Abstract
The endothelial cell has a remarkable ability for sub-specialisation, adapted to the needs of a variety of vascular beds. The role of developmental programming versus the tissue contextual environment for this specialization is not well understood. Here we describe a hierarchy of expression of HOX genes associated with endothelial cell origin and location. In initial microarray studies, differential gene expression was examined in two endothelial cell lines: blood derived outgrowth endothelial cells (BOECs) and pulmonary artery endothelial cells. This suggested shared and differential patterns of HOX gene expression between the two endothelial lines. For example, this included a cluster on chromosome 2 of HOXD1, HOXD3, HOXD4, HOXD8 and HOXD9 that was expressed at a higher level in BOECs. Quantative PCR confirmed the higher expression of these HOXs in BOECs, a pattern that was shared by a variety of microvascular endothelial cell lines. Subsequently, we analysed publically available microarrays from a variety of adult cell and tissue types using the whole “HOX transcriptome” of all 39 HOX genes. Using hierarchical clustering analysis the HOX transcriptome was able to discriminate endothelial cells from 61 diverse human cell lines of various origins. In a separate publically available microarray dataset of 53 human endothelial cell lines, the HOX transcriptome additionally organized endothelial cells related to their organ or tissue of origin. Human tissue staining for HOXD8 and HOXD9 confirmed endothelial expression and also supported increased microvascular expression of these HOXs. Together these observations suggest a significant involvement of HOX genes in endothelial cell positional identity.
Highlights
HOX genes are homeobox-containing genes conserved across mammalian species, which encode transcription factors involved in the determination of positional identity
blood derived outgrowth endothelial cells (BOECs) support neutrophil rolling, followed by firm adhesion and transmigration when stimulated by tumour necrosis factor-a in a flow-based in vitro assay, a process unique to endothelial cells to our knowledge
Our studies aimed at understanding the origins of BOECs have provided insights into endothelial positional identity and show that there are context independent differences in the regulatory network of HOX gene expression in these cells
Summary
HOX genes are homeobox-containing genes conserved across mammalian species, which encode transcription factors involved in the determination of positional identity. Dysregulated HOX expression in cancers suggests a retained cellular identity switch driving loss of normal phenotype [4,5,6]. The adult endothelial cell phenotype varies according to the local requirements placed on it by individual organs. This is of particular importance for regenerative medicine, where attempts to develop viable organs or bioprostheses rely on the production of an appropriate and functional vascular bed. We report a hierarchy of HOX gene signatures specific to endothelial cells, which we first identified in BOECs. Further comparison of transcriptomes of endothelial cells from diverse vascular beds confirmed that the HOX gene signature predicts the positional identity of endothelial cells, providing insights into the potential role of these genes in endothelial differentiation
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