Human-induced pluripotent stem cells for modelling metabolic perturbations and impaired bioenergetics underlying cardiomyopathies

Abstract

Normal cardiac contractile and relaxation functions are critically dependent on a continuous energy supply. Accordingly, metabolic perturbations and impaired mitochondrial bioenergetics with subsequent disruption of ATP production underpin a wide variety of cardiac diseases, including diabetic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, anthracycline cardiomyopathy, peripartum cardiomyopathy, and mitochondrial cardiomyopathies. Crucially, there are no specific treatments for preventing the onset or progression of these cardiomyopathies to heart failure, one of the leading causes of death and disability worldwide. Therefore, new treatments are needed to target the metabolic disturbances and impaired mitochondrial bioenergetics underlying these cardiomyopathies in order to improve health outcomes in these patients. However, investigation of the underlying mechanisms and the identification of novel therapeutic targets have been hampered by the lack of appropriate animal disease models. Furthermore, interspecies variation precludes the use of animal models for studying certain disorders, whereas patient-derived primary cell lines have limited lifespan and availability. Fortunately, the discovery of human-induced pluripotent stem cells has provided a promising tool for modelling cardiomyopathies via human heart tissue in a dish. In this review article, we highlight the use of patient-derived iPSCs for studying the pathogenesis underlying cardiomyopathies associated with metabolic perturbations and impaired mitochondrial bioenergetics, as the ability of iPSCs for self-renewal and differentiation makes them an ideal platform for investigating disease pathogenesis in a controlled in vitro environment. Continuing progress will help elucidate novel mechanistic pathways, and discover novel therapies for preventing the onset and progression of heart failure, thereby advancing a new era of personalized therapeutics for improving health outcomes in patients with cardiomyopathy.

Human engineered cardiac tissue model of hypertrophic cardiomyopathy recapitulates key hallmarks of the disease and the effect of chronic mavacamten treatment

“…Cardiomyocytes differentiated from patient-specific iPSCs and the genetically edited isogenic controls have been shown to provide valuable insights into the mechanisms of inherited cardiac diseases ( Eschenhagen and Carrier, 2019 ; Ramachandra et al, 2021 ). However, disease models using 2D cultured iPSC-CMs present some clear limitations in terms of morphology, contractility, and electrophysiology, resembling human cardiomyocytes at the embryonic stage rather than adult ( Sewanan et al, 2020 ).…”

Increased Retention of Cardiac Cells to a Glass Substrate through Streptavidin–Biotin Affinity

“…Overall, we demonstrated that this method can be applied directly to the measurement of calcium signaling in individual CMs and results in increased data collection efficiency from 20 to 80% by binding a biotinylated CM to a streptavidin surface. The overarching significance of these methods extends beyond studying primary CMs to the increasingly used induced pluripotent derived CMs in mechanistic and therapeutic studies. − …”

Large animal models of pressure overload-induced cardiac left ventricular hypertrophy to study remodelling of the human heart with aortic stenosis

“… 17 Hypertrophied cardiomyocytes are subjected to a metabolic switch, similar to the embryonic condition, from fatty acids to glucose. 2 , 28 , 29 Interestingly, it was suggested that this switch exists independently of the energy demand, probably correlating to biosynthetic/anabolic demands of the cell. 30 Furthermore, fructolysis, fructose metabolism, provides has been implicated in the pathology of hypertrophy.…”