|Year : 2015 | Volume
| Issue : 3 | Page : 241-243
Human-induced pluripotent stem cells in modeling inherited cardiomyopathies
Subhoshree Ghose, Anju Sharma, Aishwarya Agarwal, Shantanu Sengupta
Department of Genomics and Molecular Medicine, Council of Scientific and Industrial Research, Institute of Genomics and Integrative Biology, New Delhi, India
|Date of Web Publication||23-Feb-2016|
Department of Genomics and Molecular Medicine, Council of Scientific and Industrial Research, Institute of Genomics and Integrative Biology, New Delhi
Source of Support: None, Conflict of Interest: None
Our current understanding of molecular mechanisms of cardiomyopathies has been elucidated from genetic animal models. Induced pluripotent stem cells (iPSCs) can provide a platform to improve our understanding of familial cardiomyopathies diseases. iPSCs are a type of pluripotent stem cell that can be generated directly from adult cells. Identification of mutations in patients with inherited cardiomyopathies has revealed substantial molecular complexity. In spite of the complexity, the advances of iPSC-based technology may improve our understanding of familial cardiomyopathies.
Keywords: Human-induced pluripotent stem cells technology, inherited cardiomyopathy, patient-specific cell therapy
|How to cite this article:|
Ghose S, Sharma A, Agarwal A, Sengupta S. Human-induced pluripotent stem cells in modeling inherited cardiomyopathies. J Pract Cardiovasc Sci 2015;1:241-3
|How to cite this URL:|
Ghose S, Sharma A, Agarwal A, Sengupta S. Human-induced pluripotent stem cells in modeling inherited cardiomyopathies. J Pract Cardiovasc Sci [serial online] 2015 [cited 2020 May 27];1:241-3. Available from: http://www.j-pcs.org/text.asp?2015/1/3/241/177232
| Introduction|| |
Cardiac diseases have become one of the major causes of death worldwide. The common causes of heart failure are ischemia, hypertension, coronary artery disease, and idiopathic dilated cardiomyopathy (DCM).  Heart failure due to cardiomyopathy is a major concern in developing countries. Significant efforts are being made to minimize the cases of heart transplantation. Therefore, ever increasing demand for any alternative therapeutic strategy has been of utmost priority for cardiomyopathy.
Our current understanding of molecular mechanisms and cellular pathophysiology of cardiomyopathies has been elucidated from genetic animal models such as mouse, rat, and rabbit.  These animal models, however, do not always accurately recapitulate the human cardiomyopathy phenotype, which may be due to the cardiovascular differences between the divergent species.
Induced pluripotent stem cells (iPSCs) are a type of pluripotent stem cell that can be generated directly from adult cells. The iPSCs technology was pioneered by Takahashi and Yamanaka, who showed that the introduction of four specific genes encoding transcription factors could convert adult cells into pluripotent stem cells in effect showing that mature cells can be reprogrammed to become pluripotent.  A feature of human iPSCs (hiPSCs) is the ability to derive them from adult patients to study the cellular basis of disease. In many instances, the patient-derived iPSCs exhibit cellular defects not observed in iPSC from healthy patients, providing insight into the pathophysiology of the disease. Today, most of the studies of cardiomyopathy are based on transgenic mouse models and limited amounts of the myocardial biopsy specimen. Patient-specific iPSCs lines in patients with hypertrophic cardiomyopathy (HCM) and DCM have been reported and may serve as important human models of inherited diseases to improve our understanding of the disease mechanisms and enable drug screening.
| Induced Pluripotent Stem Cells|| |
iPSCs are adult cells that have been reprogrammed to an embryonic stem cell-like state by being made to express genes and factors important for maintaining the properties of embryonic stem cells. , It is not known if iPSCs and embryonic stem cells differ in clinically significant ways. Viruses are used to introduce the reprogramming factors into adult cells. iPSCs are potential tools for drug development and modeling of diseases. In 2007, Yamanaka and Thompson laboratories independently reprogrammed somatic cells into iPSCs.  The Yamanaka laboratory isolated human dermal fibroblasts and generated iPSCs using four transcription factors octamer binding transcription factor 4 (Oct4), sex-determining region-Y box 2 (Sox2), kruppel-like factor 4 (Klf4), and c-Myc via a retroviral vector system. Thompson laboratory also used human dermal fibroblasts but used Oct4, Sox 2, Nanog, and a gene LIN28 using lentiviral vector delivery system to generate iPSCs. ,
- iPSCs technology allowed researchers to reprogram mature somatic cells harvested from patients carrying an inherited disease phenotype and generate an unlimited supply of iPSCs which in turn could be differentiated into various cell types needed such as neurons, cardiac cells, pancreatic cells, liver cells, blood cells, or enterocytes for disease modeling, drug screening, and cell therapy 
- They are patient-specific and thus retain the genetic blueprint of the patient, thus providing a powerful tool for translational medicine
- This innovative technology allows to study human diseases and establish patient-specific genetic disease models in vitro, and these develop models are useful for understanding the mechanism of physiology and pathology of disease, validating therapeutic targets, and drug screening/discovery. 
