A small molecule approach to engineering vascularized tissue
A small molecule approach to engineering vascularized tissue
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DOI：
10.1016/j.biomaterials.2012.12.037
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发表时间：
2013-04-01
期刊：
影响因子：
14
通讯作者：
de Boer, Jan
中科院分区：
文献类型：
--
作者：
Doorn, Joyce;Fernandes, Hugo A. M.;de Boer, Jan
生长因子的全部成分决定了人间充质基质细胞 (hMSC) 在免疫调节和组织修复等过程中的生物参与。缺氧是分泌组的强调节剂，也是众所周知的刺激物，可以增加促血管生成分子的分泌。在这份手稿中，我们对 hMSC 细胞系进行了高通量筛选测定，以鉴定模拟缺氧的小分子。重要的是，我们表明这些小分子的作用取决于细胞类型/物种，但我们发现菲咯啉在多种细胞类型中具有强大的作用。我们发现，与去铁胺 (DFO)（一种已知的缺氧模拟物）和缺氧培养箱 (2% O-2) 相比，菲咯啉可诱导 hMSC 中缺氧靶基因的高表达。有趣的是，我们的微阵列和蛋白质组学分析表明，只有菲咯啉诱导另一种血管生成细胞因子白介素-8的高表达和分泌，这表明菲咯啉诱导缺氧的机制与DFO和缺氧不同，并且涉及其他信号通路的激活。我们证明，在体内基质胶塞测定中，单独的菲咯啉足以诱导血管形成，为其在缺血相关疾病中的应用铺平了道路。 (C) 2013 Elsevier Ltd. 保留所有权利。
The repertoire of growth factors determines the biological engagement of human mesenchymal stromal cells (hMSCs) in processes such as immunomodulation and tissue repair. Hypoxia is a strong modulator of the secretome and well known stimuli to increase the secretion of pro-angiogenic molecules. In this manuscript, we employed a high throughput screening assay on an hMSCs cell line in order to identify small molecules that mimic hypoxia. Importantly, we show that the effect of these small molecules was cell type/species dependent, but we identified phenanthroline as a robust hit in several cell types. We show that phenanthroline induces high expression of hypoxia-target genes in hMSCs when compared with desferoxamine (DFO) (a known hypoxia mimic) and hypoxia incubator (2% O-2). Interestingly, our microarray and proteomics analysis show that only phenanthroline induced high expression and secretion of another angiogenic cytokine, interleukin-8, suggesting that the mechanism of phenanthroline-induced hypoxia is distinct from DFO and hypoxia and involves the activation of other signaling pathways. We showed that phenanthroline alone was sufficient to induce blood vessel formation in a Matrigel plug assay in vivo paving the way to its application in ischeamic-related diseases. (C) 2013 Elsevier Ltd. All rights reserved.