Abstract
Despite increased use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for drug development and disease modeling studies, methods to generate large, functional heart tissues for human therapy are lacking. Here we present a “Cardiopatch” platform for 3D culture and maturation of hiPSC-CMs that after 5 weeks of differentiation show robust electromechanical coupling, consistent H-zones, I-bands, and evidence for T-tubules and M-bands. Cardiopatch maturation markers and functional output increase during culture, approaching values of adult myocardium. Cardiopatches can be scaled up to clinically relevant dimensions, while preserving spatially uniform properties with high conduction velocities and contractile stresses. Within window chambers in nude mice, cardiopatches undergo vascularization by host vessels and continue to fire Ca2+ transients. When implanted onto rat hearts, cardiopatches robustly engraft, maintain pre-implantation electrical function, and do not increase the incidence of arrhythmias. These studies provide enabling technology for future use of hiPSC-CM tissues in human heart repair.
Highlights
Despite increased use of human induced pluripotent stem cell-derived cardiomyocytes for drug development and disease modeling studies, methods to generate large, functional heart tissues for human therapy are lacking
After 3 weeks of free-floating dynamic culture[23], cardiopatches consisted of densely packed, multilayered sarcomeric α-actinin (SAA)+ CMs surrounded by a layer of vimentin+ fibroblasts (Fig. 1c) and SM22a+ smooth muscle cells (Supplementary Fig. 3A, upper) and lacked CD31+ endothelial cells (Supplementary Fig. 3A, lower)
Use of Nkx2.5 to label cardiomyocytes (Supplementary Fig. 4) and Ki67 as a marker of cell proliferation demonstrated a continuous decrease in Ki67+ CMs from 17.0 ± 0.7% at 1 week to 8.1 ± 1.1% at 3 weeks of culture, consistent with a progressive exit from the cell cycle typical of cardiac maturation and development[27]
Summary
Despite increased use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for drug development and disease modeling studies, methods to generate large, functional heart tissues for human therapy are lacking. When implanted onto rat hearts, cardiopatches robustly engraft, maintain pre-implantation electrical function, and do not increase the incidence of arrhythmias These studies provide enabling technology for future use of hiPSC-CM tissues in human heart repair. While recent focus has been on cardiac tissue miniaturization for high-throughput drug screening[7,8,12,20], no methods have been developed to generate large, functional heart tissues that would meet the “safety and efficacy” requirements for human cardiac repair At a minimum, such tissues should: (1) support fast action potential conduction to reduce risk of arrhythmias[22], (2) produce strong contractile forces to aid in mechanical pumping of native heart, (3) be sufficiently large to cover entire infarcted area, and (4) undergo vascularization to promote long-term survival. Our studies suggest the utility of the cardiopatch platform for the future development of next-generation tissue engineering therapies for ischemic heart disease
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