Abstract 803: Potential role of Histone Deacetylase 7 in Endothelial and Smooth Muscle Cell Differentiation from Stem Cells
It has been reported that endothelial and smooth muscle cells could be differentiated from the same progenitor cell, e.g. Flk-1+ cells, in response to different growth factor stimulation. However, the underlying mechanism is still unclear. In the present study, we cultivated embryonic stem cells and treated them with shear stress or growth factor stimulation. It was demonstrated that laminar flow induced stem cell differentiation toward endothelial cells, but suppressed cell differentiation into smooth muscle cells. Interestingly, shear stress concomitantly altered the activity of histone deacetylase 7 (HDAC7), a key enzyme for stem cell differentiation. When stem cells were cultured on collagen IV-coated plates, stem cells spontaneously differentiated toward smooth muscle cells, in which up-regulation of HDAC7 correlated with smooth muscle cell marker expression as demonstrated by Western blot analysis and double immunofluorescence staining. Over-expression of HDAC7 up-regulated smooth muscle cell markers, but down-regulated endothelial marker gene expression, while knockdown of HDAC7 by siRNA suppressed smooth muscle, but increased endothelial marker gene expression in the cells. PDGF treatment resulted in induction of HDAC7 transcription in stem cells, and enhancing HDAC7-mediated induction of smooth muscle marker expression. PDGF-induced smooth muscle marker expression was ablated by HDAC7 siRNA knockdown. On the other hand, VEGF stimulation led to down-regulate HDAC7 transcription and increase HDAC7 degradation, which correlated with up-regulation of endothelial marker and down-regulation of smooth muscle markers. These results suggest that both PDGF and VEGF exert their roles in stem cell differentiation through different effects on the modulation of HDAC7 expression, and that HDAC7 may function as a switching protein in determination of the bi-potential vascular progenitor cell differentiation toward either endothelial or smooth muscle cells.