Cardiac Repair in a Porcine Model of Acute Myocardial Infarction with Human Induced Pluripotent Stem Cell-Derived Cardiovascular Cells

Abstract

Summary Human induced pluripotent stem cells (hiPSCs) hold promise for myocardial repair following injury, but preclinical studies in large animal models are required to determine optimal cell preparation and delivery strategies to maximize functional benefits and to evaluate safety. Here, we utilized a porcine model of acute myocardial infarction (MI) to investigate the functional impact of intramyocardial transplantation of hiPSC-derived cardiomyocytes, endothelial cells, and smooth muscle cells, in combination with a 3D fibrin patch loaded with insulin growth factor (IGF)-encapsulated microspheres. hiPSC-derived cardiomyocytes integrated into host myocardium and generated organized sarcomeric structures, and endothelial and smooth muscle cells contributed to host vasculature. Tri-lineage cell transplantation significantly improved left ventricular function, myocardial metabolism, and arteriole density, while reducing infarct size, ventricular wall stress and apoptosis without inducing ventricular arrhythmias. These findings in a large animal MI model highlight the potential of utilizing hiPSC-derived cells for cardiac repair.

Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue

“…Okano and colleagues (236) and Bursac and colleagues (211) later demonstrated that the functional and structural properties of engineered mouse heart tissue could be significantly improved by combining stem cell-derived cardiomyocytes with noncardiomyocytes. Similarly, Ye et al (405) showed in a porcine model of MI that transplantation of engineered contractile heart tissue composed of a mixture of human iPSC-derived cardiomyocytes, endothelial cells, and smooth muscle cells is therapeutically superior to using hiPSC cardiomyocytes alone. More recently, Burridge et al (39) demonstrated that the contractility of engineered human heart tissue from iPSC-derived cardiomyocytes may be significantly improved in the presence of endothelial cells and MSCs.…”

“…The first category includes myocardial transplantation of cell types with unequivocal myogenic ability, such as uncommitted induced pluripotent stem cells (iPSC) or embryonic stem cells (ESC) (22), iPSC/ESC-derived human cardiomyocytes (61,97,304,405), or ESC/iPSC-derived cardiomyocyte precursors (97, 240,405). Gene therapy-based approaches aiming at converting scar tissue fibroblasts into cardiomyocyte-like cells (288,340) or forcing massive dedifferentiation and proliferation of surviving cardiomyocytes (68,95) are also under consideration, although still far from clinical application due to concerns over safety and technical feasibility (87).…”

“…However, further studies are needed for optimizing this strategy to enhance functional recovery, since some of the existing experiments regarding long-term engraftment of bona fide human myocardium have not definitively shown recovery of heart function (61,97,99,143,304). For example, ex vivo tissue engineering approaches, whereby human cardiomyogenic cells are combined with mesenchymal stem cells (MSCs), vasculogenic cells (42,60,405), and/or neurons (224,389) may be required prior to engraftment, for meaningful cardiac regeneration.…”

Paracrine Effects of the Pluripotent Stem Cell-Derived Cardiac Myocytes Salvage the Injured Myocardium

“…hESCs and iPSCs differentiate robustly into a highly purified population of functional cardiac myocytes in vitro 12, 13 . Functional improvement of the injured myocardium has been observed in murine, rodent, and porcine models that received either hESCs-derived cardiac myocytes (hCMs) 12, 14-20 or iPSCs-derived cardiac myocytes (iCMs) 21, 22 . Additionally, pluripotent stem cell-derived cardiac myocytes have been shown to engraft and improve heart function more effectively than non-cardiac derivatives 12, 17-19 .…”

Cardiac Regeneration and Stem Cells

“…Injection of iPS-derived cardiac myocytes, smooth muscle cells, and endothelial cells demonstrated engraftment of all cell types (128). Interestingly, there were significant improvements in LV function despite relatively low rates of engraftment compared with earlier studies using ES cell-derived cardiac myocytes in nonhuman primates (21).…”