iPS cells: A source of cardiac regeneration

Abstract

For the treatment of heart failure, a new strategy to improve cardiac function and inhibit cardiac remodeling needs to be established. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are pluripotent cells that can differentiate into cell types from all three germ layers both in vitro and in vivo. The therapeutic effect of ES/iPS cell-derived progeny was reported in animal model. Mouse and human somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) by the transduction of four transcription factors, Oct 3/4, Sox2, Klf4, and c-Myc. However, the low induction efficiency hinders the clinical application of iPS technology, and efforts have been made to improve the reprogramming efficiency. There are variations in the characteristics in ES/iPS cell lines, and the further understanding is necessary for the applications of ES/iPS cell technology. Some improvements were also made in the methods to induce cardiomyocytes from ES/iPS cells efficiently. This review article is focused on generation of iPS cells, cardiomyocyte differentiation from ES/iPS cells, and transplantation of derived cardiomyocytes.This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited".

Introduction

A variety of medical and surgical strategies have been developed for the treatment of heart failure. However, heart failure still remains a major cause of morbidity and mortality in developed countries. Medical interventions for heart failure, which include adjustment of the preload, afterload and sometimes contractility, have limited efficacy in patients. Various types of surgery, including ventricular restoration, ventricular assist device implantation and transplantation, can be applied for only a limited number of patients. Therefore, a new strategy to improve the cardiac function and inhibit cardiac remodeling needs to be established. A number of strategies to regenerate heart tissue have been devised to resolve the shortage of available transplantation organs, including the transplantation of cardiomyocytes or cardiomyogenic stem cells.

Several tissue-specific stem and progenitor cells, such as mesenchymal stem cells [1] and endothelial progenitor cells [2], have been reported to possesses the potential to differentiate into cardiomyocytes. In addition, resident cardiac stem cells in the heart have also been reported to be able to differentiate into cardiomyocytes. In 2003, Beltrami et al. reported a population of resident cardiac progenitors with the expression of c-Kit is multipotent, differentiating into cardiomyocytes, smooth cells, and endothelial cells [3]. Cardiac side population cells with the potential for Hoechst dye exclusion and Sca-1+ cells have also been reported to have the potential to express cardiomyocyte-specific genes [4], [5]. Islet-1, a LIM homeodomain transcription factor, is expressed in the progenitor cells of the secondary heart field, and they maintain the ability to differentiate into functional cardiomyocytes both in vivo and in vitro [6]. However, whether these cells are present in the adult human heart remains to be elucidated. While these tissue stem or progenitor cells are an attractive source for stem cell-based cardiac regeneration, their self-renewal potential is limited, and in vitro cardiac differentiation is inefficient.

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are pluripotent cells that can be propagated indefinitely, and can differentiate into cell types from all three germ layers both in vitro and in vivo. The therapeutic effects of human ESC- and iPSC-derived progeny have been reported in animal models for several diseases [7], [8], [9], [10], [11].