Human iPSC modeling of heart disease for drug development

Hnatiuk, Anna P.; Briganti, Francesca; Staudt, David; Mercola, Mark

doi:10.1016/j.chembiol.2021.02.016

Cited by 37 publications

(29 citation statements)

References 117 publications

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“…Human primary CMs are difficult to obtain in large quantities and preserve the contractile, electrophysiological and morphological properties for a long period in vitro, consequently impeding their application in chronic treatment studies [23]. In this context, hiPSCs have shown great potential to provide a limitless supply of physiologically relevant CMs owing to their regeneration and differentiation properties [24]. hiPSC-CMs have moderate expression of essential excitation-contraction coupling genes and functional sarcoplasmic reticulum and sarcomeres, which are key characteristics to CM function.…”

Section: Introductionmentioning

confidence: 99%

Chronic Ethanol Exposure Induces Deleterious Changes in Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells

Sun

Armand

et al. 2021

Stem Cell Rev and Rep

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Chronic alcohol consumption in adults can induce cardiomyopathy, arrhythmias, and heart failure. In newborns, prenatal alcohol exposure can increase the risk of congenital heart diseases. Understanding biological mechanisms involved in the long-term alcohol exposure-induced cardiotoxicity is pivotal to the discovery of therapeutic strategies. In this study, cardiomyocytes derived from human pluripotent stem cells (hiPSC-CMs) were treated with clinically relevant doses of ethanol for various durations up to 5 weeks. The treated cells were characterized for their cellular properties and functions, and global proteomic profiling was conducted to understand the molecular changes associated with long-term ethanol exposure. Increased cell death, oxidative stress, deranged Ca 2+ handling, abnormal action potential, altered contractility, and suppressed structure development were observed in ethanol-treated cells. Many dysregulated proteins identified by global proteomic profiling were involved in apoptosis, heart contraction, and extracellular collagen matrix. In addition, several signaling pathways including the Wnt and TGFβ signaling pathways were affected due to long-term ethanol treatment. Therefore, chronic ethanol treatment of hiPSC-CMs induces cardiotoxicity, impairs cardiac functions, and alters protein expression and signaling pathways. This study demonstrates the utility of hiPSC-CMs as a novel model for chronic alcohol exposure study and provides the molecular mechanisms associated with long-term alcohol exposure in human cardiomyocytes.

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Section: Introductionmentioning

confidence: 99%

Chronic Ethanol Exposure Induces Deleterious Changes in Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells

Sun

Armand

et al. 2021

Stem Cell Rev and Rep

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“… 15 , 16 hiPSC‐CMs have translational potential to improve current models by providing more precise and clinically relevant characteristics on responses to drug treatment. 17 They can also overcome the differences between human and animal cardiac physiology and challenges in long‐term maintenance of primary human cardiomyocytes and can be engineered for scalable manufacture. hiPSC‐CMs have provided novel insights for the study of genetic heart diseases and drug responses.…”

mentioning

confidence: 99%

Carfilzomib Treatment Causes Molecular and Functional Alterations of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes

Forghani

Rashid

Sun

et al. 2021

JAHA

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Background Anticancer therapies have significantly improved patient outcomes; however, cardiac side effects from cancer therapies remain a significant challenge. Cardiotoxicity following treatment with proteasome inhibitors such as carfilzomib is known in clinical settings, but the underlying mechanisms have not been fully elucidated. Methods and Results Using human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) as a cell model for drug‐induced cytotoxicity in combination with traction force microscopy, functional assessments, high‐throughput imaging, and comprehensive omic analyses, we examined the molecular mechanisms involved in structural and functional alterations induced by carfilzomib in hiPSC‐CMs. Following the treatment of hiPSC‐CMs with carfilzomib at 0.01 to 10 µmol/L, we observed a concentration‐dependent increase in carfilzomib‐induced toxicity and corresponding morphological, structural, and functional changes. Carfilzomib treatment reduced mitochondrial membrane potential, ATP production, and mitochondrial oxidative respiration and increased mitochondrial oxidative stress. In addition, carfilzomib treatment affected contractility of hiPSC‐CMs in 3‐dimensional microtissues. At a single cell level, carfilzomib treatment impaired Ca 2+ transients and reduced integrin‐mediated traction forces as detected by piconewton tension sensors. Transcriptomic and proteomic analyses revealed that carfilzomib treatment downregulated the expression of genes involved in extracellular matrices, integrin complex, and cardiac contraction, and upregulated stress responsive proteins including heat shock proteins. Conclusions Carfilzomib treatment causes deleterious changes in cellular and functional characteristics of hiPSC‐CMs. Insights into these changes could be gained from the changes in the expression of genes and proteins identified from our omic analyses.

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“…Numerous induced pluripotent stem cell (iPSC) models have been developed for drug screening because they reproduce clinical features of genetic, electrophysiological, myopathic and metabolic disorders as well as clinically relevant drug responses 72 , 73 . For example, treatment of iPSC-derived cardiomyocytes (iPSC-CMs) with known drugs evokes the expected physiological effects on cardiac action potentials, intracellular calcium transients and cellular contractility 72 , 74 .…”

Section: Experimental Methods Of Drug Repurposingmentioning

confidence: 99%

“…Using patient-derived and CRISPR-mediated gene-edited iPSC-CM models, we found that small-molecule activators of the unfolded protein response and RBM20 transcriptional upregulation can normalize the contractile deficits that are characteristic of dilated cardiomyopathy associated with variants in PLN and RBM20 , respectively 76 , 77 . iPSC-derived cardiac cells are well-suited to modelling inherited cardiovascular diseases because these diseases often have a cell-autonomous aetiology, are early-onset (which facilitates modelling in monocultures) and are also often monogenic (enabling the generation of isogenic control lines by gene editing) 73 . Diseases with these traits tend to be rare, so the use of iPSC models to investigate drug repositioning could help to address the deficit in new therapeutics for rare cardiovascular diseases.…”

Section: Experimental Methods Of Drug Repurposingmentioning

confidence: 99%

Repurposing drugs to treat cardiovascular disease in the era of precision medicine

et al. 2022

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Drug repurposing is the use of a given therapeutic agent for indications other than that for which it was originally designed or intended. The concept is appealing because of potentially lower development costs and shorter timelines than are needed to produce a new drug. To date, drug repurposing for cardiovascular indications has been opportunistic and driven by knowledge of disease mechanisms or serendipitous observation rather than by systematic endeavours to match an existing drug to a new indication. Innovations in two areas of personalized medicine — computational approaches to associate drug effects with disease signatures and predictive model systems to screen drugs for disease-modifying activities — support efforts that together create an efficient pipeline to systematically repurpose drugs to treat cardiovascular disease. Furthermore, new experimental strategies that guide the medicinal chemistry re-engineering of drugs could improve repurposing efforts by tailoring a medicine to its new indication. In this Review, we summarize the historical approach to repurposing and discuss the technological advances that have created a new landscape of opportunities.

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Human iPSC modeling of heart disease for drug development

Cited by 37 publications

References 117 publications

Chronic Ethanol Exposure Induces Deleterious Changes in Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells

Chronic Ethanol Exposure Induces Deleterious Changes in Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells

Carfilzomib Treatment Causes Molecular and Functional Alterations of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes

Repurposing drugs to treat cardiovascular disease in the era of precision medicine

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