Progenitor cells from the heart : in vitro study of CMPC and EPDC behavior

Cardiovascular disorders are currently the leading cause of death in the Western world. Myocardial infarction (MI) is one of the main contributors to ischemic heart disease. After ischemia, cardiomyocytes die and are replaced by fibrous scar tissue while in the remaining cardiomyocytes hypertrophy is induced. This leads to a declined heart function and will result in death due to heart failure. Without taking heart transplantation into consideration, the current therapies to treat patients after MI are aimed at restoring blood flow to ischemic cardiac tissue. However, these therapies only delay remodeling of the heart and eventually heart failure will develop. Current treatments do not repair the damaged heart and therefore, stem cell-based therapy has emerged as a potential new therapy to repair the injured heart. The rationale of stem cell transplantation is that these cells can differentiate into cardiomyocytes and endothelial cells to form new contractile cardiac tissue to repair the injured heart locally. Previous studies have shown that transplantation of stem cells improved heart function and that this was accomplished by the secretion of paracrine factors by these stem cells. We have recently shown that transplanted cardiomyocyte progenitor cells (CMPCs) improved heart function post MI, partly via paracrine signaling (Smits AM et al. Cardiovasc Res 2009). When stem cells are injected into the ischemic heart they will enter an hypoxic environment therefore the effect of hypoxia on CMPC behavior was investigated. We observed that the effect of hypoxia was depended on the exposure time of the cells to hypoxia and showed that this induced the secretion of pro-angiogenic and pro-survival factors. The effect of hypoxia was further investigated by analyzing its effect on cell survival. Cell survival was mediated via the pro-survival protein Survivin, and when overexpressed, increased proliferation and inhibited the apoptosis of CMPCs. Although improvement of cardiac function by transplantation of CMPCs was observed, the heart function was not restored to the same level as before the ischemic insult. To further improve cardiac function we co-transplantated two different populations of cardiac progenitor cells, CMPCs and epicardial-derived cells (EPDCs). Co-culture of CMPCs with EPDCs improved their growth and induced the secretion of pro-angiogenic factors. Transplantation of both progenitor cell populations showed larger improvement of the heart function than transplantation of either one of the populations alone. Although improving cardiac function after MI is important, we need to understand the mechanisms that are involved in the development of heart failure. One of these processes is the activation of the epicardium and the induction of epithelial-to-mesenchymal transformation (EMT), and we demonstrate that the human adult epicardial cells undergo EMT, induced by TGF? and regulated via ALK5, with a possible role for WT1 and PDGFRa. In conclusion, the results reported in this thesis give us more insights in the factors that are involved in the behavior of cardiac progenitor cells and we showed that CMPCs and EPDCs are good study models that can provide new insights in mechanisms important for the development of new treatments to prevent heart failure