Engineered heart tissues and induced pluripotent stem cells: Macro- and microstructures for disease modeling, drug screening, and translational studies

Abstract

Engineered heart tissue has emerged as a personalized platform for drug screening. With the advent of induced pluripotent stem cell (iPSC) technology, patient-specific stem cells can be developed and expanded into an indefinite source of cells. Subsequent developments in cardiovascular biology have led to efficient differentiation of cardiomyocytes, the force-producing cells of the heart. iPSC-derived cardiomyocytes (iPSC-CMs) have provided potentially limitless quantities of well-characterized, healthy, and disease-specific CMs, which in turn has enabled and driven the generation and scale-up of human physiological and disease-relevant engineered heart tissues. The combined technologies of engineered heart tissue and iPSC-CMs are being used to study diseases and to test drugs, and in the process, have advanced the field of cardiovascular tissue engineering into the field of precision medicine. In this review, we will discuss current developments in engineered heart tissue, including iPSC-CMs as a novel cell source. We examine new research directions that have improved the function of engineered heart tissue by using mechanical or electrical conditioning or the incorporation of non-cardiomyocyte stromal cells. Finally, we discuss how engineered heart tissue can evolve into a powerful tool for therapeutic drug testing.

Keywords: Cardiovascular disease; Disease modeling; Drug screening; Induced pluripotent stem cells; Tissue engineering.

Fig 1. Maturation and assessment of stem cell-derived cardiomyocytes

Many strategies have been reported for the maturation of cardiomyocytes. In the biochemical approach, growth hormones or adrenergic agonists are added to promote a change in cardiomyocyte function. With molecular biology approaches, cardiac specific ion channels and microRNA are overexpressed to elicit changes in the electrophysiology and calcium handling of cardiomyocytes. Bioengineering approaches have also been shown to improve sarcomeric organization and contractile function by incorporating controlled parameters of substrate stiffness, topography, electrical/mechanical conditioning, and integrated systems that improve nutrient delivery. Assessment of function ranges from examining morphology (i.e., cell shape/size, sarcomeres, T-tubules, and alignment), to molecular assays (sarcomeric and ion channel expression), and functional assays (i.e., calcium transients, electromechanical coupling, contraction, electrophysiology, and tissue grafting).

Fig 2. Application of engineered heart tissue model

Engineered heart tissue can be fabricated from diseased or healthy patient-specific iPSC-CMs. They are being utilized as models for various applications including modeling disease pathogenesis, disease diagnosis with genotype-phenotype biomarkers, pharmacological screening/efficacy testing, cardiotoxicity/safety pharmacology, and the identification of disease-associated genes.

Fig 3. Current protocols in engineered heart tissue

The most current engineered heart tissues include cardiomyocytes and an organic/synthetic scaffold, and sometimes also endothelial cells and supporting cells. The advent of iPSC-CMs makes it possible to fabricate patient-specific engineered heart tissues. There are various forms of conditioning, including mechanical stress (static and cyclic) and electrical stimulation. Measurable outputs include structural, mechanical, and electrical information as well as in vivo graft performance (survival, integration, and electromechanical coupling with the host).