IMAGINED: Integrated multi-disciplinary approach to gain insight into endethelial diversity.

Endothelial cells (ECs) 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 their 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 a diseased tissue where appropriate environmental cues may be 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 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 ECs 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 ECs 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.

Keywords:stem/progenitor cells, Endothelial diversity

Disciplines:Laboratory medicine