Background: Biomaterials have emerged as a promising approach to treat myocardial infarction (MI). Here we investigated a collagen matrix loaded with the pro-angiogenic, anti-fibrotic matricellular protein CCN1. We hypothesized that a CCN1-matrix can positively regulate the function of different cardiac cells and that it would limit adverse cardiac remodeling and dysfunction in a mouse MI model.
Methods:In vitro experiments examined the function of heart-derived fibroblasts, cardiomyocytes and bone marrow macrophages when cultured on the CCN1-matrix. In vivo, MI was induced in mice and at 1wk post-MI, mice received intramyocardial injections of: 1) PBS; 2) matrix; or 3) CCN1-matrix. Heart function was assessed by echocardiography and tissues were analyzed by histology.
Results:In vitro studies revealed that CCN1-matrix was able to reduce fibroblast proliferation by 29% (p=0.02), and TGF-β mediated induction of the myofibroblast marker α-SMA by 42.1% (p=0.014), compared to matrix culture. Furthermore, CCN1-matrix treatment of fibroblasts resulted in a 31% increase in senescence-associated β-galactosidase activity (p=0.041) and a 12.1% reduction in collagenase activity compared to matrix cultured cells (p=0.036). For cardiomyocytes, CCN1-matrix had a protective effect as there was a 39.3% increase in survival under stress conditions compared to matrix-cultured cells (p=0.03). Also, CCN1-matrix culture of macrophages resulted in a 4.2- and 2.2-fold increase in the M2 surface marker CD206 compared to TCPS and matrix, respectively (p≤0.03). In vivo, LVEF was better for CCN1-matrix treated mice (49.6%) at 4wk post-MI compared to matrix (38.7%) and PBS (28.9%) groups (p≤0.01). The relative infarct size of the CCN1-matrix treated hearts (10.1%) was also smaller compared to matrix (15.4%) and PBS (21.4%; p≤0.017). Myocardial vascular density was greater with CCN1-matrix treatment compared to matrix and PBS (by 23% and 41%, respectively; p≤0.035).
Conclusion: Here, we demonstrate that the addition of a matricellular protein can improve the therapeutic potency of a collagen biomaterial. The combination of matricellular proteins and biomaterials is a novel approach to preserve myocardial integrity and cardiac function post-MI.