Review Article
Cardiac Regenerative Therapy Using Human Pluripotent Stem Cells for Heart Failure: A State-of-the-Art Review

https://doi.org/10.1016/j.cardfail.2022.10.433Get rights and content

Highlights

  • Human-induced pluripotent stem-cell-derived cardiomyocytes (hPSC-CMs) are considered an ideal cell source in patients with severe HF requiring heart transplantation.

  • Direct intramyocardial transplantation of hPSC-CMs may improve cardiac function via early paracrine effects and later graft maturation and electrical coupling with the host myocardium.

  • Realization of cardiac regenerative therapy using hPSCs requires the efficient and cost-effective, large-scale production of hPSC-CMs, the elimination of contamination by residual undifferentiated hPSCs and hPSC-derived non-CMs, and the risk of minimization of arrhythmia and immunological rejection.

Abstract

Heart transplantation (HT) is the only definitive treatment available for patients with end-stage heart failure who are refractory to medical and device therapies. However, HT as a therapeutic option, is limited by a significant shortage of donors. To overcome this shortage, regenerative medicine using human pluripotent stem cells (hPSCs), such as human embryonic stem cells and human-induced pluripotent stem cells (hiPSCs), has been considered an alternative to HT. Several issues, including the methods of large-scale culture and production of hPSCs and cardiomyocytes, the prevention of tumorigenesis secondary to contamination of undifferentiated stem cells and non-cardiomyocytes, and the establishment of an effective transplantation strategy in large-animal models, need to be addressed to fulfill this unmet need. Although post-transplantation arrhythmia and immune rejection remain problems, the ongoing rapid technological advances in hPSC research have been directed toward the clinical application of this technology. Cell therapy using hPSC-derived cardiomyocytes is expected to serve as an integral component of realistic medicine in the near future and is being potentially viewed as a treatment that would revolutionize the management of patients with severe heart failure.

Section snippets

Cardiac Differentiation of Human Pluripotent Stem Cells

Several researchers have reported cardiac differentiation of pluripotent stem cells (PSCs) to generate human CMs artificially. hPSCs can be induced to differentiate into CMs at various sites within the heart, including the atria, ventricles, sinus nodal pacemakers, and other structures. These cells show the same electrical activity characteristics demonstrated by human CMs.28 Protocols for the differentiation of hiPSCs into CMs have been established based on the development and differentiation

Elimination of Human Pluripotent Stem Cells and Purification of Cardiomyocytes

The current cardiac differentiation methods are highly efficient in producing hPSC-CMs. However, if all hPSCs do not differentiate into CMs (particularly if the rate of differentiation is not 100%), there is an increased risk of tumorigenesis secondary to contamination by non-CMs and undifferentiated cells at the time of transplantation. This is a considerable barrier to the realization of cardiac regenerative medicine. Therefore, safe transplantation without the risk of tumorigenesis

Strategy for Transplantation of Induced Pluripotent Stem Cell-Derived Cardiomyocytes

A previous study investigating regenerative therapy with CM transplantation reported successful transplantation and grafting of hiPSC-CMs prepared from skin fibroblasts of patients with HF into rats’ hearts.52 Another study showed that human ESC (hESC)-derived CMs (hESC-CMs) transplanted into a guinea pig myocardial infarction model led to improved cardiac function and decreased ventricular arrhythmias.53 These results indicate the potential utility and feasibility of ESC- or iPSC-derived CMs

Arrhythmia After Transplantation of Human Pluripotent Stem Cell Derived-Cardiomyocytes

Arrhythmias and immune response-mediated transplant rejection are serious adverse events associated with CM transplantation. The development of arrhythmias in patients with severe HF who were injected with skeletal myoblasts has been reported.72 Connexin 43 and N-cadherin, which are essential to the establishment of electrophysiological connections between cardiomyocytes, are not expressed in myoblasts, and automatism in myoblasts73 can precipitate arrhythmias. Cardiomyocytes can establish

Future Perspectives

Technological advancements have provided effective strategies for the resolution of these issues and for further development of cardiac regeneration therapy. A clinical trial in which hPSC-CMs will be transplanted into patients with severe dilated cardiomyopathy is in progress. For post-transplantation arrhythmias and immune rejection, the optimal regimen of antiarrhythmic and immunosuppressive agents needs to be further validated. The dosage and quality of hPSC-CMs should also be optimized.

Lay Summary

Heart transplantation (HT) is the only radical treatment available for patients with end-stage heart failure. However, HT as a therapeutic option is limited by marked donor shortage. To overcome this difficulty, regenerative medicine using human-induced pluripotent stem cells (hiPSCs) has drawn increasing attention as an alternative to HT. HiPSC-CMs transplantation may improve cardiac function via paracrine effects and electrical coupling with the host myocardium. Recent technological advances

Disclosures

KF is a cofounder and CEO of Heartseed, Inc. ST is an advisor of Heartseed, Inc. ST, HK and KF own equity in Heartseed, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

This work was supported by Projects for Technological Development, Research Center Network for Realization of Regenerative Medicine by Japan, the Japan Society for the Promotion of Science (JSPS) KAKENHI 20K17129 and 22K08164 to YK, and KAKENHI 20H05744 to ST.

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