Transplantation of human induced pluripotent stem cell-derived cardiomyocytes improves myocardial function and reverses ventricular remodeling in infarcted rat hearts

Abstract

Background: Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have shed great light on cardiac regenerative medicine and specifically myocardial repair in heart failure patients. However, the treatment efficacy and the survival of iPSC-CMs in vivo after transplantation have yielded inconsistent results. Objectives: The objective of this study was to evaluate the ability of human iPSC-CMs to improve myocardial function in a rat postinfarction heart failure model.Methods: Eight-week-old male Sprague-Dawley rats were randomly selected to receive an intramyocardial injection of 5% albumin solution with or without 1 × 10 7 human iPSC-CMs 10 days after undergoing left anterior descending (LAD) coronary artery ligation. Cyclosporine A and methylprednisolone were administered before iPSC-CM injection and until the rats were killed to prevent graft rejection. Cardiac function was evaluated by echocardiography. The survival of grafted cardiomyocytes was confirmed by observing the fluorescent cell tracer Vybrant™ CM-DiI or expression of the enhanced green fluorescent protein (eGFP) in transplanted cells, or survival was demonstrated by polymerase chain reaction (PCR)-based detection of human mitochondrial DNA. Sirius red stain was used to evaluate the fibrosis ratio. Hematoxylin-eosin staining was used to observe the formation of teratomas.

Optimizing the Use of iPSC-CMs for Cardiac Regeneration in Animal Models

“…Finally, small, and large animal models of HF are important to assess if iPSC-CMs can be a viable treatment for HF. iPSC-CMs can be transplanted as single cells or sheets [42,43,[46][47][48]50,199,200,215,225,226]. Almost all studies, regardless of the animal model used have shown that iPSC-CMs engraft to the host tissue and improve cardiac function, at least transiently.…”

“…Regardless of the animal model or the clones selected, it is still being debated whether direct injection or the transplantation of iPSC-CM sheets are more beneficial because they all seem to improve cardiac function, at least transiently [42,43,[46][47][48]50,193,199,200,205,206]. While direct injection can allow the injection of cells directly into the damaged tissue, because the heart is in constant motion, iPSC-CMs embedded in scaffolds should allow for better retention.…”

“…Regardless of their maturity, researchers are currently studying the potential of iPSC-CMs for cardiac regeneration. Animal models such as rodents, canines, pigs, and primates are used [11,16,[41][42][43][44][45][46][47][48][49][50][51]. So far, some studies have shown encouraging results after iPSC-CM engraftment like long-term cell survival, increased cell maturation and contractile improvement while others have found the opposite.…”

“…So far, some studies have shown encouraging results after iPSC-CM engraftment like long-term cell survival, increased cell maturation and contractile improvement while others have found the opposite. Additionally, almost all have found the development of post-transplant cardiac arrhythmias [46,[49][50][51].…”

Cell Therapy With Human ESC-Derived Cardiac Cells: Clinical Perspectives

“…A third, and possible, the most challenging cause of cell death, is rejection of these allogeneic PSC derivatives. Currently, only drug-based immunosuppression is used to prevent rejection but despite the persisting uncertainties regarding the optimal drug regimen, it is admitted that these drugs are fraught with sideeffects which may lead to their discontinuation with an attendant loss of the grafted cells (Guan et al, 2020). A variant of this approach could be a "biological" immunomodulation by cotransplantation of MSC which have been shown, at least in a subcutaneous implantation model, to control allogeneic iPSC-CM rejection via regulatory T cells and cell-cell contact with activated lymphocytes (Yoshida et al, 2020), however, because MSC are immune evasive and not immune privileged, they can only extend the survival of the co-transplanted iPSC-derived cardiomyocytes without preventing their ultimate disappearance (Yoshida et al, 2020).…”