Cardiomyopathy in a Dish: Using Human Inducible Pluripotent Stem Cells to Model Inherited Cardiomyopathies

Abstract

Inherited cardiomyopathies including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathies (DCM), arrythmogenic right ventricular cardiomyopathy (ARVC), and other inherited forms of heart failure represent a unique set of genetically defined cardiovascular disease processes. Unraveling the molecular mechanisms of these deadly forms of human heart disease has been challenging, however recent groundbreaking scientific advances in stem cell technology has allowed for the generation of patient-specific human inducible stem cell (hiPSC)-derived cardiomyocytes (hiPSC-derived CMs). hiPSC-derived CMs retain the genetic blueprint of the patient, they can be maintained in culture, and they recapitulate the phenotypic characteristics of the disease in vitro, thus serving as a disease in a dish. This review provides an overview of in vitro modeling of inherited cardiomyopathies using patient-specific hiPSC-derived CMs.

Neonatal Transplantation Confers Maturation of PSC-Derived Cardiomyocytes Conducive to Modeling Cardiomyopathy

“…In particular, with methodological advances in differentiating PSCs into cardiomyocytes (CMs), current cardiac PSC research is centering on modeling cardiomyopathy (Kamdar et al, 2015; Lalit et al, 2014), a leading cause of heart failure. However, cardiomyopathy occurs predominantly in adult stages, making it difficult to recapitulate the true disease phenotype and to validate the efficacy of drugs discovered using PSC-derived CMs (PSC-CMs).…”

Recent Advances in the Molecular Genetics of Familial Hypertrophic Cardiomyopathy in South Asian Descendants

“…Adult somatic cells can be reprogrammed using sets of transcription factors to generate human induced pluripotent stem cells (iPSCs) and then functional cardiomyocytes (Kamdar et al, 2015), offering researchers the opportunity to study the molecular mechanisms of CVD and myocardial tissue regeneration following ischemic injury. iPSC-derived cardiomyocytes have been successfully used to study systemic diseases that present with HCM, including Pompe disease (Huang et al, 2011) and LEOPARD syndrome (Carvajal-Vergara et al, 2010).…”

Go to the Mattresses

“…In 2007, this reprogramming technology was translated to the engineering of human induced pluripotent stem cells (hiPSCs) using skin fibroblasts by both the Yamanaka (transduction of c-Myc, Oct3/4, SOX2 and Klf4) and Thomson (transduction of Oct3/4, SOX2, Nanog and Lin28) laboratories (2,3). Importantly, human donors could be fully phenotyped, and their hiPSCs, which retain their genetic blueprint, could be isolated and used to study human disease mechanisms in vitro (4). Given the potential use of these cells in understanding and treating disease, Feaster et al,, in this issue of Circulation Research , optimize the culture conditions to promote the differentiation of hiPSC-derived cardiomyocytes.…”

“…These differentiation protocols include the exposure to distinct signaling factors to direct the hiPSCs to a cardiac fate over a two week period (4–7). Refinement of these protocols has now resulted in reproducibly obtaining a relatively pure cardiomyocyte preparation (75–95% cardiomyocytes).…”