iPSC Therapy for Myocardial Infarction in Large Animal Models: Land of Hope and Dreams

Abstract

Myocardial infarction is the main driver of heart failure due to ischemia and subsequent cell death, and cell-based strategies have emerged as promising therapeutic methods to replace dead tissue in cardiovascular diseases. Research in this field has been dramatically advanced by the development of laboratory-induced pluripotent stem cells (iPSCs) that harbor the capability to become any cell type. Like other experimental strategies, stem cell therapy must meet multiple requirements before reaching the clinical trial phase, and in vivo models are indispensable for ensuring the safety of such novel therapies. Specifically, translational studies in large animal models are necessary to fully evaluate the therapeutic potential of this approach; to empirically determine the optimal combination of cell types, supplementary factors, and delivery methods to maximize efficacy; and to stringently assess safety. In the present review, we summarize the main strategies employed to generate iPSCs and differentiate them into cardiomyocytes in large animal species; the most critical differences between using small versus large animal models for cardiovascular studies; and the strategies that have been pursued regarding implanted cells’ stage of differentiation, origin, and technical application.

Combined use of magnetic microbeads for endothelial cell isolation and enhanced cell engraftment in myocardial repair

“…We have chosen early CECs because these cells could combine restoration of the vascular network by direct formation of new blood vessels and beneficial paracrine effects on the surrounding tissue. To avoid immunological problems, ethical issues and because of their availability in high numbers induced pluripotent stem cells (iPS) would be an ideal autologous source of early CECs and other cell types of the cardiovascular lineage for future therapeutic cell transplantations 44 . Our RNA-seq and qPCR data revealed that MACsorting with bead-labeled antibodies directed against an endothelial surface antigen provides high purity CECs.…”

Cell-Based and Selected Cell-Free Therapies for Myocardial Infarction: How Do They Compare to the Current Treatment Options?

“…Nonetheless, it was shown that the beneficial effect of different types of MSCs is modest due to their primarily paracrine effect. Moreover, the optimal way of their transplantation and the proper number of cells is required for a satisfactory therapeutic outcome [ 45 , 46 , 47 ]. The alternative to the cells mentioned above are embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), which can give rise to all cells of our body.…”

“…Moreover, cells differentiated from iPSCs are patient-specific, so there is almost no risk of immunological rejection. At the same time, the clinical use of iPSCs is impeded by the risk of genetic and epigenetic abnormalities and eventual teratoma formation; therefore, it is essential to fine-tune several factors, such as reprogramming techniques, cell purification, and optimal transplantation method [ 47 , 52 ].…”

Atypically Shaped Cardiomyocytes (ACMs): The Identification, Characterization and New Insights into a Subpopulation of Cardiomyocytes

“…A number of therapeutic methods, including cellular therapies using regenerated cells, such as iPSCs [ 132 , 133 ], and acellular therapies using cell-free factors, such as exosomes, microRNAs and antibodies, have been actively studied to overcome heart diseases, and both approaches have their own advantages and disadvantages [ 134 ]. It is highly likely that undifferentiated fetal heart cells are the ancestors of ACMs, with the ability to undergo cell fusion and survive for a life-long period.…”