. The structural integrity of the ECM and its signaling functions are mediated by protein-protein and protein-polysaccharide interactions. Uncovering the mechanisms regulating these interactions is critical to better understand ECM assembly and biology and envision therapeutic strategies targeting the ECM. Here, we provide a comprehensive review of the computational and experimental approaches available to identify and characterize ECM protein interactions, from individual interactions to the interactome of the full matrisome. We first review computational tools currently available to predict interactions and then describe techniques that allow the experimental determination of these interactions and the parameters governing them. Using examples from original research literature, we illustrate how each approach has been applied to identify ECM interactions and has helped advance our understanding of ECM functions in health and disease. To assist researchers interested in the field, we propose a roadmap combining computational and experimental approaches to generate cell-, tissue-, or disease-specific ECM interaction networks. Lastly, we discuss the remaining challenges and perspectives in the field of ECM interactomics.