351 General Discussion - hiPSC-CMs Disease Modelling and Future Perspectives 13 Figure 1. Induced maturity in hiPSC-CMs. (A) Sarcomeric organization, cell length, and sarcomere spacing on immunofluorescent labeled 2D cultured hiPSC-CMs by alpha-actinin. Scale bar: 8 uM. (B) The major measurable parameters of biological processes in cardiomyocyte maturation. The arrow indicates the level of the specific maturation parameters in hiPSC-CMs, the left indicates low, and the right means high maturation levels compared to adult myocytes. Abbreviations; RMP; resting membrane potential, ID; intercalated disc. (C) Connexin43 (Cx43) organization and localization on immunofluorescent labeled 2D cultured hiPSC-CMs by alpha-actinin (green) and Cx43 (red). Scale bar: 8 uM. Created with BioRender.com. ‘enough-matured’ hiPSC-derived CMs that can be used for disease modeling, testing of drug-induced toxicity, and drug refinement/discovery. Although convenient, 2D cell culture techniques have unfortunately proven to be ineffective in mimicking the contractile deficit in titin patient-derived hiPSC-CMs. Instead, the titin mutant hiPSC-CMs in the engineered heart tissue (EHT) model showed the obvious insufficient contractile force of the patient-derived hiPSC-CMs.22 RNA sequencing revealed 22 transcription factors (TFs) whose expression was progressively increased in the 3D culture systems as compared to 2D differentiations.23 By overexpressing three of the 22 identified TFs (KLF15, ESRRA, and HOPX), Kumar et al. could
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