Wnt Signaling Mediates De‐differentiation of Endothelial Cells during Neovascularization

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RATIONALEThe ability to induce de‐differentiation of resident cells in situ at the site of injury or ischemic tissues may be a useful approach for reparative and regenerative medicine. To address this possibility, here we test the capacity of 6‐bromoindirubin‐3′‐oxime (BIO) to induce neovascularization by inducing a transcriptional program centering the NANOG gene networks.RESULTSBIO not only induced 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 CD31 (PECAM‐1) and von Willibrand Factor (vWF). Increased expression of these molecules induced mesenchymal/stem‐like cellular phenotypes and increased neovascularization in Matrigel and in Corneal neovascularization assays. Furthermore, BIO induced asymmetric cell division in these cells, a hallmark of stem cell selfrenewal. In contrast, NANOG knockdown inhibited the ability of BIO treated ECs to divide asymmetrically, to form cellular aggregates, and to undergo angiogenesis.CONCLUSIONThese findings, for the first time, demonstrate the ability of BIO to induce dedifferentiation of ECs into primitive cells in relation to neovascularization by up‐regulating the transcriptional network centering the NANOG gene.Supported by NIH (R01HL079356), AHA, and T32HL072742 NIH training grants.