A tissue-engineered scale model of the heart ventricle

Abstract

Laboratory studies of the heart use cell and tissue cultures to dissect heart function yet rely on animal models to measure pressure and volume dynamics. Here, we report tissue-engineered scale models of the human left ventricle, made of nanofibrous scaffolds that promote native-like anisotropic myocardial tissue genesis and chamber-level contractile function. Incorporating neonatal rat ventricular myocytes or cardiomyocytes derived from human induced pluripotent stem cells, the tissue-engineered ventricles have a diastolic chamber volume of ~500 μL (comparable to that of the native rat ventricle and approximately 1/250 the size of the human ventricle), and ejection fractions and contractile work 50–250 times smaller and 104–108 times smaller than the corresponding values for rodent and human ventricles, respectively. We also measured tissue coverage and alignment, calcium-transient propagation and pressure/volume loops in the presence or absence of test compounds. Moreover, we describe an instrumented bioreactor with ventricular-assist capabilities, and provide a proof-of-concept disease model of structural arrhythmia. The model ventricles can be evaluated with the same assays used in animal models and in clinical settings.

Dynamic Loading of Human Engineered Heart Tissue Enhances Contractile Function and Drives Desmosome-linked Disease Phenotype

“…The dyn-EHT platform builds off of previous work from our laboratory and other investigators that have used primary, hESC and hiPSC derived cardiomyocytes to engineer functional cardiac tissues in vitro. Indeed, it is critical to acknowledge the important contributions to the field made by researchers using EHTs to model development and disease, and implementing more physiologic-like electromechanical conditioning to drive maturation (14,(16)(17)20,23,(25)(26)28,40,(61)(62)(63)(64). However, these 2D and 3D EHTs are generally isometrically constrained, which means they are unable to undergo significant fractional shortening or be stretched by preload.…”

“…Further, strategies aimed at reducing the ventricular wall stress by integrating a temporary patch over the myocardial infarct (58) or injecting materials to thicken the ventricle wall (59) have proved successful to combat the pathological remodeling observed following myocardial infarction. While there have been recent advances in engineering ventricle-like chambers using scaffolds and 3D bioprinting (22,(60)(61)(62), compared to our dyn-EHT these chambers are much more difficult to fabricate, require a relatively large number of cells to form, and must be connected to a complicated flow system with valves and pressure transducers in order to generate preload.…”

3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels

“…In addition, to better mimic cardiac disease, pathological features are being introduced using hypoxia-induced apoptosis 6 , mechanical stress 49 , or varied cardiac cell ratios 50 . Recent examples have also demonstrated how the introduction of electrical barriers such as holes in healthy cardiac tissue, or fibroblast dense regions can disrupt action potential propagation 45,51 .…”

Intensive care for human hearts in pluripotent stem cell models

“…Despite the predictive power shown even with routine 2D models, it is clear that existing lines-or, more accurately, their current embodiment in tissue culture-do not suffice to model all possible phenotypes of concern. The many acknowledged shortcomings, which have been mitigated to date only partially, include morphology (lack of sarcomere organization, T-tubules, and the normal mitochondrial density), molecular profile (weak expression of maturation-associated genes and splicing isoforms), metabolism (glycolysis, not fatty acid oxidation), contractility (lower maximum contractile force), and electrophysiology (lesser action potential upstroke velocity and amplitude) [48][49][50][51][85][86][87][88][89][90][91][92][93][94][95] . For instance, by comparison to adult human hearts, commercially available hPSC-CMs were uniformly deficient in the expression of KCNJ2, with higher than normal expression of HCN4 and large line-to-line variations in the other ion channels and membrane transporters assayed (CACNA1C, KCNH2, KCNQ1, SLC8A1, ATP1A1, ATP2A2) 51 .…”

“…In another approach, transduction of the defectively expressed gene KCNJ2 has been applied to rescue the channel levels and promote aspects of fidelity directly 98 . More generally, however, the procedures of most proven value to enhance the maturity of hPSC-CMs include the use of 3D human engineered heart tissue (EHT), mechanical or electrical conditioning, and heart-on-chip technologies, advances discussed at length elsewhere [89][90][91][92][93][94][95] . The tissue engineering solutions to create more heart-like phenotypes in hPSC-CMs range in complexity from micropatterned 2D substrates to scaffolds, organoids, microfluidics, 3D bioprinting, and even the construction of hollow spheres.…”