Progenitor cells from the heart - Cellulae Progenitores Cordis (2009)

Myocardial infarction is a leading cause of high mortality rates in Western countries. After ischemia, lost cardiomyocytes are replaced by fibrotic tissue, while remaining cardiomyocytes hypertrophy, both further impairing ventricular function. Current therapies consist of restoration of reperfusion and drug administration to attenuate chronic symptoms and prevent the development of heart failure. In recent years, the possibility of using stem cells to replace lost tissue has become a hot topic in the cardiovascular scientific community. We have recently isolated cardiomyocyte progenitor cells (CMPCs) from fetal and adult human cardiac tissue (Goumans MJ et al. Stem Cell Res 2008; Van Vliet P et al. Neth Heart J 2008; Smits AM et al. Nature Prot 2009). Upon isolation, CMPCs can be easily expanded and express several stem cell markers and cardiac transcription factors. Stimulation with specific chemicals and growth factors induces differentiation of CMPCs into smooth muscle cells and endothelial cells. We also found that while fetal CMPCs can form spontaneously beating cardiomyocytes, adult CMPCs appear to differentiate into more mature, quiescent cardiomyocytes in vitro. The adult CMPC-derived cardiomyocytes may therefore be more suitable for clinical application than their fetal counterparts. In contrast, the potential of fetal CMPCs to form additional mesodermal cell types indicates that these cells are an interesting population for studies on progenitor cell development. Several signaling pathways that are known to affect skeletal myogenesis are also involved in cardiomyogenesis. In this thesis we report our results on two of these mechanisms. First, we investigated the role of microRNAs (miRs). MiRs are non-coding, small RNA molecules that affect translation of messenger RNA towards protein and have been reported to regulate many developmental processes. We identified several interesting candidates that were differentially expressed between undifferentiated and differentiated CMPCs. These miRs could subsequently be used to improve CMPC differentiation efficiency. Second, we previously reported that stimulation of CMPCs with TGFbeta enhanced cardiomyogenic differentiation (Goumans MJ et al. Stem Cell Res 2008). We show here that TGFbeta induces hyperpolarization in undifferentiated CMPCs, leading to the formation of spontaneously beating cardiomyocytes. These results suggest a novel mechanism for cardiomyogenic differentiation. Transplantation of CMPCs or CMPC-derived cardiomyocytes in infarcted mouse hearts prevented cardiac dilatation and deterioration of cardiac function (Smits AM, submitted; Van Laake LW, Cardiac recovery by stem and progenitor cells, Thesis 2008). In addition, CMPCs differentiated in vivo into cardiomyocytes, smooth muscle cells and endothelial cells. However, the effect of hypoxia on CMPCs remained uninvestigated. Therefore, we exposed the cells to low oxygen levels in vitro and found that hypoxia results in increased proliferation. This was mediated by a pro-survival gene that, when overexpressed, further increased proliferation and inhibition of apoptosis. In conclusion, the isolation and characterization of CMPCs has allowed us to closely study their potential for both scientific research and clinical application. The results reported in this thesis may help to improve cardiomyogenic differentiation protocols and reduce the need for chemicals or growth factors to improve survival, proliferation, and/or differentiation in cardiovascular progenitor cells. Future exploration of these mechanisms may lead to a better understanding of cardiovascular cell biology and, possibly, therapeutic application of CMPCs.