Abstract 386: 6-bomoindirubin-3’-oxime Induces Dedifferentiation of Endothelial Cells During Neovascularization
RATIONALE: Endothelial cell (EC) de-differentiation is a major challenge to understanding neovascularization and regenerative medicine. Rapid re-entry into the cell cycle, asymmetric cell division (ACD), and migratory phenotypes are considered hallmarks of cellular de-differentiation. The ability to induce de-differentiation of resident cells at the site of injury or ischemic tissues may be a useful approach for reparative and regenerative medicine.
GOAL: To test the capacity of 6-bromoindirubin-3’-oxime (BIO), an inhibitor of GSK-3β, to induce neovascularization by stimulating a transcriptional program centering the NANOG gene networks in ECs.
RESULTS: We show that BIO not only induced the interaction of β-catenin with NANOG, but also increased the expression of mesenchymal and hemangioblastic cell markers NANOG, VEGFR2, BRACHYURY, and CD133, while decreasing mature EC markers von Willebrand Factor (vWF) and PECAM-1 (CD31). Increased expression of the NANOG transcriptional network induced characteristics of mesenchymal/stem-like cellular behavior in a hanging drop assay and increased robust neovascularization in vitro and in vivo. Furthermore, microscopic analyses indicated the ability of BIO to induce ACD in these cells, a hallmark of stem cell self-renewal. In contrast, NANOG-knockdown inhibited the ability of BIO treated ECs to divide asymmetrically, to form cellular aggregates, and to undergo angiogenesis.
CONCLUSION: These findings highlight the capacity of BIO to induce dedifferentiation of ECs into “stem-like“ cells by up-regulating the expression of NANOG and NANOG gene networks. Thus, we propose that BIO could become useful not only for inducing neovascularization of ischemic tissues in situ, but also for generating a large number of cells for transplantation and regenerative medicine.
- © 2012 by American Heart Association, Inc.