The Present State and Future Perspectives of Cardiac Regenerative Therapy Using Human Pluripotent Stem Cells

Abstract

The number of patients with heart failure (HF) is increasing with aging in our society worldwide. Patients with HF who are resistant to medication and device therapy are candidates for heart transplantation (HT). However, the shortage of donor hearts is a serious issue. As an alternative to HT, cardiac regenerative therapy using human pluripotent stem cells (hPSCs), such as human embryonic stem cells and induced pluripotent stem cells, is expected to be realized. Differentiation of hPSCs into cardiomyocytes (CMs) is facilitated by mimicking normal heart development. To prevent tumorigenesis after transplantation, it is important to eliminate non-CMs, including residual hPSCs, and select only CMs. Among many CM selection systems, metabolic selection based on the differences in metabolism between CMs and non-CMs is favorable in terms of cost and efficacy. Large-scale culture systems have been developed because a large number of hPSC-derived CMs (hPSC-CMs) are required for transplantation in clinical settings. In large animal models, hPSC-CMs transplanted into the myocardium improved cardiac function in a myocardial infarction model. Although post-transplantation arrhythmia and immune rejection remain problems, their mechanisms and solutions are under investigation. In this manner, the problems of cardiac regenerative therapy are being solved individually. Thus, cardiac regenerative therapy with hPSC-CMs is expected to become a safe and effective treatment for HF in the near future. In this review, we describe previous studies related to hPSC-CMs and discuss the future perspectives of cardiac regenerative therapy using hPSC-CMs.

Keywords: embryonic stem cell (ES cells); heart failure; induced pluripotent stem cell (iPS cell) (iPSC); regenerative therapy; stem cell metabolism.

Figure 1

(A) The scheme of cardiac regenerative therapy. hPSCs were established by introducing transcription factors including Oct4, Sox2, Klf4, and c-Myc to human somatic cells. Two-dimensional or three-dimensional large-scale culture systems for hPSCs and hPSC-CMs have been developed. Using these systems, we can culture a large number of hPSCs and induce their differentiation into CMs effectively. Elimination of non-CMs including undifferentiated hPSCs is important to prevent tumorigenesis. Particularly, metabolic selection is useful and cost-effective. Then, we transplant hPSC-CMs into the host myocardium. There are two main methods. One method is to transplant hPSC-CMs as a patch onto the host epicardium. The other method is to inject them using a needle into the host myocardium. (B) Intramyocardial transplantation of metabolically selected cardiomyocytes. hPSC-CMs that have undergone the metabolic selection in glucose- and glutamine-free medium supplemented with lactate are likely to engraft and become mature when they are transplanted into the ischemic region because of lactate accumulation. There is a high density of host-derived microvessels within the graft, which promotes the engraftment and maturation of transplanted hPSC-CMs.