Use of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes (hiPSC‐CMs) to Monitor Compound Effects on Cardiac Myocyte Signaling Pathways

Guo, Liang; Eldridge, Sandy; Furniss, Mike; Mussio, Jodie; Davis, Myrtle A.

doi:10.1002/9780470559277.ch150035

Cited by 31 publications

(28 citation statements)

References 61 publications

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“…Furthermore, impedance quantification of cell adhesion and spreading also contributes to an assessment of overall cell toxicity [77–80]. The recently released Cardio ECR platform (ACEA Biosciences) combines MEA and contractility recording for a simultaneous comprehensive evaluation of the excitation-contraction coupling paradigm [81]. …”

Section: Physiological Readout Modalitiesmentioning

confidence: 99%

High throughput physiological screening of iPSC-derived cardiomyocytes for drug development

Álamo

Lemons

Serrano

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

107

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Cardiac drug discovery is hampered by the reliance on non-human animal and cellular models with inadequate throughput and physiological fidelity to accurately identify new targets and test novel therapeutic strategies. Similarly, adverse drug effects on the heart are challenging to model, contributing to costly failure of drugs during development and even after market launch. Human induced pluripotent stem cell derived cardiac tissue represents a potentially powerful means to model aspects of heart physiology relevant to disease and adverse drug effects, providing both the human context and throughput needed to improve the efficiency of drug development. Here we review emerging technologies for high throughput measurements of cardiomyocyte physiology, and comment on the promises and challenges of using iPSC-derived cardiomyocytes to model disease and introduce the human context into early stages of drug discovery.

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Section: Physiological Readout Modalitiesmentioning

confidence: 99%

High throughput physiological screening of iPSC-derived cardiomyocytes for drug development

Álamo

Lemons

Serrano

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

107

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“…The impedance-based system (RTCA) has been proven to be a useful tool in a variety of assays, which including arrhythmia and compound validation [ 32 , 33 ], preclinical drug evaluation [ 34 ], monitoring compound effects [ 35 ], and cardiac disease models exploration [ 36 , 37 ]. Compared to cytotoxicity assays on H9C2 cell line [ 38 ], the RTCA cardio system provide a sensitive tool to detect potential cardiac side effects.…”

Section: Discussionmentioning

confidence: 99%

Liensinine- and Neferine-Induced Cardiotoxicity in Primary Neonatal Rat Cardiomyocytes and Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Sun

Wang

et al. 2016

IJMS

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Due to drug-induced potential congestive heart failure and irreversible dilated cardiomyopathies, preclinical evaluation of cardiac dysfunction is important to assess the safety of traditional or novel treatments. The embryos of Nelumbo nucifera Gaertner seeds are a homology of traditional Chinese medicine and food. In this study, we applied the real time cellular analysis (RTCA) Cardio system, which can real-time monitor the contractility of cardiomyocytes (CMs), to evaluate drug safety in rat neonatal CMs and human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). This study showed detailed biomechanical CM contractility in vitro, and provided insights into the cardiac dysfunctions associated with liensinine and neferine treatment. These effects exhibited dose and time-dependent recovery. Neferine showed stronger blocking effect in rat neonatal CMs than liensinine. In addition, the effects of liensinine and neferine were further evaluated on hiPS-CMs. Our study also indicated that both liensinine and neferine can cause disruption of calcium homeostasis. For the first time, we demonstrated the potential cardiac side effects of liensinine or neferine. While the same inhibition was observed on hiPS-CMs, more importantly, this study introduced an efficient and effective approach to evaluate the cardiotoxicity of the existing and novel drug candidates.

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“…Viral transduction of combined transcription factors was able to reprogram fibroblats to pluripotent stem cells, opening up a tremendous advance for personalized medicine care (Takahashi and Yamanaka, 2006 ). The use of patient-specific cells for reprogramming technologies may work as platforms for the generation of a plethora of new differentiated cells, oriented drug discovery, toxicological studies, and new research-based investigations that mimic disease (Matsa et al, 2014 ; Guo et al, 2015 ). In HCM, for example, hiPSC-derived cardiomyocytes revealed hypertrophy, disorganization of the sarcomere and increased expression of genes, e.g., NFAT and calcineurin.…”

Section: Structural Biology Efforts and Treatment In The Sarcomerementioning

confidence: 99%

Cardiac Troponin and Tropomyosin: Structural and Cellular Perspectives to Unveil the Hypertrophic Cardiomyopathy Phenotype

Marques

Oliveira

2016

Front. Physiol.

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Inherited myopathies affect both skeletal and cardiac muscle and are commonly associated with genetic dysfunctions, leading to the production of anomalous proteins. In cardiomyopathies, mutations frequently occur in sarcomeric genes, but the cause-effect scenario between genetic alterations and pathological processes remains elusive. Hypertrophic cardiomyopathy (HCM) was the first cardiac disease associated with a genetic background. Since the discovery of the first mutation in the β-myosin heavy chain, more than 1400 new mutations in 11 sarcomeric genes have been reported, awarding HCM the title of the “disease of the sarcomere.” The most common macroscopic phenotypes are left ventricle and interventricular septal thickening, but because the clinical profile of this disease is quite heterogeneous, these phenotypes are not suitable for an accurate diagnosis. The development of genomic approaches for clinical investigation allows for diagnostic progress and understanding at the molecular level. Meanwhile, the lack of accurate in vivo models to better comprehend the cellular events triggered by this pathology has become a challenge. Notwithstanding, the imbalance of Ca2+ concentrations, altered signaling pathways, induction of apoptotic factors, and heart remodeling leading to abnormal anatomy have already been reported. Of note, a misbalance of signaling biomolecules, such as kinases and tumor suppressors (e.g., Akt and p53), seems to participate in apoptotic and fibrotic events. In HCM, structural and cellular information about defective sarcomeric proteins and their altered interactome is emerging but still represents a bottleneck for developing new concepts in basic research and for future therapeutic interventions. This review focuses on the structural and cellular alterations triggered by HCM-causing mutations in troponin and tropomyosin proteins and how structural biology can aid in the discovery of new platforms for therapeutics. We highlight the importance of a better understanding of allosteric communications within these thin-filament proteins to decipher the HCM pathological state.

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Use of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes (hiPSC‐CMs) to Monitor Compound Effects on Cardiac Myocyte Signaling Pathways

Cited by 31 publications

References 61 publications

High throughput physiological screening of iPSC-derived cardiomyocytes for drug development

High throughput physiological screening of iPSC-derived cardiomyocytes for drug development

Liensinine- and Neferine-Induced Cardiotoxicity in Primary Neonatal Rat Cardiomyocytes and Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Cardiac Troponin and Tropomyosin: Structural and Cellular Perspectives to Unveil the Hypertrophic Cardiomyopathy Phenotype

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