Integrative biophysical modeling for collective tissue mechanics

集体组织力学的综合生物物理建模

基本信息

批准号：
10711311
负责人：
DAPENG BI
金额：
$ 39.3万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-08-31
项目状态：
未结题

项目摘要

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.

项目概要/摘要器官表面覆盖有上皮细胞或内皮细胞，为器官和组织提供物理屏障。这些汇合层上的细胞通常保持静止且不迁移。胚胎发育过程中基本生理过程中的主动结构重排，在每一个事件中，上皮细胞集体都必然经历形态发生、修复和重塑。从静止且不可迁移的类固体状态到动态且非迁移的类流体状态的转变传统上研究非迁徙行为与迁徙行为之间的这种显着转变。这些集体细胞行为已在二维平面上得到了广泛的探索。来自生物物理学和细胞生物学的单层上皮细胞形成二维 (2D) 平坦表面然而，它们并不适合对自然上皮细胞进行预测，而这通常是自然上皮细胞的预测。发现可以形成高度弯曲的表面，其曲率半径可与几个细胞长度相当。上皮组织还包括各种拓扑结构——球体、椭球体、管状体和鞍点——在天然情况下表面曲率如何影响胚胎、肺泡、气道、血管和分支分叉等结构。此外，细胞群的运动方式在很大程度上仍然未知；此外，细胞如何变得堵塞和不受堵塞；在弯曲表面上生长的细胞单层的成熟过程仍不清楚，而以前的建模工作更多地关注单个细胞内的力学和迁移行为尽管发育中的表皮是单层的，但哺乳动物表皮是多层上皮组织。由于高度动态，表皮发育的时间依赖性力学（即流变学）仍然难以捉摸。有两个尚未解决的关键问题：（1）什么因素驱动表皮发育，以及（2）机制如何发挥作用表皮的变化取决于测量的时间尺度？迫切需要发展理论和我将为这些关键场景开发一个集成的计算建模框架。阐明集体细胞行为的生物力学，超越传统研究的二维设置，包括曲面和多层 3D 表皮，我还将创建一个解决问题的新颖模型。核形态和上皮增殖之间的生物力学耦合。