The Erythropoietin System Protects the Heart Upon Injury by Cardiac Progenitor Cell Activation

Erythropoietin (EPO) is a growth hormone, widely known for its role in erythropoiesis. The broad expression of erythropoietin receptor (EPOR) in adult organs suggested that EPO may also affect other cells besides late erythroid progenitors. In the embryonic heart, EPOR is expressed in all cells including the immature proliferating cardiomyocytes. In contrast to the embryonic heart in adulthood, EPOR expression is decreased and mainly detected in immature proliferating cells (i.e., resident cardiac progenitor cells) rather than in terminally differentiated cells (i.e., cardiomyocytes). Since cardiac progenitor cells are considered a regenerative cell source upon cardiac injury, the protective action of the EPO system was tested by creating an erythroid-rescued EPOR knockout mouse model. Although these mice appear to have less immature proliferating myocytes during embryogenesis, they reach adulthood without apparent morphological defects. However, upon ischemia reperfusion, these animals show a greater infarct size, suggesting that the EPO/EPOR protects the heart upon injury. Indeed preclinical studies showed that EPO administration postinfarction improves cardiac function via neoangiogenesis, antiapoptotic mechanisms, and/or CPC activation. Despite the promising preclinical data, large cohort clinical studies in humans failed to show a significant amelioration in cardiac function upon systemic injection of EPO in patients with myocardial infarctions. The discrepancy between preclinical and clinical trials may be due to differences between the doses, the way of delivery, the homogeneity of the cohorts, and last but not least the species differences. These data pinpoint the importance of carrying out preclinical studies in human models of disease as engineered human cardiac tissue that will provide a better understanding of the expression pattern of EPOR and the role of its ligand in human cardiac cells. Such studies may be able to bridge the gap between preclinical rodent data and human clinical trials and thus lead to the design of more successful clinical studies.