Molecular control of ventricular growth and cardiomyocyte proliferation

Abstract

In this thesis, we show that stem cells biology may lead to future cardiac regenerative strategies. In chapter 2, we discuss the cardiac regenerative attempts in humans performed in the last decade and explore the advances made in the fields of cardiac tissue engineering and stem cells biology. In chapter 3 to 5 we describe the role of evolutionary conserved signaling pathways required for the proliferation of ventricular cardiomyocytes and the identification of novel small molecular candidates improving the culture of cardiac muscle cells. In chapter 6 and 7 we show preliminary data on the transcriptional control of cardiac progenitors during cardiac development and provide an outlook for their involvement in cardiovascular diseases. In conclusion, the work in this thesis provides a mechanistic explanation for the regional proliferation of cardiomyocytes in the fetal heart through the modulation of the evolutionary conserved Wnt/β-catenin signaling pathway. As a derivative, in vitro activation of β-catenin creates a robust method for the expansion of cardiomyocytes. Moreover, the identification of novel candidate small molecules enhancing myocyte proliferation might result in the long-term culture of cardiac muscle cells. The mapping of transcriptional regulators in cardiac development could emerge in detailed molecular and mechanistic insight in cardiac conduction disorders and cardiomyopathies, as required for prospective true substitutions of diseased myocardium.