372 Chapter 13 until safe gene-editing therapies are developed, preimplantation genetic diagnosis (IVF) for the disease-causing variant could be considered, although this decision causes a significant emotional burden.123 Can we use hiPSC-CMs to find a cure for genetic cardiomyopathies? hiPSCs represent individual donor genetics and with the recent hiPSC reprogramming technology, creating many patient-derived hiPSC lines is now feasible. Subsequently, we speculate on the potential broader future implications of hiPSC-CM models and this chapter will conclude with an attempt to answer the central question of this thesis: ‘’Can we use hiPSC-CMs to find a cure for genetic cardiomyopathies?’’ Here, the motivation towards realizing the hiPSC-CMs full potential of precision medicine is two-fold: first, to study and elucidate the molecular mechanisms caused by a pathological variant; and second, to screen for new therapeutic strategies for these cardiac pathologies. The prediction of the individual phenotype of hiPSC-CM could make it possible to focus on preventive actions and avoid the disease burden from those without any signs of disease at the heart failure level. Interestingly, in this thesis, we observed that individual cardiomyocytes can develop different degrees of lipid droplet accumulation (Chapter 8) or UPR activation and PLN aggregates (Chapter 9). A potential hypothesis for this phenotypic mosaic pattern in some of the PLN-R14del cardiomyocytes could be the allelic imbalance. In heterozygous patients with mutations that alter protein function and biomechanical properties of a cell, the imbalanced allelic expression may cause functional heterogeneity from cell to cell, which could exacerbate disease phenotype. Previously the allelic imbalance has been demonstrated in both DCM124 and HCM hearts125 which could be linked to the genetic or epigenetic risk for disease and the biological traits of an individual cell.126,127 An improved understanding of the influence of both environmental and genetic modifiers should ultimately be studied in the future to understand the causal genetic variation in each cardiomyocyte and patient. These findings will contribute to the longevity of CMs despite the imbalance transcription of the PLNR14del mutation and could predict and prevent the onset of the disease in each individual. In this thesis, we showed that multi-omics analysis of metabolically matured hiPSC-CMs could be considered the first fingerprinting for the pathological features of the disease (Chapter 8, Chapter 9). In the human body, cells do not function in mono-lineage isolation. Thus, the understanding of disease may require multi-cellular, integrated platforms, which exhibit distinct advantages over mono-lineage analyses. Microtissues such as organoids or spheroids could be used, allowing the study of hundreds of 3D conditions with relatively low amounts of cells and costs. Cardiac spheroids offer great potential for the biobanking and personalized screening of all therapeutic strategies for personalized disease modeling in cardiomyopathy patients (Chapter 11, Chapter 12). Automated kinetic analysis of individual cells and 3D constructs offers the opportunity for high-throughput screenings of many individuals’ hiPSC-CMs. As previously
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