Modeling the contribution of cardiac fibroblasts in dilated cardiomyopathy using induced pluripotent stem cells (iPSCs)

Fibrosis is implicated in nearly all forms of cardiomyopathy and significantly influences disease severity and outcomes. The primary cell responsible for fibrosis is the cardiac fibroblast, which remains understudied relative to cardiomyocytes in the context of cardiomyopathy. The development of induced pluripotent stem cell-derived cardiac fibroblasts (iPSC-CFs) allows for the modeling of patient-specific disease characteristics and provides a scalable source of fibroblasts. iPSC-CFs are invaluable for understanding molecular pathways that affect disease progression and outcomes. This review explores various aspects of cardiomyopathy, with a focus on dilated cardiomyopathy, that can be modeled using iPSC-CFs and their application in drug discovery, given the current lack of approved therapies for cardiac fibrosis. We examine how iPSC-CFs can be utilized to study heart development, fibroblast heterogeneity, and activation, with the ultimate goal of developing better therapies for patients with cardiomyopathies. SIGNIFICANCE STATEMENT: We explore how induced pluripotent stem cell-derived cardiac fibroblasts (iPSC-CFs) are used to study the fibrotic component of dilated cardiomyopathy. Most research has focused on cardiomyocytes, but iPSC-CFs serve as a valuable tool to elucidate molecular pathways leading to fibrosis and paracrine interactions with cardiomyocytes. Gaining insights into these events could aid in the development of new therapies and enable the use of patient-derived iPSC-CFs for precision medicine, ultimately improving patient outcomes.