Abstract 837: Different Disease States in Heart Have Distinct Cardiac Interstitial Cells Contributing to Fibrosis

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Cardiac fibrosis is a grim consequence for almost all myocardial injuries. In myocardial infarction (MI), what starts as a protective scarring process to prevent ventricular wall rupture becomes a pathological remodeling of the tissue with the accumulation of excess extracellular matrix (ECM) proteins. Eventually, this adaptation impedes the mechanical and electrical properties of the myocardium resulting in heart failure. Recently, we showed that periostin (Postn) expressing resident cardiac fibroblasts (CFs) are a potential therapeutic target since they differentiate into the scar associated, matrix-producing myofibroblasts (MFs) after injury. In fact, deletion of these cells after an acute injury eliminates interstitial fibrosis but results in ventricular rupture which is a hallmark outcome of impaired ECM deposition during the acute phase of MI. On the other hand, ablation of these cells during a chronic injury such as pressure overload-induced cardiac fibrosis model, we observe sustained perivascular fibrosis. Previous studies report heterogeneity of origin and function for ECM producing cells associated with different cardiac diseases. Here we utilized several novel mouse models that permit lineage tracing of all activated MFs as well as perivascular mural cells in the heart to elucidate the role and fate of these distinct cardiac interstitial cells during fibrogenesis. Cells were lineage traced with a tamoxifen-inducible cre recombinase cDNA knock-in alleles (PostnMCM and Gli1CreER) in combination with a Rosa26-eGFP cre-dependent reporter. Hearts subjected to MI, TAC or Angiotensin injury were processed for extensive histological and RNAseq analyses. Results show that interstitial fibrosis in acute MI injury is a result of Postn+ MFs activity, whereas a subset of Gli1+ mural cells are responsible for the perivascular fibrosis observed after pressure overload models. Therefore, we concluded that pathological ECM deposition resulting in fibrosis comes from disease-specific specialized sub-populations of interstitial cells of the heart with distinct gene expressions and require manipulation of alternative cell- and state-specific therapeutic targets.