Cellular microenvironment modulates the galvanotaxis of brain tumor initiating cells.
Cellular microenvironment modulates the galvanotaxis of brain tumor initiating cells.
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DOI：
10.1038/srep21583
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发表时间：
2016-02-22
影响因子：
4.6
通讯作者：
Searson P
中科院分区：
文献类型：
--
作者：
Huang YJ;Hoffmann G;Wheeler B;Schiapparelli P;Quinones-Hinojosa A;Searson P
趋电性是一个复杂的过程，代表了各种贡献机制的集体结果，包括不对称离子流入，电压门控通道的优先激活和膜组分的电泳再分布。虽然大量的研究集中在各种上下游信号通路，但对周围微环境如何相互作用并有助于定向反应知之甚少。使用能够在二维和三维微环境中进行实验的定制趋流性芯片，我们表明细胞-细胞外基质（ECM）相互作用调节脑肿瘤起始细胞（BTIC）的趋流性。检查了三种不同胶质母细胞瘤亚型的五种不同BTIC，并且当在聚-L-鸟氨酸/层粘连蛋白涂覆的表面上培养时，在直流电场（dcEF）的存在下，BTIC均向阳极迁移，而胎儿来源的神经祖细胞（fNPC）向阴极迁移。有趣的是，当包埋在由透明质酸和胶原组成的3D ECM中时，BTIC表现出相反的方向反应并向阴极迁移。对一组参与趋电性的关键分子的药理学抑制进一步揭示了BTIC中2-和3D趋电性之间的机制差异。肌球蛋白II和磷脂酰肌醇3-激酶（PI 3 K）被发现在不同的微环境中具有显着不同的作用。
Galvanotaxis is a complex process that represents the collective outcome of various contributing mechanisms, including asymmetric ion influxes, preferential activation of voltage-gated channels, and electrophoretic redistribution of membrane components. While a large number of studies have focused on various up- and downstream signaling pathways, little is known about how the surrounding microenvironment may interact and contribute to the directional response. Using a customized galvanotaxis chip capable of carrying out experiments in both two- and three-dimensional microenvironments, we show that cell-extracellular matrix (ECM) interactions modulate the galvanotaxis of brain tumor initiating cells (BTICs). Five different BTICs across three different glioblastoma subtypes were examined and shown to all migrate toward the anode in the presence of a direct-current electric field (dcEF) when cultured on a poly-L-ornithine/laminin coated surface, while the fetal-derived neural progenitor cells (fNPCs) migrated toward the cathode. Interestingly, when embedded in a 3D ECM composed of hyaluronic acid and collagen, BTICs exhibited opposite directional response and migrated toward the cathode. Pharmacological inhibition against a panel of key molecules involved in galvanotaxis further revealed the mechanistic differences between 2- and 3D galvanotaxis in BTICs. Both myosin II and phosphoinositide 3-kinase (PI3K) were found to hold strikingly different roles in different microenvironments.