Abstract

Cardiovascular disease is a major cause of morbidity and mortality throughout the world. Most cardiovascular diseases, such as ischemic heart disease and cardiomyopathy, are associated with loss of functional cardiomyocytes. Unfortunately, the heart has a limited regenerative capacity and is not able to replace these cardiomyocytes once lost. In recent years, stem cells have been put forward as a potential source for cardiac regeneration. Pre-clinical studies that use stem cell-derived cardiac cells show promising results. The mechanisms, though, are not well understood, results have been variable, sometimes transient in the long term, and often without a mechanistic explanation. There are still several major hurdles to be taken. Stem cell-derived cardiac cells should resemble original cardiac cell types and be able to integrate in the damaged heart. Integration requires administration of stem cell-derived cardiac cells at the right time using the right mode of delivery. Once delivered, transplanted cells need vascularization, electrophysiological coupling with the injured heart, and prevention of immunological rejection. Finally, stem cell therapy needs to be safe, reproducible, and affordable. In this review, we will give an introduction to the principles of stem cell based cardiac repair.

Keywords: Stem cell, Regeneration, Heart, Cardiomyocytes

Repairing the injured body with its own tissue as a substrate has captured human fascination for a long time. In Greek mythology, the Lernaean Hydra was a serpent-like creature with multiple heads that regenerated each time they were cut off and Prometheus, a titan punished by Zeus for stealing fire, had a liver that was able to regenerate each night after it was eaten by an eagle. In 1740, Abraham Tembley discovered that microscopic, freshwater animals had the ability to regenerate their head after amputation, later followed by others who discovered that amphibians have the ability to regenerate their tails, limbs, jaws, and eyes.[1],[2] It took scientists until 1933 before they discovered that some human organs, such as the liver, also have the ability to regenerate.[3]

Regenerative therapies are of major interest in cardiovascular medicine. Most cardiovascular diseases, including ischemic heart disease and cardiomyopathy, are associated with loss of functional cardiomyocytes and in other diseases, such as sick sinus syndrome, specific cardiac cell properties are missing. Unlike the Lernaean Hydra or the human liver, the heart does not have the ability to regenerate itself spontaneously once damaged. Cardiomyocytes are terminally differentiated and have a limited proliferative capacity. Lost cardiomyocytes are replaced by fibroblasts and connective tissue with the remaining cardiomyocytes becoming hypertrophic, which may eventually lead to heart failure. On the contrary, stem cells proliferate indefinitely and can be directed to differentiate into specialized cell types such as cardiomyocytes. The goal of stem cell-based regenerative medicine in cardiovascular disease, therefore, is to create healthy, functional cardiac cells that are able to integrate in the injured heart and restore its function.

In the past decades, several stem cell types have been discovered. These stem cells can be subdivided based on their differentiation capacity. Pluripotent stem cells, such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), are able to differentiate into all three embryonic germ layers, whereas multipotent stem cells can differentiate into a number of closely related cell types of a single embryonic germ layer. Cardiomyocytes were derived from several stem cell sources (). Other types of stem cells do not differentiate into cardiomyocytes themselves, but support cardiac repair by different mechanisms (). In this review, we will refer to all stem cell-derived cardiomyocytes and differentiated cell types enriched for cardiomyocytes as stem cell-derived cardiomyocytes (SCD-CMs), while we will refer to non-cardiomyocyte derivatives (such as vascular cells) as stem cell-derived cardiac support cells (SCD-CSCs).

Summary of stem cells used for cardiac repair.

Characteristics of stem cells studied for cardiac regeneration potential.

In this review, we will give an introduction to the principles of stem cell-based cardiac repair. Our aim is to give a concise up-to date overview of the therapeutic possibilities of stem cells for cardiac injury. First, we describe general requirements for stem cell therapy. After that, we will discuss in more detail the different stem cell sources and their therapeutic effects, since these vary for each cell type.

In order to be suitable for cardiac repair, stem cell-derived cardiac cells should resemble the original cardiac cell types and be able to integrate in the damaged heart. Integration requires administration of stem cell-derived cardiac cells at the right time using the right mode of delivery. Once delivered, transplanted cells need vascularization, electrophysiological coupling with the injured heart, and prevention of immunological rejection. Ideally there would also be beneficial effects on the host myocardium, for example, by stimulating proliferation or differentiation of local progenitors, neovascularization or by inhibiting apoptosis. The minimum requirement for the donor cells is to have no adverse effects. Finally, stem cell therapy needs to be safe, reproducible, and affordable. Each of these requirements will be discussed separately. ()

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Stem cells for cardiac repair: an introduction

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