A two-dimensional model of the colonic crypt accounting for the role of the basement membrane and pericryptal fibroblast sheath.
A two-dimensional model of the colonic crypt accounting for the role of the basement membrane and pericryptal fibroblast sheath.
复制标题
结肠隐窝的二维模型，涉及基底膜和周围成纤维细胞鞘的作用。
DOI：
10.1371/journal.pcbi.1002515
复制
发表时间：
2012
影响因子：
4.3
通讯作者：
Osborne JM
中科院分区：
文献类型：
--
作者：
Dunn SJ;Appleton PL;Nelson SA;Näthke IS;Gavaghan DJ;Osborne JM
基底膜的作用对于维持上皮层的完整性和结构至关重要，它既充当机械支撑，又形成上皮细胞与周围结缔组织之间的物理界面。本文在结肠隐窝内衬的上皮单层、试管状内陷的背景下探讨了该膜的功能，该内陷刺破了肠道内壁并协调细胞的定期周转以每隔几天补充上皮层。为了研究扰乱系统动力学并可能导致结直肠癌的基因突变的后果，必须能够追踪隐窝中出现的组织水平变化。为此，需要具有现实的、可变形几何形状的理论地穴模型。提出了一种新的离散隐窝模型，该模型侧重于细胞和组织水平行为之间的相互作用，同时结合了关键的亚细胞成分。该模型基于对隐窝组织结构的实验观察，对周围组织和肌肉的作用进行了新颖的描述，这些观察也已被报道。考虑二维 (2D) 横截面几何形状，并且允许隐窝的形状演化和变形。模拟结果揭示了隐窝的形状如何机械地促进通常与基部干细胞相关的不对称分裂事件。该模型预测，上皮细胞迁移可能是由于隐窝环处的细胞损失和密度依赖性细胞分裂之间的反馈而引起的，这一假设可以在湿实验室中进行研究。这项工作构成了研究隐窝结构变形的基础，这种变形可能是由于表现出突变表型的细胞增殖而发生的，而这些实验在体内或体外是不可能的。在结直肠癌发生时，可以观察到 Lieberkühn 隐窝的结构和动态发生显着变化。这些试管状的腺体有规律地分布在肠道表面，并衬有单层上皮细胞，这些细胞每隔几天就会分裂并向上迁移，以更新肠道表面。隐窝结构分解的过程，以及随后提供给突变细胞以允许腺瘤生长形成的顺应环境，目前尚未得到很好的表征。理解此过程的一个限制因素是能否轻松观察发生的初始变化，这些变化对于破坏系统的正常行为是必要的。然而，模拟几何形状和组织结构的隐窝预测理论模型可用于进行计算机实验并进一步加深这种理解。这里介绍的模型解决了隐窝的组织结构及其为上皮层提供的稳定性，同时保持可变形且不强加固定的几何形状。
The role of the basement membrane is vital in maintaining the integrity and structure of an epithelial layer, acting as both a mechanical support and forming the physical interface between epithelial cells and the surrounding connective tissue. The function of this membrane is explored here in the context of the epithelial monolayer that lines the colonic crypt, test-tube shaped invaginations that punctuate the lining of the intestine and coordinate a regular turnover of cells to replenish the epithelial layer every few days. To investigate the consequence of genetic mutations that perturb the system dynamics and can lead to colorectal cancer, it must be possible to track the emerging tissue level changes that arise in the crypt. To that end, a theoretical crypt model with a realistic, deformable geometry is required. A new discrete crypt model is presented, which focuses on the interaction between cell- and tissue-level behaviour, while incorporating key subcellular components. The model contains a novel description of the role of the surrounding tissue and musculature, based upon experimental observations of the tissue structure of the crypt, which are also reported. A two-dimensional (2D) cross-sectional geometry is considered, and the shape of the crypt is allowed to evolve and deform. Simulation results reveal how the shape of the crypt may contribute mechanically to the asymmetric division events typically associated with the stem cells at the base. The model predicts that epithelial cell migration may arise due to feedback between cell loss at the crypt collar and density-dependent cell division, an hypothesis which can be investigated in a wet lab. This work forms the basis for investigation of the deformation of the crypt structure that can occur due to proliferation of cells exhibiting mutant phenotypes, experiments that would not be possible in vivo or in vitro. At the onset of colorectal carcinogenesis, marked changes can be observed in the structure and dynamics of the crypts of Lieberkühn. These test tube shaped glands regularly punctuate the surface of the gut and are lined with a monolayer of epithelial cells which divide and migrate upwards to renew the intestinal surface every few days. The process by which the crypt structures breakdown, and the compliant environment that can be subsequently provided to mutated cells to allow the formation of adenomatous growths, is not yet well characterised. A limiting factor in the understanding of this process is the ability to observe easily the initial changes that occur, and which are necessary to disrupt the normal behaviour of the system. However, a predictive, theoretical model of the crypt that mimics the geometry and the tissue architecture can be used to perform in silico experiments and further such understanding. A model is introduced here that addresses the tissue structure of the crypt, and the stability it provides to the epithelial layer, while remaining deformable and without imposing a fixed geometry.
登录
查看更多内容
影响因子：
3.2
作者：
Fleming, Elizabeth S.;Zajac, Mark;Tirnauer, Jennifer S.
通讯作者：
Tirnauer, Jennifer S.
影响因子：
3.9
作者：
Heath, JP
通讯作者：
Heath, JP
影响因子：
3.5
作者：
Edwards, Carina M.;Chapman, S. Jonathan
通讯作者：
Chapman, S. Jonathan
影响因子：
--
作者：
CHENG, H;LEBLOND, CP
通讯作者：
LEBLOND, CP
影响因子：
9.2
作者：
Effler, Janet C.;Kee, Yee-Seir;Robinson, Douglas N.
通讯作者：
Robinson, Douglas N.