Beyond Family: Modeling Non-hereditary Heart Diseases With Human Pluripotent Stem Cell-Derived Cardiomyocytes

Abstract

Non-genetic cardiac pathologies develop as an aftermath of extracellular stressconditions. Nevertheless, the response to pathological stimuli depends deeply on intracellular factors such as physiological state and complex genetic backgrounds. Without a thorough characterization of their in vitro phenotype, modeling of maladaptive hypertrophy, ischemia and reperfusion injury or diabetes in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) has been more challenging than hereditary diseases with defined molecular causes. In past years, greater insights into hPSC-CM in vitro physiology and advancements in technological solutions and culture protocols have generated cell types displaying stress-responsive phenotypes reminiscent of in vivo pathological events, unlocking their application as a reductionist model of human cardiomyocytes, if not the adult human myocardium. Here, we provide an overview of the available literature of pathology models for cardiac non-genetic conditions employing healthy (or asymptomatic) hPSC-CMs. In terms of numbers of published articles, these models are significantly lagging behind monogenic diseases, which misrepresents the incidence of heart disease causes in the human population.

Integrating nonlinear analysis and machine learning for human induced pluripotent stem cell‐based drug cardiotoxicity testing

“…In current study, the hiPSC‐CMs were used from tone donor (donor 1434, male). The hiPSC‐CMs from this donor have been well characterized in a number of publications (Blanchette et al., 2019; Burnett et al., 2021a; Martewicz et al., 2020), showing the ability to generate clinically‐relevant data. hiPSC‐CMs derived from female donors were shown to be more sensitive to hERG blockers, based on qualitative assessments (Zeng et al., 2019) and were more sensitive to drug‐induced QT prolongation (Huo et al., 2019).…”

Cellular interplay between cardiomyocytes and non-myocytes in diabetic cardiomyopathy

“… 316–318 Although cardiomyocytes derived from patient iPSCs have conventionally been used to model a variety of hereditary monogenic cardiac disorders, 327 , 328 they are increasingly being appreciated for their ability to faithfully capture the cardiac pathophysiology of various non-hereditary lifestyle-related cardiac diseases and cardiac diseases with polygenic risk variants like T2DM. 329 Indeed, cardiomyocytes derived from iPSCs generated from T2DM patients have been shown to recapitulate known cardiomyopathic phenotypes including cellular hypertrophy, impaired contractility, calcium handling abnormalities, metabolic dysregulation, and abnormal TGF-β signalling in the absence of diabetic culture conditions. 308 , 316 …”

Environmental Alterations during Embryonic Development: Studying the Impact of Stressors on Pluripotent Stem Cell-Derived Cardiomyocytes

“…Moreover, many other complications can result from both environmental and nutritional stressors without any genetic predisposition. For example, ischemia-reperfusion injury, metabolic dysregulations and hypertension lead to heart failure in adulthood [149]. Pluripotent stem cells derived CMs can be exposed in vitro to various stressors to investigate their effects on CM function.…”