UCLA

Cardiovascular disease (CVD) is the leading cause of mortality in the developed world and is exacerbated by the presence of cardiac fibrosis. Cardiac fibrosis is defined as the accumulation of extracellular matrix (ECM) proteins that form scar tissue. The presence of fibrosis in the heart can lead to arrhythmia and reduced contractility, increasing the risk for heart failure. There is currently a deficit of effective treatments to prevent or reverse the process of developing cardiac fibrosis in CVD. Studies are currently focused on understanding the complex myriad of cells that contribute to this process. This dissertation focuses on two different cell types in the heart and their contributions to fibrosis: pericytes and fibroblasts. Understanding these cells and their roles in cardiac fibrosis may unveil potential therapeutic targets for treating CVD.

Cardiac pericytes are a heterogeneous mural cell population that interact closely with endothelial cells to maintain vascular stability. Pericytes in other organs have previously been reported to also play a functional role in ischemic injury response. Findings in spinal cord injury or kidney ischemia have identified pericytes to express ECM proteins and directly contribute to the formation of scar tissue. In order to determine whether pericytes in the heart play a similar role, we used NG2CreER/+ mice to lineage-trace NG2+ cardiac pericytes and determined that a subset of these cells proliferate and express ECM proteins after myocardial infarction (MI). However, due to the heterogeneity of the pericyte population, we noted that NG2 may only label a subpopulation of pericytes in the heart. Therefore, we developed a protocol in which pericytes could be enriched for analysis at the single cell resolution without using any markers. By using this protocol on uninjured murine hearts and hearts that had undergone MI, we identified a subpopulation of pericytes that are potentially responsive to injury. These findings provide a foundation for future studies on cardiac pericytes and their functional role in cardiac fibrosis.

Cardiac fibroblasts (CFbs) are known to be the major cellular source for ECM proteins in the heart. We sought to answer two questions regarding this cell type: 1) whether CFbs from various genetic backgrounds contribute to fibrosis uniquely and 2) whether CFbs express any circulating biomarkers that can be used for detecting fibrosis. CFbs from mice with varying susceptibility to isoproterenol-induced cardiac fibrosis were characterized based on their levels of proliferation and activation. While levels of activation correlated with extent of fibrosis, the levels of proliferation in these cells did not. We then looked at secreted proteins that were expressed by CFbs after injury and validated a significant decrease in circulating levels of the full-length CILP protein in heart failure patients compared to healthy volunteers. These findings support the growing body of research being done on CFbs and their role in developing cardiac fibrosis.