Department of Biology, James Madison University, Harrisonburg, Virginia, United States of America.
Department of Chemistry & Biochemistry and Center for Materials Science, James Madison University, Harrisonburg, Virginia, United States of America.
PLoS One. 2022 Mar 25;17(3):e0265403. doi: 10.1371/journal.pone.0265403. eCollection 2022.
Directed cell migration arises from cells following a microenvironmental gradient (e.g. of a chemokine) or polarizing feature (e.g. a linear structure). However cells not only follow, but in many cases, also generate directionality cues by modifying their microenvironment. This bi-directional relationship is seen in the alignment of extracellular matrix (ECM) fibers ahead of invading cell masses. The forces generated by many migrating cells cause fiber alignment, which in turn promotes further migration in the direction of fiber alignment via contact guidance and durotaxis. While this positive-feedback relationship has been widely described for cells invading en masse, single cells are also able to align ECM fibers, as well as respond to contact guidance and durotaxis cues, and should therefore exhibit the same relationship. In this study, we directly tested this hypothesis by studying the migration persistence of individual HT-1080 fibrosarcoma cells migrating in photocrosslinked collagen matrices with limited remodeling potential. Our results demonstrate that this positive-feedback relationship is indeed a fundamental aspect of cell migration in fibrillar environments. We observed that the cells' inability to align and condense fibers resulted in a decrease in persistence relative to cells in native collagen matrices and even relative to isotropic (glass) substrates. Further experiments involving 2D collagen and electrospun polymer scaffolds suggest that substrates composed of rigid, randomly oriented fibers reduce cells' ability to follow another directionality cue by forcing them to meander to follow the available adhesive area (i.e. fibers). Finally, our results demonstrate that the bi-directional relationship between cell remodeling and migration is not a "dimensionality" effect, but a fundamental effect of fibrous substrate structure.
细胞的定向迁移源于细胞沿着微环境梯度（例如趋化因子）或极化特征（例如线性结构）的迁移。然而，细胞不仅会跟随这些线索，而且在许多情况下，还会通过改变微环境来产生导向性线索。这一双向关系在细胞群侵入时细胞外基质 (ECM) 纤维的排列中可见。许多迁移细胞产生的力导致纤维排列，纤维排列反过来又通过接触引导和趋硬性促进进一步向纤维排列方向迁移。虽然这种正反馈关系已广泛描述为细胞群的入侵，但单细胞也能够排列 ECM 纤维，以及对接触引导和趋硬性线索做出反应，因此应该表现出相同的关系。在这项研究中，我们通过研究在具有有限重塑潜力的光交联胶原基质中迁移的单个 HT-1080 纤维肉瘤细胞的迁移持久性，直接检验了这一假设。我们的结果表明，这种正反馈关系确实是纤维状环境中细胞迁移的一个基本方面。我们观察到，细胞无法排列和浓缩纤维会导致迁移持久性降低，相对于天然胶原基质中的细胞，甚至相对于各向同性（玻璃）底物中的细胞也是如此。涉及二维胶原和静电纺丝聚合物支架的进一步实验表明，由刚性、随机取向纤维组成的基质通过迫使它们蜿蜒以跟随可用的附着区域（即纤维），降低了细胞跟随另一个方向性线索的能力。最后，我们的结果表明，细胞重塑和迁移之间的双向关系不是“维度”效应，而是纤维状基质结构的基本效应。
