Osteopontin Promotes Infarct Repair
2Leviev Cardiovascular and Thoracic Center, Sheba Medical Center, Tel Hashomer, IL., Israel
Introduction: Macrophages are crucial for infarct repair and myocardial regeneration. The protein osteopontin (OPN) is secreted by macrophages at the site of injury. Understanding how macrophages promote myocardial regeneration can help to create new therapies for infarct repair.
Objective: To determine the role of OPN in myocardial regeneration and repair.
Methods: We subjected neonatal mice to apical resection (AR). To determine the role of OPN in myocardial regeneration in neonatal hearts, we used neonatal cardiomyocytes (NCMs) culture, NCMs viability assays, gene expression analysis, functional in vitro assays, and histology. To assess temporal changes in left ventricular (LV) remodeling and function, we used echocardiography, speckle-tracking strain imaging, and histology.
Results: The crucial role of OPN in myocardial regeneration was confirmed by impaired healing in OPN deficient neonatal mice. In vitro, OPN stimulated NCMs cell cycle re-entry and NCMs migration. Moreover, OPN interacted with the CD44 receptor to translocate cytoplasmatic yes-associated protein 1 (YAP1) into the nucleus, resulting in the upregulation of transcriptional factors and cell cycle genes associated with NCMs proliferation. Blocking CD44 eliminated the effects of OPN on NCMs. Last, in adult mice, a single injection of OPN into the ischemic zone improved scar formation, LV remodeling, and function 30 days after MI.
Conclusions: OPN plays a role in myocardial regeneration in the neonatal heart. OPN activates cell cycle re-entry in neonatal cardiomyocytes and improves endogenous healing and LV function after MI in adult hearts. Therefore, OPN can become a new cell-free treatment to improve infarct repair.