(A) During the proliferative phase of cardiac repair, fibroblasts and macrophages contribute to the formation of a cell-derived provisional matrix, enriched with a wide range of matricellular macromolecules that do not serve a primary structural role, but modulate cellular phenotype and function. Specialized matrix proteins (such as ED-A domain fibronectin) and matricellular proteins, such as TSPs, tenascin-C (TNC), osteopontin (OPN), SPARC, periostin, osteoglycin, and members of the CCN family, bind to the matrix and modulate growth factor and protease activity. Specific matricellular proteins have been reported as regulating inflammation, participating in fibrogenic and angiogenic responses, modulating cardiomyocyte survival, and contributing to assembly of the structural matrix. (B) Matricellular proteins may be critical in spatial and temporal regulation of growth factor signaling. Immunohistochemical staining using a peroxidase-based technique (black) shows the strikingly selective localization of the prototypical matricellular protein TSP1 (arrows), a critical activator of TGF-β, in the border zone of a healing canine myocardial infarction (one hour ischemia followed by seven days reperfusion). Spatially and temporally restricted induction of matricellular proteins regulates growth factor signaling, preventing expansion of profibrotic responses beyond the infarcted area, despite possible diffusion of the soluble mediators in viable segments. Counterstained with eosin. Reproduced with permission from Circulation (75). Scale bar: 50 μm. GAGs, glycosaminoglycosans.