UNCOVERING THE MICROENVIRONMENTAL BASIS FOR INHERITED DILATED CARDIOMYOPATHY

Abstract

Inherited mutations in contractile and structural myofibrillar genes, which decrease cardiomyocyte tension generation, are principal drivers of dilated cardiomyopathy (DCM) – the leading cause of heart failure. Progress towards developing precision therapeutics for and defining the underlying determinants of DCM has been cardiomyocyte-centric with negligible attention directed towards fibroblasts despite their role in regulating the best predictor of DCM severity, cardiac fibrosis. Given that failure to reverse fibrosis is a major limitation of both standard of care and first in class precision therapeutics for DCM, this thesis examines whether cardiac fibroblast-mediated regulation of the heart’s material properties is essential for the DCM phenotype. Here we develop biomaterials and animal models to study fibroblast behavior in response to DCM microenvironmental stimuli. Hydrogel biomaterial crosslinks that may be enzymatically degraded by evolved sortases enable the recovery of single cell suspensions to study environmental cues driving fibroblast activation. In a mouse model of inherited DCM, we report that prior to the onset of fibrosis and dilated myocardial remodeling both the myocardium and extracellular matrix (ECM) stiffen, and the resident cardiac fibroblast population undergoes proliferation, which can be blocked by genetically suppressing p38a in cardiac fibroblasts. This fibroblast-targeted intervention unexpectedly masked the primary cardiomyocyte defect in contractile function and prevented dilated cardiomyocyte remodeling. Together, these findings challenge the long-standing paradigm that ECM remodeling is a secondary complication to inherited defects in cardiomyocyte contractile function. Instead, cardiac fibroblasts are essential contributors to the DCM phenotype, thus suggesting DCM-specific therapeutics will require fibroblast-specific strategies.