Functional Vascular Tissue Engineering Inspired by Matricellular Proteins

Modern regenerative medicine, and tissue engineering specifically, has benefited from a greater appreciation of the native extracellular matrix (ECM). Fibronectin, collagen, and elastin have entered the tissue engineer's toolkit; however, as fully decellularized biomaterials have come to the forefront in vascular engineering it has become apparent that the ECM is comprised of more than just fibronectin, collagen, and elastin, and that cell-instructive molecules known as matricellular proteins are critical for desired outcomes. In brief, matricellular proteins are ECM constituents that contrast with the canonical structural proteins of the ECM in that their primary role is to interact with the cell. Of late, matricellular genes have been linked to diseases including connective tissue disorders, cardiovascular disease, and cancer. Despite the range of biological activities, this class of biomolecules has not been actively used in the field of regenerative medicine. The intent of this review is to bring matricellular proteins into wider use in the context of vascular tissue engineering. Matricellular proteins orchestrate the formation of new collagen and elastin fibers that have proper mechanical properties-these will be essential components for a fully biological small diameter tissue engineered vascular graft (TEVG). Matricellular proteins also regulate the initiation of thrombosis via fibrin deposition and platelet activation, and the clearance of thrombus when it is no longer needed-proper regulation of thrombosis will be critical for maintaining patency of a TEVG after implantation. Matricellular proteins regulate the adhesion, migration, and proliferation of endothelial cells-all are biological functions that will be critical for formation of a thrombus-resistant endothelium within a TEVG. Lastly, matricellular proteins regulate the adhesion, migration, proliferation, and activation of smooth muscle cells-proper control of these biological activities will be critical for a TEVG that recellularizes and resists neointimal formation/stenosis. We review all of these functions for matricellular proteins here, in addition to reviewing the few studies that have been performed at the intersection of matricellular protein biology and vascular tissue engineering.