Will iPSC-cardiomyocytes revolutionize the discovery of drugs for heart disease?

Bruyneel, Arne A.N.; McKeithan, Wesley L.; Feyen, Dries; Mercola, Mark

doi:10.1016/j.coph.2018.07.003

Cited by 22 publications

(23 citation statements)

References 81 publications

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“…The unmet need for cardioprotection against the toxic effects of cancer chemotherapy poses a daunting challenge for the cardiologist and oncologist alike. As is true for cardiac muscle cell protection more generally, such as with acute ischemic injury, cardiac drug discovery has been slowed or stymied by the lack of human preclinical models for target validation and compound development 17,18 . The advent of hPSC-CMs provides an auspicious alternative to previous technologies, which has proven its predictive power at least in safety pharmacology 13,16 and has justifiably raised expectations about its ability to distinguish or prioritise among potential remedies, in the years to come.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, explicit disparities have been reported in drug effects relating to cardioprotection and cardiotoxicity in this model, compared with human cells 40,41 . For this reason, we then tested the MAP4K4 inhibitors' predicted ability to block cell killing by DOX in hPSC-CMs, a platform with greater fidelity to human cardiac biology and relevance to drug development [12][13][14][15][16][17][18] . Specifically, a functional requirement for MAP4K4 has been proven in this human model, in connection with other cardiac death signals 11 .…”

Section: Inhibitors Of Map4k4 Confer Protection From Dox In Human Pscmentioning

confidence: 99%

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Selective protection of human cardiomyocytes from anthracycline cardiotoxicity by small molecule inhibitors of MAP4K4

Golforoush

Narasimhan

Guerrero

et al. 2020

Sci Rep

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Given the poor track record to date of animal models for creating cardioprotective drugs, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have been proposed as a therapeutically relevant human platform to guide target validation and cardiac drug development. Mitogen-Activated Protein Kinase Kinase Kinase Kinase-4 (MAP4K4) is an "upstream" member of the MAPK superfamily that is implicated in human cardiac muscle cell death from oxidative stress, based on gene silencing and pharmacological inhibition in hPSC-CMs. A further role for MAP4K4 was proposed in heart muscle cell death triggered by cardiotoxic anti-cancer drugs, given its reported activation in failing human hearts with doxorubicin (DOX) cardiomyopathy, and its activation acutely by DOX in cultured cardiomyocytes. Here, we report successful protection from DOX in two independent hPSC-CM lines, using two potent, highly selective MAP4K4 inhibitors. The MAP4K4 inhibitors enhanced viability and reduced apoptosis at otherwise lethal concentrations of DOX, and preserved cardiomyocyte function, as measured by spontaneous calcium transients, at sub-maximal ones. Notably, in contrast, no intereference was seen in tumor cell killing, caspase activation, or mitochondrial membrane dissipation by DOX, in human cancer cell lines. Thus, MAP4K4 is a plausible, tractable, selective therapeutic target in DOX-induced human heart muscle cell death. With earlier diagnosis and improved treatments for cancer, cardiovascular disease has become the main alternative cause of death in cancer survivors 1-4. This heightened risk is ascribable to the cardiac toxicity of several routine anti-cancer agents including, especially, anthracyclines like doxorubicin (DOX) 5. Though some relief can result from standard heart failure medications, no approved therapy apart from the iron chelator dexrazoxane addresses the responsible cytotoxic mechanisms and effector pathways operating in the damaged cardiomyocytes. For anthracyclines, these include diverse reported mediators-binding to nuclear topoisomerase 2β, thereby triggering DNA double-strand breaks, p53-dependent apoptosis, mitochondrial dysfunction, reactive oxygen species, and programmed iron-dependent cell death (ferroptosis) 1,6,7. Cardiotoxicity can be acute, early, or late; early intervention based on subclinical abnormalities may be key to averting the delayed or cumulative effects 8. Notably, acute toxicity is seen in up to 30% of patients receiving anthracyclines, soon after infusion 4. Current cardioprotection trials in cancer rely chiefly on routine heart failure medications (ACE inhibitors, β-blockers, angiotensin receptor blockers), which mitigate the symptoms and signs, with little or no demonstrated impact on cardiomyocyte death. Therapeutic progress has been hampered, in part, by the failure of animal models alone to predict clinical success in cardioprotection. For instance, nearly all strategies for protection in ischemic heart disease, a more intensively studied indication, have failed between phases I and I...

