Epigenetic Regulation of Phosphodiesterases 2A and 3A Underlies Compromised β-Adrenergic Signaling in an iPSC Model of Dilated Cardiomyopathy

Wu, Haodi; Lee, Jaecheol; Vincent, Ludovic G.; Wang, Qingtong; Gu, Mingxia; Lan, Feng; Churko, Jared M.; Sallam, Karim; Matsa, Elena; Sharma, Arun; Gold, Joseph; Engler, Adam J.; Xiang, Yang; Bers, Donald M.; Wu, Joseph C.

doi:10.1016/j.stem.2015.04.020

Cited by 161 publications

(162 citation statements)

References 43 publications

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“…iPSC can be propagated indefinitely, differentiated into EC and smooth muscle cells (11), and used for vascular disease modeling (12) and drug screening (13), as shown with iPSCderived cardiomyocytes (14,15).…”

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confidence: 99%

Induced Pluripotent Stem Cell Model of Pulmonary Arterial Hypertension Reveals Novel Gene Expression and Patient Specificity

Chappell³

et al. 2017

Am J Respir Crit Care Med

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Rationale: Idiopathic or heritable pulmonary arterial hypertension is characterized by loss and obliteration of lung vasculature. Endothelial cell dysfunction is pivotal to the pathophysiology, but different causal mechanisms may reflect a need for patient-tailored therapies.Objectives: Endothelial cells differentiated from induced pluripotent stem cells were compared with pulmonary arterial endothelial cells from the same patients with idiopathic or heritable pulmonary arterial hypertension, to determine whether they shared functional abnormalities and altered gene expression patterns that differed from those in unused donor cells. We then investigated whether endothelial cells differentiated from pluripotent cells could serve as surrogates to test emerging therapies.Methods: Functional changes assessed included adhesion, migration, tube formation, and propensity to apoptosis. Expression of bone morphogenetic protein receptor type 2 (BMPR2) and its target, collagen IV, signaling of the phosphorylated form of the mothers against decapentaplegic proteins (pSMAD1/5), and transcriptomic profiles were also analyzed.Measurements and Main Results: Native pulmonary arterial and induced pluripotent stem cell-derived endothelial cells from patients with idiopathic and heritable pulmonary arterial hypertension compared with control subjects showed a similar reduction in adhesion, migration, survival, and tube formation, and decreased BMPR2 and downstream signaling and collagen IV expression. Transcriptomic profiling revealed high kisspeptin 1 (KISS1) related to reduced migration and low carboxylesterase 1 (CES1), to impaired survival in patient cells. A beneficial angiogenic response to potential therapies, FK506 and Elafin, was related to reduced slit guidance ligand 3 (SLIT3), an antimigratory factor.Conclusions: Despite the site of disease in the lung, our study indicates that induced pluripotent stem cell-derived endothelial cells are useful surrogates to uncover novel features related to disease mechanisms and to better match patients to therapies.

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confidence: 99%

Induced Pluripotent Stem Cell Model of Pulmonary Arterial Hypertension Reveals Novel Gene Expression and Patient Specificity

Chappell³

et al. 2017

Am J Respir Crit Care Med

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“…Despite the immaturity of the derived hiPSC-CMs, this study paved the way for a subsequent study by Wu et al, which showed more mechanistically that the mutated TNNT2 caused the cardiomyopathic phenotypes by nuclear translocation, followed by epigenetic activation of the phosphodiesterase 2A/3A (PDE2A/PDE3A) genes leading to contractile dysfunction. 79 These studies demonstrated the ability of hiPSC technology to enable mechanistic studies on patient-specific cardiomyocytes.…”

Section: Disease Modeling Using Patient-specific Hipsc Derivativesmentioning

confidence: 96%

Induced pluripotent stem cells: at the heart of cardiovascular precision medicine

2016

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The advent of human induced pluripotent stem cell (hiPSC) technology has revitalized much of the efforts within the past decade to more fully realize the potential of human embryonic stem cells (hESCs). Adding to the possibility of generating unlimited supplies of any cell types of interest, the hiPSC technology now enables the derivation of cells with patient-specific phenotypes. With the Precision Medicine Initiative, it is clear that the hiPSC technology will play a vital role in the advancement of cardiovascular research and medicine. This review summarizes the tremendous and continuing progress that has been made in the field of hiPSC technology, with particular emphasis on cardiovascular disease modeling and drug development. Wherever appropriate, the growing roles of hiPSC technology in the practice of precision medicine will be specifically discussed.

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“…Using this approach, disease-contributing factors at the epigenetic level have been identified. For example, in an iPSC model of dilated cardiomyopathy with a mutation in the TNNT2 protein, it was found that phosphodiesterases (PDE) contribute to the disease and that the upregulation of PDE occurs as a result of decreases in a repressive histone modification (H3K27me3) at enhancers of PDE genes [10]. Studies such as this have contributed to the recent advances in our elucidation of aberrant signalling pathways in patients with specific cardiomyopathies.…”

Section: Targeting Patient-specific Cardiomyopathiesmentioning

confidence: 99%

Mind the Gap: Genetic Variation and Personalized Therapies for Cardiomyopathies

Zhang

MacCosham

2018

Lifestyle Genomics

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Inherited cardiomyopathies are cardiovascular disorders that are one of the leading causes of death and are strongly associated with genetic mutations. These include hypertrophic, dilated, restrictive, as well as arrhythmogenic right ventricular cardiomyopathies. Among the patients presenting with these specific forms of cardiomyopathies, there is significant phenotypic, genotypic, and environmental heterogeneity. Over the years, the identification of the underlying mutations common to specific forms of cardiomyopathies have facilitated clinic diagnosis. However, the variation between patient genetics and phenotypes highlights the need for improved understanding of these diseases and the development of innovative treatments. To better understand the diseases, researchers are capitalizing on two innovative technologies: cardiac reprogramming and gene editing using CRISPR-Cas9. Deriving cardiomyocytes from patient blood samples and gene editing allows for the efficient generation of cellular and animal models that allow researchers to model the disease more accurately. In addition, the recent advances in high throughput drug screening allows for the efficient testing of patient-derived cardiomyocytes for patient-specific susceptibility to various drugs that are currently approved. In addition, this technology can facilitate the development of new pharmacological compounds for the treatment of specific cardiomyopathies. Overall, the recent technological advances in molecular medicine now presents an opportunity to gain unprecedented insight into solving the complex issue of inherited cardiomyopathies. These techniques pave the way for the new generation of personalized medicine in treating cardiovascular diseases.

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Epigenetic Regulation of Phosphodiesterases 2A and 3A Underlies Compromised β-Adrenergic Signaling in an iPSC Model of Dilated Cardiomyopathy

Cited by 161 publications

References 43 publications

Induced Pluripotent Stem Cell Model of Pulmonary Arterial Hypertension Reveals Novel Gene Expression and Patient Specificity

Induced Pluripotent Stem Cell Model of Pulmonary Arterial Hypertension Reveals Novel Gene Expression and Patient Specificity

Induced pluripotent stem cells: at the heart of cardiovascular precision medicine

Mind the Gap: Genetic Variation and Personalized Therapies for Cardiomyopathies

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