Low-dose 6-bromoindirubin-3'-oxime induces partial dedifferentiation of endothelial cells to promote increased neovascularization.
Low-dose 6-bromoindirubin-3'-oxime induces partial dedifferentiation of endothelial cells to promote increased neovascularization.
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DOI：
10.1002/stem.1658
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发表时间：
2014-06
期刊：
影响因子：
5.2
通讯作者：
Wary, Kishore K.
中科院分区：
文献类型：
--
作者：
Kohler, Erin E.;Baruah, Jugajyoti;Urao, Norifumi;Ushio-Fukai, Masuko;Fukai, Tohru;Chatterjee, Ishita;Wary, Kishore K.
关键词：
内皮细胞（EC）去分化与新生血管形成的关系是一个知之甚少的过程。在这份报告中，我们讨论了Wnt信号在成人组织中新生血管形成机制中的作用。在此，我们发现，低剂量的6-溴靛玉红-3 ′-肟（BIO），一种糖原合成酶激酶（GSK）-3β的竞争性抑制剂，诱导β-catenin的稳定化及其随后与细胞核中的转录因子NANOG的直接相互作用。该事件诱导粘附连接处VE-钙粘蛋白丢失，EC增殖增加，伴有不对称细胞分裂（ACD），并在悬滴试验中形成细胞聚集体，表明获得了去分化状态。在染色质免疫沉淀测定中，核NANOG蛋白结合到EC中的NANOG-和VEGFR 2-启动子，并且在基于细胞的测定中加入BIO激活了NANOG-启动子-荧光素酶报告系统。因此，NANOG敲低降低了BIO诱导的NOTCH-1表达，从而降低了细胞增殖、ACD和新血管形成。在基质胶塞试验中，BIO诱导增加的新血管形成，继发于VEGF的存在。此外，在后肢缺血的小鼠模型中，BIO增强了新血管形成，这与EC中NOTCH-1的表达增加和新血管周围平滑肌α-肌动蛋白（SMA）+细胞募集增加相结合。因此，这些结果显示了低剂量的BIO增强继发于VEGF的新血管形成的能力，该过程伴随着通过β-连环蛋白和NANOG信号传导途径的EC的部分去分化。
Endothelial cell (EC) dedifferentiation in relation to neovascularization is a poorly understood process. In this report we addressed the role of Wnt signaling in the mechanisms of neovascularization in adult tissues. Here, we show that a low-dose of 6-bromoindirubin-3′-oxime (BIO), a competitive inhibitor of Glycogen Synthase Kinase (GSK)-3β, induced the stabilization of β-catenin and its subsequent direct interaction with the transcription factor NANOG in the nucleus of ECs. This event induced loss of VE-cadherin from the adherens junctions, increased EC proliferation accompanied by asymmetric cell division (ACD), and formed cellular aggregates in a hanging drop assays indicating the acquisition of a dedifferentiated state. In a chromatin immunoprecipitation assay, nuclear NANOG protein bound to the NANOG- and VEGFR2-promoters in ECs, and the addition of BIO activated the NANOG-promoter-luciferase reporter system in a cell-based assay. Consequently, NANOG-knockdown decreased BIO-induced NOTCH-1 expression, thereby decreasing cell proliferation, ACD and neovascularization. In a Matrigel plug assay, BIO induced increased neovascularization, secondary to the presence of VEGF. Moreover, in a mouse model of hind limb ischemia, BIO augmented neovascularization that was coupled with increased expression of NOTCH-1 in ECs and increased smooth muscle α-actin (SMA)+ cell recruitment around the neovessels. Thus, these results show the ability of a low-dose of BIO to augment neovascularization secondary to VEGF, a process that was accompanied by a partial dedifferentiation of ECs via β-catenin and the NANOG signaling pathway.
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DOI：
10.1038/jid.2008.445
发表时间：
2009-07
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Chien AJ;Conrad WH;Moon RT
通讯作者：
Moon RT
影响因子：
64.5
作者：
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通讯作者：
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影响因子：
64.5
作者：
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通讯作者：
Zon LI
影响因子：
9.3
作者：
Leri, Annarosa;Kajstura, Jan;Anversa, Piero
通讯作者：
Anversa, Piero
影响因子：
5.6
作者：
Bertrand, JA;Thieffine, S;Flocco, M
通讯作者：
Flocco, M