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Section: Discussionmentioning

confidence: 99%

Section: Inhibitors Of Map4k4 Confer Protection From Dox In Human Pscmentioning

confidence: 99%

Selective protection of human cardiomyocytes from anthracycline cardiotoxicity by small molecule inhibitors of MAP4K4

Golforoush

Narasimhan

Guerrero

et al. 2020

Sci Rep

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“…In an age in which the frontier of personalized medicine seems more attainable than ever, iPSC‐CM technology provides an unprecedented opportunity to advance areas like regenerative medicine, disease modelling and toxicity screening (Bruyneel et al . ).…”

Section: Constructing the Baseline Model From Multiple Datasetsmentioning

confidence: 97%

To their own beat: modelling variability in induced pluripotent stem cell‐derived cardiomyocytes

Pullinger

Gong

2019

The Journal of Physiology

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“…Further post-natal maturation occurred by P21 with downregulation of calmodulin-interacting proteins, Bex1 and Bex4, previously shown to promote muscle regeneration ( 144 ). Albeit, one should consider the potential bias introduced by size limits inherent to the microfluidics system used to select large mature CMs, these datasets are useful to define precise developmental stages of human and mouse embryonic stem cells-derived CMs, prompting the utility for characterization of induced pluripotent stem cells-derived CMs that are becoming the gold standard in cardiac drug discovery ( 27 , 145 ). Notably, analysis of single cells from Nkx2.5 +/− murine hearts were used as a model for congenital heart disease and allowed to define lineage-specific maturation defects, including expected changes in the CM lineage but also in the endothelial lineage compartment.…”

Section: Single Cell State-of-the-heartmentioning

confidence: 99%

Single Cell Gene Expression to Understand the Dynamic Architecture of the Heart

Massaia

Chaves

Samari

et al. 2018

Front. Cardiovasc. Med.

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The recent development of single cell gene expression technologies, and especially single cell transcriptomics, have revolutionized the way biologists and clinicians investigate organs and organisms, allowing an unprecedented level of resolution to the description of cell demographics in both healthy and diseased states. Single cell transcriptomics provide information on prevalence, heterogeneity, and gene co-expression at the individual cell level. This enables a cell-centric outlook to define intracellular gene regulatory networks and to bridge toward the definition of intercellular pathways otherwise masked in bulk analysis. The technologies have developed at a fast pace producing a multitude of different approaches, with several alternatives to choose from at any step, including single cell isolation and capturing, lysis, RNA reverse transcription and cDNA amplification, library preparation, sequencing, and computational analyses. Here, we provide guidelines for the experimental design of single cell RNA sequencing experiments, exploring the current options for the crucial steps. Furthermore, we provide a complete overview of the typical data analysis workflow, from handling the raw sequencing data to making biological inferences. Significantly, advancements in single cell transcriptomics have already contributed to outstanding exploratory and functional studies of cardiac development and disease models, as summarized in this review. In conclusion, we discuss achievable outcomes of single cell transcriptomics' applications in addressing unanswered questions and influencing future cardiac clinical applications.

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Will iPSC-cardiomyocytes revolutionize the discovery of drugs for heart disease?

Cited by 22 publications

References 81 publications

Selective protection of human cardiomyocytes from anthracycline cardiotoxicity by small molecule inhibitors of MAP4K4

Selective protection of human cardiomyocytes from anthracycline cardiotoxicity by small molecule inhibitors of MAP4K4

To their own beat: modelling variability in induced pluripotent stem cell‐derived cardiomyocytes

Single Cell Gene Expression to Understand the Dynamic Architecture of the Heart

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