Abstract
hiPSC-CMs are a novel model system for cardiovascular diseases, with proven utility in cardiac channelopathies, however, how accurately hiPSC-CMs recapitulate the signaling pathways regulating contractility and remodeling of adult cardiomyocytes remains to be determined. As ß-ARs are key regulators of both contractility and remodeling, we examined ß-AR signaling at different stages of hiPSC-CM maturation. hiPSCs, derived from healthy controls, were studied at 0, 14, 30, and 60d after cardiac induction under isoproterenol (ISO) stimulation ± ß1 or ß2 antagonists. Flag-tagged ß-ARs were transfected into hiPSC-CMs for trafficking studies. Compared to the ß1:ß2 ratio of 70:30 in adult ventricular cardiomyocytes, ß2-AR expression was higher in early stage (d14-30) hiPSC-CMs; ß1-ARs increased with maturation (d14-d60), reflective of the normal developmental pattern. Downstream signaling also matured from d14-60, regulating both function (PLB and TnI) and remodeling (ERK). The majority of cAMP generation and PKA activation at d30 was through ß2-ARs; by d60-90, ß1-AR signaling contributed equally. In contrast to studies in rodent cells, ß2-ARs did not show compartmentalization of PKA signaling. Between d30-60, components of the SR (RYR, PLB and CSQ) and caveolae (Cav3) matured, suggesting development of functional compartmentalization machinery. Finally, hiPSC-CMs showed ß2-AR downregulation and internalization in response to ISO, an important component of the normal cardiomyocyte response to pathologic stimulation. Thus, hiPSC-CM ß-AR signaling matures with time after cardiac induction, recapitulating many of the features of post-natal and several of adult cardiomyocytes. hiPSC-CM models of human cardiomyopathies are a reasonable platform for studying ß-AR signaling. Furthermore, the maturation of ß-AR signaling can be used as a read-out for hiPSC-CM maturity.
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