Integrative biophysical modeling for collective tissue mechanics

项目摘要/摘要 器官表面覆盖有上皮细胞或内皮细胞，为器官和 身体。这些融合层上的细胞通常保持静止和不迁移。然而，他们也可以经历 在胚胎发育的基本生理过程中积极的结构重排， 形态发生、修复和重塑。在这些事件中的每一个中，一个上皮性集体都必须经历 从静止和非迁移的类固体状态到动态和非迁移的类流体状态的转变 迁徙。非迁徙行为和迁徙行为之间的这种显著的转变传统上是在 二维平面上单元格的上下文。这些集体的细胞行为已经在 来自生物物理学和细胞生物学的形成二维(2D)平面的上皮细胞的单层 透视。然而，它们不能很好地适应对自然上皮细胞的预测，而自然上皮细胞通常是 发现可以形成高度弯曲的表面，其中曲率半径可以与几个单元长度相媲美。 上皮组织也包括各种拓扑结构-球体、椭球体、管状和鞍点-在自然 胚胎、肺泡、呼吸道、导管和分支分叉等结构。曲面曲率如何影响 细胞集体运动的方式在很大程度上仍不清楚；此外，细胞是如何变得拥挤和不拥挤的 在细胞的成熟过程中，生长在曲面上的单层细胞仍不清楚。此外，鉴于 以前的建模工作更多地关注单个细胞内细胞的力学和迁移行为 单层，哺乳动物的表皮是一个多层的上皮组织。尽管发育中的表皮是 高度动态的，依赖于时间的机制(即，流变学)的表皮发育仍然难以捉摸。那里 有两个关键的悬而未决的问题：(1)什么线索驱动表皮发育，以及(2)机制是如何 表皮的大小取决于测量的时间尺度？迫切需要发展理论和实践 这些关键场景的计算模型。我将开发一个集成的计算建模框架 要阐明集体细胞行为的生物力学，超越常规研究的二维 设置，包括曲面和多层3D表皮。我还将创建一个新的模型，以解决 细胞核形态与上皮细胞增殖之间的生物力学耦合。

Project Summary/Abstract Organ surfaces are covered with epithelial cells or endothelial cells, providing physical barriers for organs and bodies. Cells on these confluent layers often remain static and non-migratory. However, they can also undergo active structural rearrangements during basic physiological processes ranging across embryonic development, morphogenesis, repair, and remodeling. In each of these events, an epithelial collective necessarily undergoes a transition from a solid-like state which is quiescent and non-migratory to a fluid-like state which is dynamic and migratory. This striking transition between non-migratory versus migratory behaviors is traditionally studied in the context of cells on a flat surface in 2D. These collective cellular behaviors have been widely explored in monolayers of epithelial cells that form two-dimensional (2D) flat surfaces, from both biophysics and cell biology perspectives. However, they are not well-adapted to make predictions for natural epithelia, which are typically found to form highly curved surfaces, where the radius of curvature can be comparable to a few cell lengths. Epithelial tissues also comprise various topologies – spheres, ellipsoids, tubes, and saddle points — in native structures such as embryos, alveoli, airways, vessels, and branching bifurcations. How surface curvature affects the way a cell collective moves remains largely unknown; furthermore, how cells become jammed and unjammed during the maturation of a cell monolayer growing on a curved surface remains unclear. Further, whereas previous modeling efforts have focused more on the mechanics and migratory behavior of cells within a single monolayer, the mammalian epidermis is a multilayered epithelial tissue. Although the developing epidermis is highly dynamic, the time-dependent mechanics (i.e., rheology) of epidermal development remains elusive. There are two key unresolved questions: (1) what cues drive epidermal development, and (2) how does the mechanics of the epidermis depend on the timescale of measurement? There is an urgent need to develop theoretical and computational models for these critical scenarios. I will develop an integrated computation modeling framework to elucidate the biomechanics of collective cell behavior beyond the conventionally studied two-dimensional settings, including curved surfaces and multilayered 3D epidermis. I will also create a novel model that addresses the biomechanical couplings between nuclear morphologies and epithelial proliferation.