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: 11.02). 04/2011; 108(9):1146-56. DOI: 10.1161/CIRCRESAHA.111.240374
Source: PubMed


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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Available from: Joseph C Wu, Mar 23, 2015
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    • "However, there are limitations to use of animal models in terms of an accurate recapitulation of human disease (Takahashi and Yamanaka 2013). The successful derivation of human iPSCs by the dedifferentiation of somatic cells provides significant potential to overcome obstacles in the field of cardiovascular and neurodegenerative diseases (Narsinh et al. 2011). "
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    ABSTRACT: Cardiovascular and neurodegenerative diseases are the most common health threats in developed countries. Limited cell derivation and cell number in cardiac tissue makes it difficult to study the cardiovascular disease using the existing cardiac cell model. Regarding the neurodegenerative disorders, the most potential sources of cell therapeutics such as fetal-derived primary neurons and human embryonic stem cells (ESCs) are associated with ethical or technical limitations. The successful derivation of human-induced pluripotent stem cells (iPSCs) by de-differentiation of somatic cells offers significant potential to overcome hurdles in the field of the replacement therapy. Human iPSCs are functionally similar to human embryonic stem cells, and can be derived autologously without the ethical challenges associated with human ESCs. The iPSCs can, in turn, be differentiated into all cell types including neurons, cardiac cells, blood and liver cells, etc. Recently, target tissues derived from human iPSCs such as cardiomyocytes (CMs) or neurons have been used for new disease modeling and regenerative medicine therapies. Diseases models could be advantageous in the development of personalized medicine of various pathological conditions. This paper reviews efforts aimed at both the practical development of iPSCs, differentiation to neural/cardiac lineages, and the further use of these iPSCs-derived cells for disease modeling, as well as drug toxicity testing.
    Full-text · Article · Oct 2015 · General Physiology and Biophysics
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    • "Suicide genes have also been employed as cytotoxic strategy, in vitro and in vivo models (Huber et al., 1991; Clark et al., 1997; Nor et al., 2002; Nakayama et al., 2005; Hodish et al., 2009; Evans and Dey, 2011; Duarte et al., 2012; Mazor et al., 2012), including combination with replication competent oncolytic viruses (Ahn et al., 2009; Kaur et al., 2009), with some evidence of clinical benefit in solid tumors (Pandha et al., 1999; Freytag et al., 2003, 2007; Nemunaitis et al., 2003; Voges et al., 2003; Li et al., 2007; Xu et al., 2009). Finally, non-integrating vectors (Banasik and McCray, 2010), strategies for the replacement or correction of defective genes (Narsinh et al., 2011; Mukherjee and Thrasher, 2013; Li et al., 2014), together with effective suicide gene strategies, may lead to a more broad application of stem cell or inducible pluripotent stem cell based applications in cancer and regenerative medicine. "
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    ABSTRACT: Adoptive T-cell therapy can involve donor lymphocyte infusion (DLI) after allogeneic hematopoietic stem cell transplantation, the administration of tumor infiltrating lymphocyte (TILs) expanded ex-vivo, or more recently the use of T cell receptor (TCR) or chimeric antigen receptor (CAR) redirected T cells. However cellular therapies can pose significant risks, including graft-versus-host-disease and other on and off-target effects, and therefore strategies need to be implemented to permanently reverse any sign of toxicity. A suicide gene is a genetically encoded molecule that allows selective destruction of adoptively transferred cells. Suicide gene addition to cellular therapeutic products can lead to selective ablation of gene-modified cells, preventing collateral damage to contiguous cells and/or tissues. The ‘ideal’ suicide gene would ensure the safety of gene modified cellular applications by granting irreversible elimination of ‘all’ and ‘only’ the cells responsible for the unwanted toxicity. This review presents the suicide gene safety systems reported to date, with a focus on the state-of-the-art and potential applications regarding two of the most extensively validated suicide genes, including the clinical setting: herpes-simplex-thymidine-kinase (HSV-TK) and inducible-caspase-9 (iCasp9).
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    • "iPS cells, which closely resemble embryonic stem (ES) cells, can be derived from human somatic tissues from a variety of diseases to recapitulate complex physiological phenotypes. Patient-specific iPS cells may provide an additional tool for studying human heart disease [6]. Here, to identify the key elements responsible for hypoplasia of left heart development, we generated disease-specific iPS cells in patients with congenital heart malformation, identified unique genes differentially expressed in HLHS, and explored the responsible regulatory network involved in myocardial patterning and morphogenesis during cardiac development with respect to LV hypoplasia in humans. "
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    ABSTRACT: The genetic basis of hypoplastic left heart syndrome (HLHS) remains unknown, and the lack of animal models to reconstitute the cardiac maldevelopment has hampered the study of this disease. This study investigated the altered control of transcriptional and epigenetic programs that may affect the development of HLHS by using disease-specific induced pluripotent stem (iPS) cells. Cardiac progenitor cells (CPCs) were isolated from patients with congenital heart diseases to generate patient-specific iPS cells. Comparative gene expression analysis of HLHS- and biventricle (BV) heart-derived iPS cells was performed to dissect the complex genetic circuits that may promote the disease phenotype. Both HLHS- and BV heart-derived CPCs were reprogrammed to generate disease-specific iPS cells, which showed characteristic human embryonic stem cell signatures, expressed pluripotency markers, and could give rise to cardiomyocytes. However, HLHS-iPS cells exhibited lower cardiomyogenic differentiation potential than BV-iPS cells. Quantitative gene expression analysis demonstrated that HLHS-derived iPS cells showed transcriptional repression of NKX2-5, reduced levels of TBX2 and NOTCH/HEY signaling, and inhibited HAND1/2 transcripts compared with control cells. Although both HLHS-derived CPCs and iPS cells showed reduced SRE and TNNT2 transcriptional activation compared with BV-derived cells, co-transfection of NKX2-5, HAND1, and NOTCH1 into HLHS-derived cells resulted in synergistic restoration of these promoters activation. Notably, gain- and loss-of-function studies revealed that NKX2-5 had a predominant impact on NPPA transcriptional activation. Moreover, differentiated HLHS-derived iPS cells showed reduced H3K4 dimethylation as well as histone H3 acetylation but increased H3K27 trimethylation to inhibit transcriptional activation on the NKX2-5 promoter. These findings suggest that patient-specific iPS cells may provide molecular insights into complex transcriptional and epigenetic mechanisms, at least in part, through combinatorial expression of NKX2-5, HAND1, and NOTCH1 that coordinately contribute to cardiac malformations in HLHS.
    Full-text · Article · Jul 2014 · PLoS ONE
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