Genetic and Tissue Engineering Approaches to Modeling the Mechanics of Human Heart Failure for Drug Discovery

Greenberg, Michael J.; Daily, Neil; Wang, Ann; Conway, Michael; Wakatsuki, Toshiyuki

doi:10.3389/fcvm.2018.00120

Cited by 17 publications

(15 citation statements)

References 162 publications

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“…For example, the heart rate of a mouse is ∼600 beats per minute, which is in stark contrast to ∼60 beats per minute in the human. 303 There are also differences in the cardiac physiology arising from the different machinery in calcium handling, as well as a different expression of contractile protein isoforms and ion channels. 303 Thus, there will inevitably be results obtained from animal models that cannot be translated to humans.…”

Section: Preclinical Models Of Diabetic Cardiomyopathymentioning

confidence: 99%

Cellular interplay between cardiomyocytes and non-myocytes in diabetic cardiomyopathy

Phang

Ritchie

Hausenloy

et al. 2022

Cardiovascular Research

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Patients with Type 2 diabetes mellitus (T2DM) frequently exhibit a distinctive cardiac phenotype known as diabetic cardiomyopathy. Cardiac complications associated with T2DM include cardiac inflammation, hypertrophy, fibrosis and diastolic dysfunction in the early stages of the disease, which can progress to systolic dysfunction and heart failure. Effective therapeutic options for diabetic cardiomyopathy are limited and often have conflicting results. The lack of effective treatments for diabetic cardiomyopathy is due in part, to our poor understanding of the disease development and progression, as well as a lack of robust and valid preclinical human models that can accurately recapitulate the pathophysiology of the human heart. In addition to cardiomyocytes, the heart contains a heterogeneous population of non-myocytes including fibroblasts, vascular cells, autonomic neurons and immune cells. These cardiac non-myocytes play important roles in cardiac homeostasis and disease, yet the effect of hyperglycaemia and hyperlipidaemia on these cell types are often overlooked in preclinical models of diabetic cardiomyopathy. The advent of human induced pluripotent stem cells provides a new paradigm in which to model diabetic cardiomyopathy as they can be differentiated into all cell types in the human heart. This review will discuss the roles of cardiac non-myocytes and their dynamic intercellular interactions in the pathogenesis of diabetic cardiomyopathy. We will also discuss the use of sodium-glucose cotransporter 2 inhibitors as a therapy for diabetic cardiomyopathy and their known impacts on non-myocytes. These developments will no doubt facilitate the discovery of novel treatment targets for preventing the onset and progression of diabetic cardiomyopathy.

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Section: Preclinical Models Of Diabetic Cardiomyopathymentioning

confidence: 99%

Cellular interplay between cardiomyocytes and non-myocytes in diabetic cardiomyopathy

Phang

Ritchie

Hausenloy

et al. 2022

Cardiovascular Research

View full text Add to dashboard Cite

show abstract

“…In contrast, cardiovascular drug development is decreasing due to challenges in gauging the pathophysiology of many heart diseases and the effects of drugs on healthy hearts ( Eder et al, 2016 ). This is not only because heart size, beat rate, and ion channel expression differ between humans and small animals, but also because variants and mutations that cause or predispose humans to cardiovascular diseases (CVDs) have an inconsistent impact on transgenic mice despite having a genetic equivalent ( Greenberg et al, 2018 ). Moreover, drug development is lengthy and costly and is difficult due to the limited value of current preclinical assessment systems for predicting clinical adverse drug reactions, such as proarrhythmic and cardiotoxic effects.…”

Section: Introductionmentioning

confidence: 99%

Human Engineered Heart Tissue Models for Disease Modeling and Drug Discovery

Tani

Tohyama

2022

Front. Cell Dev. Biol.

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The emergence of human induced pluripotent stem cells (hiPSCs) and efficient differentiation of hiPSC-derived cardiomyocytes (hiPSC-CMs) induced from diseased donors have the potential to recapitulate the molecular and functional features of the human heart. Although the immaturity of hiPSC-CMs, including the structure, gene expression, conduct, ion channel density, and Ca2+ kinetics, is a major challenge, various attempts to promote maturation have been effective. Three-dimensional cardiac models using hiPSC-CMs have achieved these functional and morphological maturations, and disease models using patient-specific hiPSC-CMs have furthered our understanding of the underlying mechanisms and effective therapies for diseases. Aside from the mechanisms of diseases and drug responses, hiPSC-CMs also have the potential to evaluate the safety and efficacy of drugs in a human context before a candidate drug enters the market and many phases of clinical trials. In fact, novel drug testing paradigms have suggested that these cells can be used to better predict the proarrhythmic risk of candidate drugs. In this review, we overview the current strategies of human engineered heart tissue models with a focus on major cardiac diseases and discuss perspectives and future directions for the real application of hiPSC-CMs and human engineered heart tissue for disease modeling, drug development, clinical trials, and cardiotoxicity tests.

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“…Engineered tissues may allow mechanistic study of the cellular interactions that enhance cardiac function ( Bursac et al, 2010 ). Human engineered cardiac tissues (hECTs) can serve to bridge the gap between current animal models, providing a species-specific model of human myocardium, and also overcomes limitations of the 2D culture systems ( Vunjak Novakovic et al, 2014 ; Greenberg et al, 2018 ). Human pluripotent stem cells now provide a nearly limitless supply of differentiated human cardiomyocytes (CMs) ( Lian et al, 2012 ; Bhattacharya et al, 2014 ), and use of these cells to create 3-D hECTs allows direct measurement of twitch force and related characteristics of cardiac muscle contractility, with extended time in culture ( Turnbull et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Cardiac Tissue Engineering: Inclusion of Non-cardiomyocytes for Enhanced Features

Munawar

Turnbull

2021

Front. Cell Dev. Biol.

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Engineered cardiac tissues (ECTs) are 3D physiological models of the heart that are created and studied for their potential role in developing therapies of cardiovascular diseases and testing cardio toxicity of drugs. Recreating the microenvironment of the native myocardium in vitro mainly involves the use of cardiomyocytes. However, ECTs with only cardiomyocytes (CM-only) often perform poorly and are less similar to the native myocardium compared to ECTs constructed from co-culture of cardiomyocytes and nonmyocytes. One important goal of co-culture tissues is to mimic the native heart’s cellular composition, which can result in better tissue function and maturity. In this review, we investigate the role of nonmyocytes in ECTs and discuss the mechanisms behind the contributions of nonmyocytes in enhancement of ECT features.

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Genetic and Tissue Engineering Approaches to Modeling the Mechanics of Human Heart Failure for Drug Discovery

Cited by 17 publications

References 162 publications

Cellular interplay between cardiomyocytes and non-myocytes in diabetic cardiomyopathy

Cellular interplay between cardiomyocytes and non-myocytes in diabetic cardiomyopathy

Human Engineered Heart Tissue Models for Disease Modeling and Drug Discovery

Cardiac Tissue Engineering: Inclusion of Non-cardiomyocytes for Enhanced Features

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