Cell lineage tracing and fate mapping methods have identified multiple origins of progenitor cells, macrophages and extracellular matrix (ECM)-producing cells that become mobilized after injury to repair cardiac tissue. These studies also revealed, that in the disease environment, resident cells become plastic, changing their stereotypical identities to adopt pro-inflammatory and pro-fibrotic phenotypes. At present, the functional significance of this heterogeneity among reparative cells is poorly understood. We recently demonstrated that vascular endothelial cells are a major source of cardiac cell heterogeneity, supplying about 40% of Sca1+ progenitor cells that reside in the adventitia of coronary arteries during homeostasis, and 30% of ECM-producing cells after acute ischemic injury. Vascular inflammation is a key trigger of endothelial plasticity in pathological conditions. We discovered that the BMP antagonist Grem2 limits the magnitude of the inflammatory response by suppressing the pro-inflammatory phenotype of endothelial cells. We hypothesize that reparative cells of diverse origins play distinct roles after cardiac injury, and that inflammatory processes and BMP signaling affect their plasticity and fate decisions in the adult heart. To test these concepts, we will determine molecular signatures, spatiotemporal distribution and ECM production characteristics among ECM-producing cell populations of distinct origins after acute ischemic injury, investigate the role of inflammation and BMP signaling in EC plasticity, and, assess whether the origin of Sca1+ cardiac progenitor cells dictates their function. Cardiovascular diseases are responsible for the majority of deaths in the U.S. and worldwide. The proposed research will establish mechanisms that control cellular plasticity and fate decisions of cardiac repair cells in the disease environment. From a clinical perspective, our findings will provide new targets to favorably manipulate cardiac tissue repair in order to limit ventricular remodeling and prevent heart failure.
Recent studies discovered multiple independent sources of cells that take part in wound healing after a heart attack. This proposal will determine the functional differences among this heterogeneous population of cells in order to identify new therapeutic strategies to repair heart tissue damage.
