15 General Introduction and Thesis Outline 1 Figure 1. Generation of hIPSC-CMs by modulating the Wnt signaling pathway. Created with BioRender.com A major limitation, however, remains the batch-to-batch variability of hiPSC-CM efficiency and the inability to robustly expand generally dense-cultured functional hiPSC-CMs for more than 5 fold.36–39 Recently, we described that concomitant Wnt pathway regulation and removal of cell-cell contact inhibition via low cell density serial passaging resulted in a massive proliferative response of hiPSC-CMs (Figure 2).40,41 The developmental clues and the role of the Wnt signaling pathway resulted not only in the efficient generation of hiPSC-CMs but also in a highly efficient detailed method for the expansion and passaging of functional hiPSC-CMs. However, the lack of maturity of the hiPSC-CMs generated by the described di erentiation protocols is an important limitation to overcome for optimal human in vitro modeling. Figure 2. Expansion of hiPSC-CMs by modulating the Wnt signaling pathway. Created with BioRender.com 1.5 Cardiomyocyte maturation HiPSC-CMs have emerged as a promising experimental tool for translational heart research. In theory, with the cardiac expansion method, hiPSC-CMs can provide an unlimited source of human cardiomyocytes that entail the use of human cardiac tissue or cells with minimal ethical and practical concerns. However, their usability as a human adult CM model is limited by their immature phenotype, represented in general by structural underdevelopment, metabolism based on glucose or lactate instead of fatty acids, slow Ca2+ signals, and negative force-frequency relationship that impact the features of electrophysiological parameters.42–45 Applying hiPSC-CMs for adult cardiomyopathy disease modeling or drug research purposes, the immature status may influence to some extent the observed effects by impacting the excitation-contraction coupling. Therefore, to overcome this limitation,
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