Human Biomimetic System RIKEN Hakubi Research Team, RIKEN Cluster for Pioneering Research (CPR), Wako, Saitama, Japan.
Department of Biological System, Osaka Prefecture University, Sakai, Osaka, Japan.
Commun Biol. 2021 Jun 28;4(1):808. doi: 10.1038/s42003-021-02350-4.
Collective migration of epithelial cells is a fundamental process in multicellular pattern formation. As they expand their territory, cells are exposed to various physical forces generated by cell-cell interactions and the surrounding microenvironment. While the physical stress applied by neighbouring cells has been well studied, little is known about how the niches that surround cells are spatio-temporally remodelled to regulate collective cell migration and pattern formation. Here, we analysed how the spatio-temporally remodelled extracellular matrix (ECM) alters the resistance force exerted on cells so that the cells can expand their territory. Multiple microfabrication techniques, optical tweezers, as well as mathematical models were employed to prove the simultaneous construction and breakage of ECM during cellular movement, and to show that this modification of the surrounding environment can guide cellular movement. Furthermore, by artificially remodelling the microenvironment, we showed that the directionality of collective cell migration, as well as the three-dimensional branch pattern formation of lung epithelial cells, can be controlled. Our results thus confirm that active remodelling of cellular microenvironment modulates the physical forces exerted on cells by the ECM, which contributes to the directionality of collective cell migration and consequently, pattern formation.
上皮细胞的集体迁移是多细胞形态发生的基本过程。当它们扩展其领地时，细胞会受到细胞间相互作用和周围微环境产生的各种物理力的影响。虽然相邻细胞施加的物理压力已经得到了很好的研究，但对于包围细胞的龛位如何在时空上重塑以调节细胞的集体迁移和形态发生知之甚少。在这里，我们分析了时空重塑的细胞外基质 (ECM) 如何改变作用于细胞的阻力，从而使细胞能够扩大其领地。我们使用了多种微制造技术、光镊以及数学模型来证明细胞运动过程中 ECM 的同时构建和断裂，并表明周围环境的这种修饰可以指导细胞运动。此外，通过人为地重塑微环境，我们表明可以控制细胞的集体迁移的方向性以及肺上皮细胞的三维分支模式形成。因此，我们的结果证实了细胞微环境的主动重塑调节了 ECM 对细胞施加的物理力，这有助于细胞的集体迁移的方向性，进而影响形态发生。
