De rol van voorlopercellen van het hart bij regeneratie van het myocardium
09 / 2004 - 01 / 2010
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)
Adult cardiomyocytes have a limited potential to divide. After myocardial infarction, injured cardiomyocytes are replaced by fibrotic tissue promoting the development of heart failure. Cell transplantation has emerged as a potential therapy and stem cells may be an important and powerful cellular source. Although stem cells have been isolated from many adult tissues, the search for a cardiac stem cell has been considered futile given the accepted lack of regenerative potential of cardiomyocytes. Pluripotent adult stem cells are presently the most attractive option to explore for transplantation as they are autologous. While clinical trials have already been initiated using adult stem cells, findings suggest that the predominant in vivo effects may be neoangiogenesis or arteriogenesis and not cardiomyocyte differentiation. While this may be useful in early post-infarct phases, it is crucial that new stem cell sources that are more effective in cardiomyocyte replacement be investigated. The recently discovered cardiac progenitor cells (CPCs) may have this potential; however a thorough understanding of how these cells function, how they might be expanded in culture and their true potential as a source for cell transplantation remains to be elucidated. The aim of this application is 1) to establish the importance of CPCs in the heart in vivo for myocardial repair and 2) to obtain new insights into the molecular signals required for self-renewal, expansion and differentiation of CPCs. We will use three approaches: 1) determine the role of CPCs in myocardial repair using lineage specific ablation in mice, 2) obtain new insights into the molecular signals governing self-renewal, differentiation and plasticity of CPCs by performing a genome wide screen in human and mouse CPCs in development, disease and normal hearts, 3) isolate CPCs from human adult heart, and assess whether these CPCs may be exploited for transplantation therapy.