Enhanced Survival of Transplanted Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes by the Combination of Cell Sheets With the Pedicled Omental Flap Technique in a Porcine Heart

Abstract

Background— Transplantation of cardiomyocytes that are derived from human induced pluripotent stem cell–derived cardiomyocytes (hiPS-CMs) shows promise in generating new functional myocardium in situ, whereas the survival and functionality of the transplanted cells are critical in considering this therapeutic impact. Cell-sheet method has been used to transplant many functional cells; however, potential ischemia might limit cell survival. The omentum, which is known to have rich vasculature, is expected to be a source of blood supply. We hypothesized that transplantation of hiPS-CM cell sheets combined with an omentum flap may deliver a large number of functional hiPS-CMs with enhanced blood supply. Methods and Results— Retrovirally established human iPS cells were treated with Wnt signaling molecules to induce cardiomyogenic differentiation, followed by superparamagnetic iron oxide labeling. Cell sheets were created from the magnetically labeled hiPS-CMs using temperature-responsive dishes and transplanted to porcine hearts with or without the omentum flap (n=8 each). Two months after transplantation, the survival of superparamagnetic iron oxide–labeled hiPS-CMs, assessed by MRI, was significantly greater in mini-pigs with the omentum than in those without it; histologically, vascular density in the transplanted area was significantly greater in mini-pigs with the omentum than in those without it. The transplanted tissues contained abundant cardiac troponin T–positive cells surrounded by vascular-rich structures. Conclusions— The omentum flap enhanced the survival of hiPS-CMs after transplantation via increased angiogenesis, suggesting that this strategy is useful in clinical settings. The combination of hiPS-CMs and the omentum flap may be a promising technique for the development of tissue-engineered vascular-rich new myocardium in vivo.

Magnetic resonance hypointensive signal primarily originates from extracellular iron particles in the long-term tracking of mesenchymal stem cells transplanted in the infarcted myocardium

“…Even recently, SPIO was still used to label and assess the long-term (2 months) survival of human-induced pluripotent stem cellderived cardiomyocytes in infarcted myocardia of mini-pigs. 15 However, the ability of iron oxide nanoparticles to reliably evaluate long-term stem cell engraftment in the heart has been increasingly suspected. SPIO may not stay inside the transplanted cells over time, but it may be phagocytized by macrophages.…”

Engineered Cardiac Tissues Generated from Immature Cardiac and Stem Cell-Derived Cells: Multiple Approaches and Outcomes

“…The constructs used for cardiac tissue repair include the implantation of multicellular cardiospheres [18], various formulations of 2D cellular sheets [19][20][21][22], and various formulations of 3D tissues [5][6][7][8]13]. The composition of the noncellular constituents varies from minimal constituents for cardiosphere clusters to a range of ECM components [23,24] and growth factors [25][26][27] selected for their ability to facilitate CM survival and functional maturation.…”

“…Preclinical implantation models have been primarily small animals (rodents); however, there is an increasing experience with the preclinical testing of ECTs using large animal models including pigs [22] and, eventually, nonhuman primates. The in vivo results have been very encouraging and confirm the capacity of implanted ECTs to survive, functionally couple, and recover damaged myocardium within the context of the experimental design [33].…”

Perspectives of induced pluripotent stem cells for cardiovascular system regeneration

“…Importantly, few surviving cells were found when human iPSC-derived cardiomyocytes grafts were monitored eight weeks after transplantation, and no teratoma formation was observed. 53,54 Templin et al injected human iPSCs (hiPSCs) in pig models of myocardial infarction and found that hiPSCS could be detected for up to 15 weeks in pig myocardium. More importantly, they observed hiPSC-derived endothelial cells contributed to vascularization of infracted myocardium.…”