Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA.
Wyss Institute for Biologically Inspired Engineering, Cambridge, MA, USA.
Nat Mater. 2023 Jan;22(1):117-127. doi: 10.1038/s41563-022-01400-4. Epub 2022 Dec 1.
Biomolecular and physical cues of the extracellular matrix environment regulate collective cell dynamics and tissue patterning. Nonetheless, how the viscoelastic properties of the matrix regulate collective cell spatial and temporal organization is not fully understood. Here we show that the passive viscoelastic properties of the matrix encapsulating a spheroidal tissue of breast epithelial cells guide tissue proliferation in space and in time. Matrix viscoelasticity prompts symmetry breaking of the spheroid, leading to the formation of invading finger-like protrusions, YAP nuclear translocation and epithelial-to-mesenchymal transition both in vitro and in vivo in a Arp2/3-complex-dependent manner. Computational modelling of these observations allows us to establish a phase diagram relating morphological stability with matrix viscoelasticity, tissue viscosity, cell motility and cell division rate, which is experimentally validated by biochemical assays and in vitro experiments with an intestinal organoid. Altogether, this work highlights the role of stress relaxation mechanisms in tissue growth dynamics, a fundamental process in morphogenesis and oncogenesis.
细胞外基质环境的生物分子和物理线索调节细胞的集体动力学和组织模式。然而，基质的粘弹性如何调节细胞的集体空间和时间组织还不完全清楚。在这里，我们表明，包裹着乳腺上皮细胞球形组织的基质的被动粘弹性特性指导组织在空间和时间上的增殖。基质的粘弹性促使球体的对称性破裂，导致形成侵入性的指状突起，YAP 核易位，并在体外和体内以 Arp2/3 复合物依赖性的方式发生上皮-间充质转化。对这些观察结果的计算模型使我们能够建立一个与形态稳定性相关的相图，该相图与基质粘弹性、组织粘度、细胞迁移率和细胞分裂率有关，通过生化分析和具有肠类器官的体外实验进行了实验验证。总的来说，这项工作强调了在组织生长动力学中，应力松弛机制在形态发生和癌变中的重要作用。
