Modeling Cardiac Disease Mechanisms Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Progress, Promises and Challenges

Abstract

Cardiovascular diseases (CVDs) are a class of disorders affecting the heart or blood vessels. Despite progress in clinical research and therapy, CVDs still represent the leading cause of mortality and morbidity worldwide. The hallmarks of cardiac diseases include heart dysfunction and cardiomyocyte death, inflammation, fibrosis, scar tissue, hyperplasia, hypertrophy, and abnormal ventricular remodeling. The loss of cardiomyocytes is an irreversible process that leads to fibrosis and scar formation, which, in turn, induce heart failure with progressive and dramatic consequences. Both genetic and environmental factors pathologically contribute to the development of CVDs, but the precise causes that trigger cardiac diseases and their progression are still largely unknown. The lack of reliable human model systems for such diseases has hampered the unraveling of the underlying molecular mechanisms and cellular processes involved in heart diseases at their initial stage and during their progression. Over the past decade, significant scientific advances in the field of stem cell biology have literally revolutionized the study of human disease in vitro. Remarkably, the possibility to generate disease-relevant cell types from induced pluripotent stem cells (iPSCs) has developed into an unprecedented and powerful opportunity to achieve the long-standing ambition to investigate human diseases at a cellular level, uncovering their molecular mechanisms, and finally to translate bench discoveries into potential new therapeutic strategies. This review provides an update on previous and current research in the field of iPSC-driven cardiovascular disease modeling, with the aim of underlining the potential of stem-cell biology-based approaches in the elucidation of the pathophysiology of these life-threatening diseases.

Mending a broken heart: In vitro, in vivo and in silico models of congenital heart disease

“…(2) preservation of the donor's genomic and epigenetic profile to study precise genetic mutations (Parrotta et al, 2020). Here, we review the use and potential applications of iPSC-derived cardiac models for investigating the pathophysiology of complex CHD and designing novel treatment strategies.…”

“…Since this ground-breaking study was first published, a plethora of reprogramming cocktails have been designed to convert various somatic cells to pluripotency ( Lee et al, 2010 ; Liao et al, 2008 ; Maherali et al, 2008 ; Okita et al, 2013 ). The key advantages of iPSCs are (1) derivation from human somatic cells, which in some jurisdictions would more readily receive ethical approval for generation and use ( Bilic and Izpisua Belmonte, 2012 ); and (2) preservation of the donor's genomic and epigenetic profile to study precise genetic mutations ( Parrotta et al, 2020 ). Here, we review the use and potential applications of iPSC-derived cardiac models for investigating the pathophysiology of complex CHD and designing novel treatment strategies.…”

“…Patient-derived iPSCs and iPSC-derived cardiomyocytes have well-established advantages as models of cardiac disease, given that they recapitulate the pathophysiological characteristics of a broad range of CHDs ( Ebert et al, 2012 ; Parrotta et al, 2020 ). However, it is uncertain how closely these in vitro iPSCs and iPSC-derived cardiomyocytes recapitulate the disease phenotype of the donor, particularly its severity.…”

Deciphering the Role of Wnt and Rho Signaling Pathway in iPSC-Derived ARVC Cardiomyocytes by In Silico Mathematical Modeling

“…Induced pluripotent stem cells (iPSCs) have emerged as a powerful technology for modeling human diseases in vitro [ 24 , 25 , 26 ]. Despite molecular differences between iPSCs and ESCs [ 27 , 28 ], a growing number of scientific reports show the utility of iPSCs in understanding the molecular basis of cardiac diseases and heart remodeling [ 29 , 30 ]. Using an iPSC-based strategy, the activity of RhoA-ROCK pathway was recently linked to the maintenance of an activated MRTF/SRF (Myocardin-Related Transcriptional Factors/Serum Response Factor) transcriptional program, which is responsible for the regulation of cardiomyocytes identity in a human model of ARVC [ 31 ].…”

In Vitro CSC-derived Cardiomyocytes Exhibit the Typical microRNA-mRNA Blueprint of Endogenous Cardiomyocytes

“…In vitro differentiation of embryonic stem cells (ESCs), as well as of induced pluripotent stem cells (iPSCs), into CMs recapitulate the CM development, differentiation and maturation in the embryonic life [12][13][14] . These in vitro iPSC-based model systems have revealed different roles played by speci c miRs in cardiomyocyte differentiation.…”