Regulation of interactions between cells and extracellular matrix: a command performance on several stages

Cell behaviors that feature prominently in development and disease — shape, adhesion, migration, differentiation — have become some of the major watchwords in cell biology today. These activities are mediated by interactions of cells with an extracellular environment, consisting in most cases of a heterogeneous, macromolecular matrix that is specific, not only to a given tissue, but to cells contributing to the compartmentalization of organs and tissues. That cell-matrix communication, defined broadly as receptor-ligand interactions resulting in signal transduction for the initiation/modification of cell behavior, is now a dominant theme in basic biomedical research attests to the insight of embryologists working nearly one hundred years ago, as well as investigators within the last quarter-century, who showed that cell shape was linked to cell fate and cell performance (1). In a recent minireview series on integrins, predominant but not exclusive mediators of information between cells and the extracellular milieu, John McDonald recalled the concept of “dynamic reciprocity,” coined originally to describe the interdependent relationship of cells to matrix, which changes with cellular differentiation or tissue remodeling (2). This Perspective series on cell-matrix interactions brings together, in a novel juxtaposition, mediators of cell shape in vivo and in vitro. The six articles, each focusing largely on one protein or proteoglycan (or family) in the context of its general effects on cell behavior as a function of extracellular matrix integrity, range in content from cell adhesion and counteradhesion, to connective tissue structure and function. However, readers will note a leitmotif throughout the articles that relates to the interpretation of extracellular signals at the cell surface. Several years ago, Paul Bornstein turned the phrase “matricellular proteins,” defined as secreted macromolecules that interact with cell-surface receptors, extracellular matrix (ECM), growth factors, and/or proteases but do not in themselves subserve strictly or exclusively structural roles (3). Originally limited to SPARC (secreted protein acidic and rich in cysteine), thrombospondin 1 (TSP1), and tenascin C, this group now includes other proteins and proteoglycans, some of which are featured in this Perspective series (TSP2, tenascin X, syndecans, osteopontin). Matricellular proteins (or the families to which they belong) are structurally unrelated glycoproteins that, under certain conditions, disrupt cell-matrix interactions (counter- or de-adhesion) and are associated with remodeling, morphogenesis, and vascular growth (3, 4). Thus, the grouping is one based on function, with variability among its constituents resulting from cell/tissue specificity, pathology versus normal development, compensatory effects of other proteins, etc. The matricellular proteins, which often act as extracellular “adapters” or “interface molecules,” have modular structures, the domains of which account for a pleiotropy of functions. In contrast to the severe or lethal phenotypes seen in mice with targeted deletions of, for example, VEGF, collagen I, or fibronectin, animals null for the matricellular proteins mentioned above are viable and appear superficially normal, due in part to compensatory or overlapping functions subserved by related genes. However, upon closer examination, both developmental and challenge phenotypes have become apparent in many of these animals (e.g., vascular, wound healing, bone, immunocompromise, hemostasis, and connective tissue) that confirm and extend the significant roles exerted by this group of macromolecules in the design, maintenance, and repair of most tissues.