Endothelial cells (EC) lining the inside of blood/lymphatic vessels in different organs show significant heterogeneity caused by cell-intrinsic and -extrinsic factors. While intrinsic properties are preserved in vitro, EC-extrinsic characteristics are lost upon isolation from the in vivo context. Thus, getting a grasp on EC diversity requires an approach that integrates EC-intrinsic and -extrinsic cues. EC 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, EC progenitor-based revascularization studies have not asked whether cells acquire the desired EC phenotype once engrafted in diseased tissue where appropriate environmental cues are lacking. Unraveling mechanisms of EC heterogeneity should allow designing tailor-made therapies, which remains the main challenge in curing vessel-related disease. This research program proposes to use an unprecedented integrated in vitro/in vivo multi-disciplinary approach based on stem/progenitor cells and small animal models to: (i) expand our knowledge of EC diversity; (ii) exploit that knowledge to design specialized vascular therapies for (lymph)vascular disorders. In phase 1, gene-profiles (‘blueprints’) will be obtained by micro-array on EC isolated from various organs and macrovessels of different species with (intrinsic blueprint) or without (extrinsic blueprint) further culture. In phase 2, (co-)culture techniques that simulate the in vivo context will be applied to generate EC with the desired blueprint and appropriate function/morphology, by EC differentiation from adult stem cells. In phase 3, information obtained from phase 1/2 will be validated in vivo by (i) testing the expression profile of selected blueprint-genes, (ii) by morpholino knock-down of these genes in zebrafish, (iii) by transplanting stem cells, pre-specialized or not, into models of vascular bed or organ-specific disorders.
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