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Integrated Multi-disciplinary Approach to Gain INsight into Endothelial Diversity

Final Report Summary - IMAGINED (Integrated Multi-disciplinary Approach to Gain INsight into Endothelial Diversity)

BACKGROUND AND SIGNIFICANCE: Endothelial cells lining the inside of blood/lymphatic vessels in different organs show significant heterogeneity at the molecular, morphological and functional level. Endothelial cell heterogeneity likely forms the basis of vessel-type restricted disorders and may explain the side effects and limited success of ‘broad-spectrum’ (anti-)angiogenic therapies. Also, endothelial progenitor-based revascularisation studies have not asked whether cells acquire the desired endothelial cell phenotype once engrafted in a diseased tissue where environmental cues necessary to induce the correct phenotype may be lacking. Unravelling mechanisms of endothelial cell heterogeneity should allow designing tailor-made therapies, which remains a major challenge in curing vessel-related disease.

AIMS AND ACHIEVEMENTS: This research programme, called ‘IMAGINED – Integrated Multi-disciplinary Approach to Gain INsight into Endothelial Diversity’ has used an integrated in vitro/in vivo multi-disciplinary approach based on stem/progenitor cells and small animal models to: (i) expand our knowledge of endothelial cell diversity; (ii) exploit that knowledge to design specialised vascular therapies for (lymph)vascular disorders. In phase 1, gene-profiles (‘blueprints’) were obtained from 3 freshly isolated subtypes of macrovascular endothelial cells (arterial, venous and lymphatic endothelial cells) and 3 subtypes of microvascular endothelial cells (heart, brain and liver capillary endothelial cells). Within each of the 6 blueprints, we identified genes coding for transcription factors most of which were not associated before with the corresponding endothelial cell subtypes. Since transcription factors are known to play a central role in cell specification, we decided to use these factors in phase 2 to generate specialised endothelial cells from human endothelial progenitors which we derived from peripheral blood of healthy volunteers or from cord blood. We successfully generated cells with functional and molecular characteristics of arterial or cardiac microvascular endothelial cells. In phase 3, we validated the role of 2 arterial and 2 cardiac endothelial transcription factors by confirming their vascular bed-restricted expression in murine and human tissues and showing their functional importance in these vascular beds by manipulation of their expression in zebrafish or mice. In follow-up experiments, we will test the efficacy for vascular regeneration of endothelial progenitors that have been converted to arterial or cardiac endothelial cells prior to their transplantation in ischemic limbs or hearts, respectively.