Abstract 16275: Increased Expression of NANOG Induces the Transitioning of Endothelial Cells into a Stem-Like State
RATIONALE: Given that NANOG binds to and activates the FLK-1 (Fetal Liver Kinase-1) receptor to induce proliferation and angiogenesis in endothelial cells (ECs), increased expression of NANOG may signal transitioning of these cells into a “stem-like” state. Here we address the ability of 6-bromoindirubin-3’-oxime (BIO), which is a small pharmacological inhibitor of glycogen synthase kinase (GSK)-3β, to induce increased expression of NANOG in ECs.
RESULTS: We show that BIO not only induced the interaction of βcatenin with NANOG, but also increased the expression of several mesenchymal and hemangioblastic cell markers including NANOG, FLK1, BRACHYURY, and CD133. Whereas BIO decreased the expression of the endothelial cell markers von Willebrand Factor (vWF) and PECAM-1 (CD31). Increased expression of these molecules induced characteristics of mesenchymal/stem-like cellular behavior in a hanging drop assay and increased robust angiogenesis in vitro and in vivo. Furthermore, microscopic analyses indicated the ability of BIO to induce asymmetric cell division (ACD) in these cells, which is 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 in a hanging drop assay, and the pro-angiogenic phenotypes of these cells.
CONCLUSION: These findings demonstrate the capacity of BIO to induce dedifferentiation of ECs into “stem-like” cells by up-regulating the expression of NANOG and NANOG target genes. Thus, we propose that BIO could become useful not only for inducing neovascularization of ischemic tissues, but also for generating a large number of cells for transplantation and regenerative medicine.
- © 2011 by American Heart Association, Inc.