Cell type specificity and heterogeneity of endothelial specific gene regulation

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How a specific cell type in a multicellular organism acquire its unique characteristics, which distinguishes it from other cell types, remains an unanswered biological question. For example how do cells that line inner side of blood vessels, known as endothelial cells, acquire their unique characteristics that makes them different from, for instance neuronal cells, or skin epithelial cells. This mystery has remained specifically unresolved with regard to understanding how endothelial cells- the cell type that initiate vascular network formation - acquire their specific characteristics. Furthermore, endothelial cells of vascular beds in various organs are not identical and exhibit differences in structure and function from each other. This "endothelial cell heterogeneity" is evolved to meet the specialized needs of different organs. The molecular basis of endothelial cell heterogeneity also remains unknown. There is a major gap in our current knowledge regarding how endothelial cells establish their unique cellular identity, and how they acquire organ-specific characteristics, which is the long-term objective of our research program. The specific short-term objective of our research program is designed to address this gap through exploring which transcriptional and epigenetic regulators are altered when endothelial cell phenotype is revoked and re-established and how do these alterations correlate with regulation of endothelial specific genes. We have established a system in which induced pluripotent stem cells (iPS) are generated from human umbilical vein endothelial cells, and then differentiated into non-endothelial, as well as back into endothelial cells. This system has provided a unique opportunity, as an in vitro mimicry of developmental process, to explore the molecular basis of repression (when changing endothelial cells to iPS) and activation (when changing iPS back to endothelial cells) of endothelial specific genes, including von Willebrand factor (VWF). As a result of our previous studies, we have generated a set of unique tools, including endothelial specific promoters with organ-specific activation patterns; as well as knowledge regarding transacting factors that participate in regulation of VWF transcription. We now propose to use these tools, generated information, and endothelial-iPS-endothelial differentiation system to determine the mechanisms that restrict VWF, as well as other endothelial specific genes' expression to endothelial cells in general. We also propose to explore how the expression of target endothelial specific genes, such as VWF is differentially regulated in endothelial cells of distinct vascular beds. The information obtained will provide insights towards understanding how endothelial cells phenotype and it's heterogeneity is accomplished through understanding the molecular mechanisms that contribute to cell type and organ-specific regulation of endothelial specific genes.