B-adrenergic receptor (B-AR) signaling pathways in human induced pluripotent stem cell-derived cardiomyocytes, hiPSC-CMs

Stanford University, Stanford CA

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Abstract

? DESCRIPTION (provided by applicant): Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are a novel but still evolving model system for cardiovascular diseases. A key question is how accurately these cells recapitulate the biology of human adult cardiomyocytes. Although hiPSC-CMs have been characterized in terms of global gene expression, little is known about the expression and function of the critical signaling pathways regulating function and structural remodeling in cardiomyocytes. We hypothesize that in hiPSC-CMs, the complex dual role of ?-AR signaling in regulating cardiac function and structural remodeling is established during cardiomyocyte maturation. If true, then ss-AR signaling can be used as a read-out for hiPSC-CM maturation. We also hypothesize that some of the alterations in ?-AR signaling seen in patients with dilated cardiomyopathy are myocyte-autonomous and due to intracellular crosstalk rather than catecholamine excess. If this is the case, we would expect that hiPSC-CMs from patients with a genetic dilated cardiomyopathy will demonstrate alterations in ?-AR signaling. Aim 1 will evaluate ?-AR signaling mechanisms in hiPSC-CMs: (a) the maturation in ?-AR signaling at different stages after hiPSC differentiation into cardiomyocytes; (b) whether ?-ARs demonstrate subtype specific signaling in hiPSC-CMs; (c) whether ?-ARs exhibit compartmentalization of subtype-specific signaling; and (d) whether downregulation mechanisms are functional. Aim 2 will determine whether ?-AR signaling alterations (e.g. downregulation) occur in hiPSC-CMs from patients with dilated cardiomyopathy; and delineate whether different genotypes (e.g. troponin T vs. phospholamban) of dilated cardiomyopathy lead to different ?- AR signaling alterations. These studies will determine how closely hiPSC-CM ?-AR signaling recapitulates that of adult cardiomyocytes and how useful hiPSC-CMs will be for evaluating disease mechanisms or for drug screening in cardiac diseases where ?-AR signaling plays a major role. If alterations in ?-AR signaling are present in hiPSC-CMs isolated from patients, these data would shift our paradigm for heart failure pathophysiology, suggesting that some of the classic alterations in ?-AR signaling are cell-autonomous and not due only to chronically increased sympathetic stimulation.