Derivation of human induced pluripotent stem cells for cardiovascular disease modeling.

Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Circulation Research (Impact Factor: 11.09). 04/2011; 108(9):1146-56. DOI: 10.1161/CIRCRESAHA.111.240374
Source: PubMed

ABSTRACT The successful derivation of human induced pluripotent stem cells (hiPSCs) by dedifferentiation of somatic cells offers significant potential to overcome obstacles in the field of cardiovascular disease. hiPSC derivatives offer incredible potential for new disease models and regenerative medicine therapies. However, many questions remain regarding the optimal starting materials and methods to enable safe, efficient derivation of hiPSCs suitable for clinical applications. Initial reprogramming experiments were carried out using lentiviral or retroviral gene delivery methods. More recently, various nonviral methods that avoid permanent and random transgene insertion have emerged as alternatives. These include transient DNA transfection using plasmids or minicircles, protein transduction, or RNA transfection. In addition, several small molecules have been found to significantly augment hiPSC derivation efficiency, allowing the use of a fewer number of genes during pluripotency induction. We review these various methods for the derivation of hiPSCs, focusing on their ultimate clinical applicability, with an emphasis on their potential for use as cardiovascular therapies and disease-modeling platforms.

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    ABSTRACT: The advent of induced pluripotent stem cells (iPSCs) 1 revolutionized Human Genetics by allowing us to generate pluripotent cells from easily accessible somatic tissues. This technology can have immense implications for regenerative medicine, but iPSCs also represent a paradigm shift in the study of complex human phenotypes, including gene regulation and disease 2-5. Yet, an unresolved caveat of the iPSC model system is the extent to which reprogrammed iPSCs retain residual phenotypes from their precursor somatic cells. To directly address this issue, we used an effective study design to compare regulatory phenotypes between iPSCs derived from two types of commonly used somatic precursor cells. We show that the cell type of origin only minimally affects gene expression levels and DNA methylation in iPSCs. Instead, genetic variation is the main driver of regulatory differences between iPSCs of different donors. Research on human subjects is limited by the availability of samples. Practical and ethical considerations dictate that functional molecular studies in humans can generally only make use of frozen post mortem tissues, a small collection of available cell lines, or easily accessible primary cell types (such as blood or skin cells). The discovery that human somatic cells can be reprogrammed into a pluripotent state 6,7 and can then be differentiated 8 into multiple somatic lineages, has the potential to profoundly change human research by providing us access to a wide range of cell types from practically any donor individual. Though much progress has been made since the initial development of iPSC reprogramming technology, and human iPSCs have been used in a wide range of studies, the usefulness of iPSCs as a model system for the study of human phenotypes is still extensively debated
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    ABSTRACT: Induced pluripotent stem cells (iPSCs) hold great promise for basic research and regenerative medicine. They offer the same advantages as embryonic stem cells (ESCs) and moreover new perspectives for personalized medicine. iPSCs can be generated from adult somatic tissues by over-expression of a few defined transcription factors, including Oct4, Sox2, Klf4, and c-myc. For regenerative medicine in particular, the technology provides great hope for patients with incurable diseases or potentially fatal disorders such as heart failure. The endogenous regenerative potentials of adult hearts are extremely limited and insufficient to compensate for myocardial loss occurring after myocardial infarction. Recent discoveries have demonstrated that iPSCs have the potential to significantly advance future cardiovascular regenerative therapies. Moreover, iPSCs can be generated from somatic cells of patients with genetic basis for their disease. This human iPSC derivates offer tremendous potential for new disease models. This paper reviews current applications of iPSCs in cardiovascular regenerative medicine and discusses progress in modeling cardiovascular diseases using iPSCs-derived cardiac cells. © 2015 by the Society for Experimental Biology and Medicine.
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    Circulation Research 12/2014; 115(12):e71-8. DOI:10.1161/CIRCRESAHA.114.305567 · 11.09 Impact Factor


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