Human induced pluripotent stem cells carrying the MYBPC3 c.2373insG mutation exhibited hypocontractility in 3D models and metabolic and structural defects in 2D models compared to isogenic controls.
Different in vitro models (2D vs 3D) of MYBPC3-mutated hiPSCs reveal distinct hypertrophic cardiomyopathy phenotypes, emphasizing the need for appropriate model selection in basic research.
Hypertrophic cardiomyopathy (HCM) is a complex cardiac disorder caused by mutations in sarcomeric protein genes, showing variable penetrance and disease severity among patients. Key pathological features include left ventricular hypertrophy, myofibrillar disarray and contractile defects. Here, we used human induced pluripotent stem cells (hiPSCs) carrying the MYBPC3 c.2373insG mutation to investigate disease phenotypes across three in vitro platforms: cardiac microtissues (cMTs) generated from pre-differentiated cells, cardioids formed directly from hiPSCs and 2D hiPSC-derived cardiomyocytes. Both 3D models exhibited either altered contractile properties or calcium transients compared to isogenic controls, mirroring hypocontractility which is observed in some patients. In contrast, MYBPC3 -c.2373insG hiPSC-derived cardiomyocytes cultured in 2D showed disrupted sarcomere organisation and altered metabolism with increased oxygen consumption rate, but no measurable contractility defects. In addition, cMTs displayed a haploinsufficient phenotype, consistent with clinical observations in patients harbouring this mutation. Together, these findings show that different features of HCM pathology may best be revealed using different in vitro models, underscoring the need to select systems appropriate to the biological question. This work provides a platform to further explore the mechanisms underlying HCM, offering insights into how this condition might be more effectively studied and, eventually, treated. • Modelled hypertrophic cardiomyopathy using MYBPC3 mutant and corrected hiPSCs. • 3D cardiac microtissues and cardioids show a hypocontractile phenotype. • HCM 3D cardiac models have contractile and calcium handling abnormalities. • HCM 2D hiPSC-CMs have higher oxygen consumption rate and sarcomere disorganisation. • MyBP-C haploinsufficiency is revealed in HCM cardiac microtissues.
Yiangou et al. (Fri,) conducted a other in Hypertrophic cardiomyopathy (HCM). 3D cardiac microtissues, cardioids, and 2D hiPSC-derived cardiomyocytes vs. Isogenic controls was evaluated on Disease phenotypes including contractile properties, calcium transients, sarcomere organisation, and metabolism. Human induced pluripotent stem cells carrying the MYBPC3 c.2373insG mutation exhibited hypocontractility in 3D models and metabolic and structural defects in 2D models compared to isogenic controls.