Furthermore, it avoids the ethical concerns that have plagued the embryonic stem cell field. hiPSCs-derived cardiomyocytes (CMs) have the potential to acquire the physiological and genetic features of adult healthy cardiac muscles which make them suitable for translational medicine.
| Current Progress|| |
Recently, iPSCs technologies bestow a major breakthrough by the generation of disease models of inherited cardiomyopathy in the field of heart failure research, though there are huge concerns over modeling cardiomyopathy disease using iPSCs-derived CMs because of variable clinical and genetic features of the disease. Several hiPSCs models have been developed to investigate inherited cardiomyopathies with varied phenotypes including DCM, restrictive cardiomyopathy (RCM), HCM, arrhythmogenic right ventricular cardiomyopathy (ARVC), Barth syndrome, and Friedreich ataxia.  In early 2009, there was the first report of the application of iPSCs in patients with LEOPARD syndrome associated with HCM.
For this, adult human somatic tissues including dermal fibroblasts and other organ-specific tissues, such as cardiac biopsies, are obtained from patients with inherited cardiomyopathies due to genetic mutations to develop patient-specific hiPSC lines. Then, the human somatic tissue is cultured in vitro, and with the use of integrating systems (retroviral and lentiviral systems) or nonintegrating systems (Sendai virus and micro-RNAs), the reprograming factors such as Sox2, Oct4, c-Myc, and KLF4 are introduced into the cells, where they are able to generate iPSCs. , After introduction of the transcription factors, the cultured cells express pluripotency factors. Within 14-21 days, hiPSC colonies can be identified and characterized by their expression of pluripotent markers such as Oct4, stage-specific embryonic antigen-4, alkaline phosphatase, transgene silencing, and formed teratoma as introduced into SCID mice demonstrating the pluripotency of the iPSCs. The iPSCs colonies are clonally expanded on murine embryonic fibroblasts and differentiated into CMs using directed differentiation protocols containing modulation of the bone morphogenetic protein, transforming growth factor β, and fibroblastic growth factor pathways to specify iPSCs to a cardiac fate. , It is a multistep process that involves transition of epithelial to mesenchymal and mesodermal and cardiac specification that leads to functional CM-like cells.
Till date, a number of genetic cardiomyopathies have also been examined using iPSCs models, for example,
- Sun et al. and Liang and Du derived hiPSCs from skin cells of a family cohort with DCM having point mutation in cardiac troponin T Type 2 gene, a tropomyosin binding subunit of the troponin complex, mutation in which have also been linked to HCM and RCM. The DCM iPSC-derived CMs exhibited susceptibility to stress, altered regulation of calcium flux, and reduced contractile force, etc., as compared to iPSCs-derived CMs attained from healthy controls in the same family 
- Another model of familiar HCM was demonstrated by Lan et al. and Liang and Du where patient-specific iPSCs were derived from a 10-member family carrying a missense mutation in the myosin heavy chain 7 gene (R663H). iPSC-derived CMs displayed several features of HCM phenotype like abnormal Ca 2+ handling and contractile arrhythmia
- Caspi et al. studied hiPSC-derived CMs obtained from two patients with ARVC due to a heterozygous plakophilin 2 mutation (A324fs335X). CMs with severe desmosomal distortion had increased lipid accumulation, indicates a link between desmosomal malfunction and lipid accumulation. 
Upcoming reports described a combination of plasmid DNA-based nonviral transfection method to generate healthy contractile CMs from human skin fibroblast and human umbilical vein endothelial cells. 
| Conclusion|| |
Thus, hiPSC-derived CMs retain the patient's specific genetic mutation and give an unprecedented opportunity to develop in vitro patient-specific inherited cardiomyopathies model in a dish. These models are useful to investigate the molecular and cellular mechanisms of disease and to test novel therapies, which eventually can be used to treat patients. Despite limitations like developmental immaturity of hiPSC-derived CMs as compared to adult CMs, it is a promising field wherein future, hiPSC-derived CMs can serve as functional multi-cell type organ models for inherited cardiomyopathy. Till now, no reports of iPSC-derived models of RCM have been reported, but active research is going on.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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