Human Engineered Heart Tissue Models for Disease Modeling and Drug Discovery

Abstract

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.

The changing landscape of drug clinical trials on cardiometabolic diseases in China, 2009–2021

“…Inclisiran, a siRNA targeting PCSK9, has already been registered for two trials in China. Also, many new technologies may bring breakthroughs including high-throughput screening platforms (small molecules and natural products), multi-omics technology, artificial intelligence (AI) technology, [ 56 , 57 ] human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM), [ 58 , 59 ], 3D bioprinting organoid, [ 60 , 61 ] and the humanized genetic modified models, [ 62 , 63 ]. which may greatly reduce the cost and risk of new drugs before the clinical trials.…”

Advances in 3D Organoid Models for Stem Cell-Based Cardiac Regeneration

“…Engineered heart tissues (EHTs) differ from cardiac organoids as they rely on scaffolds, such as pillars, molds, or biowires, to generate 3D cardiac microtissues, as reviewed elsewhere [ 65 , 66 ]. Although EHTs are technically complex and not readily scalable for pre-clinical studies, they have importantly provided direct comparative studies between 2D and 3D models of cardiac disease.…”

Combining Cell Technologies With Biomimetic Tissue Engineering Applications: A New Paradigm for Translational Cardiovascular Therapies

“…The use of human primary cells or hiPSCs within cardiac tissue-engineered constructs allows for a xenogeneic-free and patient-specific approach that significantly reduces the chances of implant rejection due to a foreign body response. 12 , 47 , 48 Stem cells derived from various tissues of the patient, for example, skin, dental tissue, peripheral blood, and urine can be used for this purpose. Moreover, practical and reliable methods for handling hiPSCs under xenogeneic-free culture conditions need to be standardized to facilitate clinical translation.…”