Cardiogenic differentiation and transdifferentiation of progenitor cells

Abstract

In recent years, cell transplantation has drawn tremendous interest as a novel approach to preserving or even restoring contractile function to infarcted hearts. A typical human infarct involves the loss of approximately 1 billion cardiomyocytes, and, therefore, many investigators have sought to identify endogenous or exogenous stem cells with the capacity to differentiate into committed cardiomyocytes and repopulate lost myocardium. As a result of these efforts, dozens of stem cell types have been reported to have cardiac potential. These include pluripotent embryonic stem cells, as well various adult stem cells resident in compartments including bone marrow, peripheral tissues, and the heart itself. Some of these cardiogenic progenitors have been reported to contribute replacement muscle through endogenous reparative processes or via cell transplantation in preclinical cardiac injury models. However, considerable disagreement exists regarding the efficiency and even the reality of cardiac differentiation by many of these stem cell types, making these issues a continuing source of controversy in the field. In this review, we consider approaches to cell fate mapping and establishing the cardiac phenotype, as well as the present state of the evidence for the cardiogenic and regenerative potential of the major candidate stem cell types.

Figure 1. Genetic fate mapping study indicating the replacement of adult mammalian cardiomyocytes by endogenous stem cells following injury

MerCreMer mice (tamoxifen-dependent Cre recombinase expression from the α–MHC promoter) were crossed with the Z/EG reporter strain (ubiquitous lacZ expression, which is replaced by EGFP expression following Cre recombination), resulting in double heterozygous MerCreMer-ZEG mice. Pulsing the latter animals with tamoxifen induces a reporter switch from lacZ to EGFP expression in cardiomyocytes only. No reduction in the ratio of EGFP+ to lacZ+ cardiomyocytes was observed during normal aging, but a decrease in this ratio was observed following myocardial infarction, suggesting that new cardiomyocytes had been recruited from progenitor cells. (Summary of the experimental design used by Hsieh et al.22).

Figure 2. Sources of reported cardiogenic stem cells for potential use in cardiac repair

Numerous stem cell types have been reported to be capable of differentiating into cardiomyocytes. These include multiple adult stem cell types within compartments including the bone marrow, the heart, and the circulation/peripheral tissues, as well pluripotent embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Efforts to “remuscularize” injured hearts are focused on either enhancing the participation of such progenitors in endogenous repair or delivering replacement cardiomyocytes derived from these cells. HSCs=hematopoietic stem cells, MSCs=mesenchymal stem cells, MAPCs=multipotent adult progenitor cells, BMSCs=bone marrow stem cells, VSESCs=very small embryonic stem cell-like stem cells, SP=side population, ADSCs=adipose stem cells, EPCs=endothelial progenitor cells, UCBSCs=umbilical cord blood stem cells, EGS=embryonic germ cells.