Collagen Fiber Architecture Regulates Hypoxic Sarcoma Cell Migration,ACS Biomaterials Science & Engineering

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Collagen Fiber Architecture Regulates Hypoxic Sarcoma Cell Migration
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2017-05-08 00:00:00 , DOI: 10.1021/acsbiomaterials.7b00056
Daniel M. Lewis , Vitor Tang , Nupur Jain , Ariel Isser , Zhiyong Xia ₁ , Sharon Gerecht

Affiliation

Collagen is prevalent in the microenvironment of many cancer types and has been demonstrated to play an important role during disease progression. We previously showed the importance of hypoxic gradients in sarcoma cell migration. Here, we utilized an oxygen gradient collagen gel platform to determine the impact of collagen fiber density and hypoxic gradient on sarcoma cell migration. The oxygen gradient was created by regulating the oxygen diffusion coefficient along with the cellular oxygen consumption rate. Collagen fiber density in the hydrogels is modified by changing the preincubation period of the collagen gel solution at 4 °C, controlling fiber density independently of collagen concentration and oxygen tension. High fiber density gels have wider and longer fibers but a similar microscale pore size with a larger nanoscale pore size and quicker stress relaxation time, compared to the low fiber density gel. Both gels have the same Young’s modulus. We analyzed responses of sarcoma cells encapsulated in the different hydrogels for 3 days. In the nonhypoxic low fiber density constructs, sarcoma cells exhibit a larger aspect ratio, and the matrix has less fiber alignment compared to the nonhypoxic high fiber density constructs. Interestingly, we found a minimal effect of fiber density on cell migration and the ability of the cells to degrade the matrix in nonhypoxic constructs. When compared with hypoxic constructs, we observed the opposite trend, where cells in low fiber density constructs exhibit a lower aspect ratio and the matrix has more aligned fibers compared to hypoxic high fiber density constructs. Sarcoma cells encapsulated in high fiber density hypoxic gels migrated faster and degraded the matrix more rapidly compared to the low fiber density hypoxic constructs. Overall, we show that hypoxic cell migration and matrix degradation are enhanced in high fiber density gels, while hypoxic matrix alignment is prominent in low fiber density gels. Our results suggest that the differences in cellular responses under hypoxic gradients are due to the hydrogel architecture including fiber density, size (length and width), and stress relaxation.

中文翻译：

胶原蛋白纤维结构调节缺氧性肉瘤细胞迁移

胶原蛋白在许多癌症的微环境中普遍存在，并且已被证明在疾病发展过程中起着重要的作用。先前我们显示了低氧梯度在肉瘤细胞迁移中的重要性。在这里，我们利用氧梯度胶原凝胶平台来确定胶原纤维密度和低氧梯度对肉瘤细胞迁移的影响。通过调节氧的扩散系数以及细胞的耗氧率来产生氧梯度。通过改变胶原蛋白凝胶溶液在4°C的预孵育时间来改变水凝胶中的胶原蛋白纤维密度，从而独立于胶原蛋白浓度和氧气张力控制纤维密度。与低纤维密度凝胶相比，高纤维密度凝胶具有更宽和更长的纤维，但具有相似的微米级孔径和较大的纳米级孔径以及更快的应力松弛时间。两种凝胶具有相同的杨氏模量。我们分析了封装在不同水凝胶中3天的肉瘤细胞的反应。在非低氧低纤维密度构建体中，肉瘤细胞的长径比更大，与非低氧高纤维密度构建体相比，基质的纤维排列较少。有趣的是，我们发现纤维密度对细胞迁移和细胞降解非低氧构建体中基质的能力影响最小。与低氧结构相比，我们观察到相反的趋势，与低氧高纤维密度构建体相比，低纤维密度构建体中的细胞显示出较低的长宽比，并且基质具有更多排列的纤维。与低纤维密度低氧构建体相比，包裹在高纤维密度低氧凝胶中的肉瘤细胞迁移更快，基质降解更快。总的来说，我们显示高纤维密度凝胶中缺氧细胞迁移和基质降解得到增强，而低纤维密度凝胶中缺氧基质排列更显着。我们的结果表明，低氧梯度下细胞反应的差异是由于水凝胶的结构，包括纤维密度，大小（长度和宽度）和应力松弛。与低纤维密度低氧构建体相比，包裹在高纤维密度低氧凝胶中的肉瘤细胞迁移更快，基质降解更快。总的来说，我们显示高纤维密度凝胶中缺氧细胞迁移和基质降解得到增强，而低纤维密度凝胶中缺氧基质排列更显着。我们的结果表明，低氧梯度下细胞反应的差异是由于水凝胶的结构，包括纤维密度，大小（长度和宽度）和应力松弛。与低纤维密度低氧构建体相比，包裹在高纤维密度低氧凝胶中的肉瘤细胞迁移更快，并且基质降解更快。总的来说，我们表明低纤维密度凝胶中缺氧的细胞迁移和基质降解在高纤维密度凝胶中得到增强，而低氧基质排列则在低纤维密度凝胶中显着。我们的结果表明，低氧梯度下细胞反应的差异是由于水凝胶的结构，包括纤维密度，大小（长度和宽度）和应力松弛。

更新日期：2017-05-08

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