Angiogenesis in a 3D model containing adipose tissue stem cells and endothelial cells is mediated by canonical Wnt signaling.
Angiogenesis in a 3D model containing adipose tissue stem cells and endothelial cells is mediated by canonical Wnt signaling.
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含有脂肪组织干细胞和内皮细胞的 3D 模型中的血管生成由经典 Wnt 信号传导介导
DOI：
10.1038/boneres.2017.48
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发表时间：
2017
期刊：
影响因子：
12.7
通讯作者：
Lin Y
中科院分区：
文献类型：
--
作者：
Cai X;Xie J;Yao Y;Cun X;Lin S;Tian T;Zhu B;Lin Y
脂肪源性基质细胞（Adipose-derived stromal cells，ASCs）在再生医学领域受到了广泛关注。我们对成人新生血管形成的理解的进展进一步表明了ASCs在促进血管再生方面的潜力，尽管刺激其血管生成行为的具体线索仍然存在争议。在这项研究中，我们建立了一个三维（3D）血管生成模型，通过共培养ASCs和内皮细胞（ECs）在胶原凝胶中，发现ASC-EC指导的血管生成是由经典的Wnt途径调节。此外，在将我们的基于胶原凝胶的3D血管生成模型注射到裸鼠体内后收集的植入物中发生的血管生成被证实是功能性的，并且也受到经典Wnt途径的调节。在我们的系统中，Wnt调控血管生成，涉及血管长度、血管密度、血管芽和连接数的变化。然后显示Wnt信号传导在血管生成期间通过β-连环蛋白在其在ASC和EC中的胞质积累后的核转位来调节ASC介导的旁分泌信号传导。这种易位增强了核辅因子Lef-1和细胞周期蛋白D1的表达，并激活了血管内皮生长因子A（VEGFA）、碱性成纤维细胞生长因子（bFGF）和胰岛素样生长因子1（IGF-1）的血管生成转录。3D胶原模型中的血管生成过程似乎遵循经典Wnt信号传导，并且该模型可以帮助我们理解经典Wnt通路在ASC用于血管再生中的重要性。
Adipose-derived stromal cells (ASCs) have gained great attention in regenerative medicine. Progress in our understanding of adult neovascularization further suggests the potential of ASCs in promoting vascular regeneration, although the specific cues that stimulate their angiogenic behavior remain controversial. In this study, we established a three-dimensional (3D) angiogenesis model by co-culturing ASCs and endothelial cells (ECs) in collagen gel and found that ASC-EC-instructed angiogenesis was regulated by the canonical Wnt pathway. Furthermore, the angiogenesis that occurred in implants collected after injections of our collagen gel-based 3D angiogenesis model into nude mice was confirmed to be functional and also regulated by the canonical Wnt pathway. Wnt regulation of angiogenesis involving changes in vessel length, vessel density, vessel sprout, and connection numbers occurred in our system. Wnt signaling was then shown to regulate ASC-mediated paracrine signaling during angiogenesis through the nuclear translocation of β-catenin after its cytoplasmic accumulation in both ASCs and ECs. This translocation enhanced the expression of nuclear co-factor Lef-1 and cyclin D1 and activated the angiogenic transcription of vascular endothelial growth factor A (VEGFA), basic fibroblast growth factor (bFGF), and insulin-like growth factor 1 (IGF-1). The angiogenesis process in the 3D collagen model appeared to follow canonical Wnt signaling, and this model can help us understand the importance of the canonical Wnt pathway in the use of ASCs in vascular regeneration.
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