Department of Physics, University of California, Merced, CA 95343.
Department of Materials and Biomaterials Science and Engineering, University of California, Merced, CA 95343.
Proc Natl Acad Sci U S A. 2023 Nov 7;120(45):e2301555120. doi: 10.1073/pnas.2301555120. Epub 2023 Nov 1.
Cells self-organize into functional, ordered structures during tissue morphogenesis, a process that is evocative of colloidal self-assembly into engineered soft materials. Understanding how intercellular mechanical interactions may drive the formation of ordered and functional multicellular structures is important in developmental biology and tissue engineering. Here, by combining an agent-based model for contractile cells on elastic substrates with endothelial cell culture experiments, we show that substrate deformation-mediated mechanical interactions between cells can cluster and align them into branched networks. Motivated by the structure and function of vasculogenic networks, we predict how measures of network connectivity like percolation probability and fractal dimension as well as local morphological features including junctions, branches, and rings depend on cell contractility and density and on substrate elastic properties including stiffness and compressibility. We predict and confirm with experiments that cell network formation is substrate stiffness dependent, being optimal at intermediate stiffness. We also show the agreement between experimental data and predicted cell cluster types by mapping a combined phase diagram in cell density substrate stiffness. Overall, we show that long-range, mechanical interactions provide an optimal and general strategy for multicellular self-organization, leading to more robust and efficient realizations of space-spanning networks than through just local intercellular interactions.
细胞在组织形态发生过程中自行组织成具有功能的有序结构，这一过程类似于胶体自组装成工程软物质。了解细胞间的机械相互作用如何驱动有序和功能性的多细胞结构的形成，在发育生物学和组织工程中非常重要。在这里，我们通过将基于主体的弹性基底上收缩细胞模型与内皮细胞培养实验相结合，表明细胞之间的基底变形介导的力学相互作用可以将它们聚类并排列成分支网络。受血管生成网络的结构和功能的启发，我们预测了网络连通性的度量（如渗流概率和分形维数）以及局部形态特征（包括节点、分支和环）如何取决于细胞的收缩性和密度以及基底的弹性特性（包括刚度和可压缩性）。我们通过在细胞密度-基底刚度的组合相图上进行映射，预测并通过实验证实了细胞网络的形成依赖于基底的刚度，在中等刚度下达到最佳状态。我们还通过将实验数据与预测的细胞簇类型进行映射，证明了实验数据与预测的细胞簇类型之间的一致性。总的来说，我们表明，长程机械相互作用为多细胞自组织提供了一种最优且通用的策略，与仅仅通过局部细胞间相互作用相比，这种策略可以实现更稳健和高效的空间跨越网络。
