Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO 80303, USA.
The BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80303, USA.
Sci Adv. 2024 May 31;10(22):eadn0235. doi: 10.1126/sciadv.adn0235.
The ability of cells to organize into tissues with proper structure and function requires the effective coordination of proliferation, migration, polarization, and differentiation across length scales. Skeletal muscle is innately anisotropic; however, few biomaterials can emulate mechanical anisotropy to determine its influence on tissue patterning without introducing confounding topography. Here, we demonstrate that substrate stiffness anisotropy coordinates contractility-driven collective cellular dynamics resulting in C2C12 myotube alignment over millimeter-scale distances. When cultured on mechanically anisotropic liquid crystalline polymer networks (LCNs) lacking topography, C2C12 myoblasts collectively polarize in the stiffest direction. Cellular coordination is amplified through reciprocal cell-ECM dynamics that emerge during fusion, driving global myotube-ECM ordering. Conversely, myotube alignment was restricted to small local domains with no directional preference on mechanically isotropic LCNs of the same chemical formulation. These findings provide valuable insights for designing biomaterials that mimic anisotropic microenvironments and underscore the importance of stiffness anisotropy in orchestrating tissue morphogenesis.
细胞有组织地形成具有适当结构和功能的组织的能力需要在不同尺度上有效地协调增殖、迁移、极化和分化。骨骼肌肉具有内在的各向异性；然而，很少有生物材料能够模拟机械各向异性，以确定其对组织模式形成的影响，而不会引入混淆的形貌。在这里，我们证明了基质刚度各向异性协调了收缩驱动的集体细胞动力学，导致 C2C12 肌管在毫米级距离上的排列。当在缺乏形貌的机械各向异性液晶聚合物网络（LCN）上培养时，C2C12 成肌细胞在最硬的方向上集体极化。细胞协调通过融合过程中出现的细胞-ECM 动态得到放大，从而驱动全局肌管-ECM 有序化。相反，在具有相同化学配方的机械各向同性 LCN 上，肌管排列受到限制，仅在小的局部区域，没有方向偏好。这些发现为设计模仿各向异性微环境的生物材料提供了有价值的见解，并强调了刚度各向异性在协调组织形态发生中的重要性。
