Pluripotent Stem Cell-Derived Cardiomyocytes as a Platform for Cell Therapy Applications: Progress and Hurdles for Clinical Translation

Abstract

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Regenerative therapy has been applied to restore lost cardiac muscle and cardiac performance. Induced pluripotent stem cells (iPSCs) can provide an unlimited source of cardiomyocytes and therefore play a key role in cardiac regeneration. Despite initial encouraging results from pre-clinical studies, progress toward clinical applications has been hampered by issues such as tumorigenesis, arrhythmogenesis, immune rejection, scalability, low graft-cell survival, and poor engraftment. Here, we review recent developments in iPSC research on regenerating injured heart tissue, including novel advances in cell therapy and potential strategies to overcome current obstacles in the field.

Keywords: arrhythmogenicity; cardiomyocytes; engraftment; immune rejection; pluripotent stem cells; regenerative medicine; tissue engineering; tumorigenicity.

Figure 1

Cardiac Cell Therapy Using PSC-CMs Illustration of recent cell therapy approaches to recover lost cardiac muscle following severe myocardial injury. (A) As alternatives to direct injection of PSC-CMs in the injured heart, (B) tissue engineering approaches have been employed to increase the survival and functional engraftment of cells following delivery. (C) The integration of endothelial cells forming vascular networks into PSC-CM cell sheets facilitates delivery of oxygen and nutrients to the graft, greatly augmenting its engraftment and function as a novel contractile unit. Providing a structural framework with hydrogel and other cell types complementary to CMs such as ECs and smooth muscle cells may boost functional integration into the host myocardium. (D) The secretion of growth factors and cytokines represents another way that administered PSC-CMs might benefit cardiac performance following injury. (E) Finally, the use of scaffolds formulated from fibrin patches containing PSC-derived cardiac progenitor cells (CPCs) is another therapeutic application. PSCs, pluripotent stem cells; PSC-CMs, PSC-derived cardiomyocytes; ECs, endothelial cells; SMCs, smooth muscle cells; Isl-1, Islet-1; SSEA-1, stage-specific embryonic antigen-1.

Figure 2

Illustration of the “Mountain” of Obstacles to Overcome in Clinical Translation of PSC-CMs in Heart Disease (A) Careful screening of PSC lines and state-of-the-art methodologies for the expansion and maintenance of PSCs are required to avoid genomic instability. (B) Engineering novel ways to eliminate undifferentiated PSCs from PSC derivatives can prevent teratoma formation. (C) To produce clinically relevant numbers of PSC-CMs, novel ways of PSC-CM manufacturing need to be developed. Advances in stirred-based bioreactors have allowed the maintenance and expansion of PSCs as well as the generation of PSC-CMs in a large scale that is sufficient to meet clinical demands. (D) The latest improvements in cardiac differentiation protocols toward specific cardiac subtypes will tremendously minimize the risk of arrhythmias caused by injection of mixed pools of PSC-CMs in fibrotic areas of the myocardium. (E) Creation of HLA-matched iPSC banks and engineering of immunoprivileged PSC-CMs will greatly reduce the risk of immune rejection of the grafted cells. HLA, human leukocyte antigen.