Organ-specific 'ZIP-codes'

Endothelial cells show a substantial functional heterogeneity depending on the tissue in which they are located. These functional differences were shown to be partly imprinted in the transcriptome. Till date, heterogeneity of the transcriptome has been studied in various organs in a physiological state and acute inflammatory conditions. However, potential fluctuations in endothelial heterogeneity upon changes in the physiological state upon chronic inflammation and the effect of environmental factors on the transcriptomic signature throughout the day are barely studied. In this thesis we aimed to characterize endothelial heterogeneity by means of a publicly available dataset, Tabula Muris, and two new transcriptomic studies. We established a dataset with small bulk RNA sequencing of aorta and lung endothelial cells isolated from mice in steady-state and mice exposed to an acute inflammatory condition. Our second transcriptomic dataset, obtained by single cell sequencing, contained endothelial cells from eight organs (aorta, bladder, bone, colon, kidney, ileum, liver, and lung) which were isolated from mice in steady-state, acute (endotoxemia), and chronic inflammatory (hyperglycemia and hyperlipidemia) conditions. Additionally, circadian rhythmicity was studied by collection the cells at different times of the day (8 am or 8 pm). Analysis of the Tabula Muris provided us with a list of organ-specific genes from mice in a steady state. The effect of an acute inflammatory condition in our small bulk dataset was defined by comparing genetic profiles within and between treatments. Heterogeneity in our single cell dataset was verified by means of differentially expressed, marker, and organ-specific genes detection. Differentially expressed and marker genes seem interesting for possible application strategies while organ-specific genes had often a number of read counts that was too low to be of interest. This study presents the first data on endothelial heterogeneity under both physiologic and different pathologic conditions at different times of the day. Herewith, adding a new dimension to the field of endothelial heterogeneity and providing a resource for endothelial cell specific gene expression across heterogeneous vascular beds. The cells in this atlas have an enormous yet largely untapped diagnostic and therapeutic potential. As a future perspective, selection of genes encoding for surface proteins might result in the establishment of organ-specific ‘ZIP’-codes, allowing to take a first step towards organ-specific drug delivery