Final Activity Report Summary - Wt1 cardiovascular (Role of Wt1 in cardiovascular development in embryonic and adult life)
Wilms tumour 1 (Wt1) is a gene originally identified as having been mutated in 10 to 15 % of the cases of the childhood kidney cancer called Wilms tumour. Mice which lack Wt1 die before birth. They have no kidneys, gonads or spleen and are thought to die from heart defects. Wt1 is present in the epicardium, which is the outermost layer of the heart. However, the function of Wt1 in the epicardium and in heart development is unknown.
During heart development, the cells of the epicardium undergo a process, called epithelial to mesenchymal transition (EMT), which allows them to leave the sheet-like structure of the epicardium and become more mobile. These cells then undergo a differentiation process to become involved in making up the blood vessel that supplies the heart.
I found that an epicardial-specific deletion of Wt1 led to a reduction in mesenchymal progenitor cells and their derivatives, including coronary smooth muscle and endothelial cells. I demonstrated that Wt1 was essential for EMT in cultured epicardial cells through direct transcriptional activation of Snail-1 and repression of E-cadherin, two of the major mediators of EMT. I also found that Wt1-deficient embryonic stem cells (ES) were unable to form mesodermal precursor cells during differentiation, and that this could be bypassed by reintroducing Snail-1 into these cells. The latter confirmed the importance of EMT, Wt1 and Snail-1 in the generation of differentiated cells.
These new insights into the molecular mechanisms regulating cardiovascular progenitor cells and EMT were anticipated to shed light on the pathogenesis of heart diseases and could potentially help the development of cell-based therapies.
During heart development, the cells of the epicardium undergo a process, called epithelial to mesenchymal transition (EMT), which allows them to leave the sheet-like structure of the epicardium and become more mobile. These cells then undergo a differentiation process to become involved in making up the blood vessel that supplies the heart.
I found that an epicardial-specific deletion of Wt1 led to a reduction in mesenchymal progenitor cells and their derivatives, including coronary smooth muscle and endothelial cells. I demonstrated that Wt1 was essential for EMT in cultured epicardial cells through direct transcriptional activation of Snail-1 and repression of E-cadherin, two of the major mediators of EMT. I also found that Wt1-deficient embryonic stem cells (ES) were unable to form mesodermal precursor cells during differentiation, and that this could be bypassed by reintroducing Snail-1 into these cells. The latter confirmed the importance of EMT, Wt1 and Snail-1 in the generation of differentiated cells.
These new insights into the molecular mechanisms regulating cardiovascular progenitor cells and EMT were anticipated to shed light on the pathogenesis of heart diseases and could potentially help the development of cell-based therapies.