Matrix-driven changes in metabolism support cytoskeletal activity to promote cell migration.
Matrix-driven changes in metabolism support cytoskeletal activity to promote cell migration.
复制标题
基质驱动的代谢变化支持细胞骨架活性，促进细胞迁移。
DOI：
10.1016/j.bpj.2021.02.044
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发表时间：
2021
影响因子：
3.4
通讯作者：
Reinhart-King,CynthiaA
中科院分区：
文献类型：
--
作者：
Wu,Yusheng;Zanotelli,MatthewR;Zhang,Jian;Reinhart-King,CynthiaA
微环境提供主动和被动的机械提示，调节细胞形态，粘附，迁移和代谢。尽管细胞对这些机械信号的反应通常需要能量密集型肌动蛋白细胞骨架重塑和肌动球蛋白收缩性，但目前尚不清楚细胞如何动态地适应其代谢活动以改变机械信号来支持迁移。在这里，我们研究了细胞代谢活性的变化，在不同的二维和三维微环境条件下，以及这些变化如何与细胞骨架活性和迁移。利用聚丙烯酰胺凝胶上的胶原微图案，细胞内的能量水平和氧化磷酸化被发现与细胞的伸长和扩展和必要的膜皱褶。为了确定这种关系是否在更生理的三维基质中成立，使用胶原基质来显示细胞内能量状态也与扩张活性相关，并且随着基质密度增加而增加。氧化磷酸化的药理学抑制揭示了癌细胞依赖于氧化磷酸化来满足在致密基质中的扩散活性和迁移的升高的能量需求。总之，这些研究结果表明，在物理微环境的扩散和迁移过程中，细胞骨架活性的机械调节是由改变的代谢谱驱动的。
The microenvironment provides both active and passive mechanical cues that regulate cell morphology, adhesion, migration, and metabolism. Although the cellular response to those mechanical cues often requires energy-intensive actin cytoskeletal remodeling and actomyosin contractility, it remains unclear how cells dynamically adapt their metabolic activity to altered mechanical cues to support migration. Here, we investigated the changes in cellular metabolic activity in response to different two-dimensional and three-dimensional microenvironmental conditions and how these changes relate to cytoskeletal activity and migration. Utilizing collagen micropatterning on polyacrylamide gels, intracellular energy levels and oxidative phosphorylation were found to be correlated with cell elongation and spreading and necessary for membrane ruffling. To determine whether this relationship holds in more physiological three-dimensional matrices, collagen matrices were used to show that intracellular energy state was also correlated with protrusive activity and increased with matrix density. Pharmacological inhibition of oxidative phosphorylation revealed that cancer cells rely on oxidative phosphorylation to meet the elevated energy requirements for protrusive activity and migration in denser matrices. Together, these findings suggest that mechanical regulation of cytoskeletal activity during spreading and migration by the physical microenvironment is driven by an altered metabolic profile.