Abstract
The extracellular matrix (ECM) plays a key role in the viability and survival of implanted human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We hypothesized that coating of three-dimensional (3D) cardiac tissue-derived hiPSC-CMs with the ECM protein fibronectin (FN) would improve the survival of transplanted cells in the heart and improve heart function in a rat model of ischemic heart failure. To test this hypothesis, we first explored the tolerance of FN-coated hiPSC-CMs to hypoxia in an in vitro study. For in vivo assessments, we constructed 3D-hiPSC cardiac tissues (3D-hiPSC-CTs) using a layer-by-layer technique, and then the cells were implanted in the hearts of a myocardial infarction rat model (3D-hiPSC-CTs, n = 10; sham surgery control group (without implant), n = 10). Heart function and histology were analyzed 4 weeks after transplantation. In the in vitro assessment, cell viability and lactate dehydrogenase assays showed that FN-coated hiPSC-CMs had improved tolerance to hypoxia compared with the control cells. In vivo, the left ventricular ejection fraction of hearts implanted with 3D-hiPSC-CT was significantly better than that of the sham control hearts. Histological analysis showed clear expression of collagen type IV and plasma membrane markers such as desmin and dystrophin in vivo after implantation of 3D-hiPSC-CT, which were not detected in 3D-hiPSC-CMs in vitro. Overall, these results indicated that FN-coated 3D-hiPSC-CT could improve distressed heart function in a rat myocardial infarction model with a well-expressed cytoskeletal or basement membrane matrix. Therefore, FN-coated 3D-hiPSC-CT may serve as a promising replacement for heart transplantation and left ventricular assist devices and has the potential to improve survivability and therapeutic efficacy in cases of ischemic heart disease.
Highlights
Despite recent developments in novel drug therapies for heart failure [1], surgical treatments such as implantation of a left ventricular assist device and heart transplantation remain the last lines of defense for heart failure patients
The transplanted FN-Gcoated 3D-hiPSC-CT was histologically detected up to 12 weeks after transplantation, which may contribute to cardiac function recovery
The expression of fibronectin in the original FN-G-coated 3D-hiPSC-CT was reduced, while the expression of other types of extracellular matrix (ECM) that are more appropriate for improving cardiac performance was promoted in the transplanted 3D-hiPSC-CT after 12 weeks
Summary
Despite recent developments in novel drug therapies for heart failure [1], surgical treatments such as implantation of a left ventricular assist device and heart transplantation remain the last lines of defense for heart failure patients. Major complications of these procedures, including a high risk of device-induced infection or cerebral hemorrhage [2], and donor shortages [3] limit the application of these interventions For these reasons, regenerative medicine such as cell therapy has been aggressively introduced to treat heart failure. Regenerative medicine such as cell therapy has been aggressively introduced to treat heart failure With these efforts, new cardiac constructs that include three-dimensional (3D) human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) tissue, repeated transplantation of layered cell sheets [4], the mixing of vascular endothelium to construct a tissue [5], and creating tissue with blood vessels in vitro [6] have been developed. The therapeutic efficacy and the specific cardiac proteins or ECM remodeling effects that contribute to cardiomyogenesis in heart tissue regeneration after in vivo transplantation remain unclear
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