On the biomechanics of stem cell niche formation in the gut - modelling growing organoids
On the biomechanics of stem cell niche formation in the gut - modelling growing organoids
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DOI：
10.1111/j.1742-4658.2012.08646.x
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发表时间：
2012-09-01
期刊：
影响因子：
5.4
通讯作者：
Galle, Joerg
中科院分区：
文献类型：
--
作者：
Buske, Peter;Przybilla, Jens;Galle, Joerg
肠组织的体外培养已经尝试了几十年。直到最近Sato等人[Sato，T.，弗里斯河G.，Snippert，H. J.，货车de Wetering，M.，Barker，N.，Stange，D. E、货车埃斯，J.H.，Abo，A.，库贾拉山口彼得斯，P. J.，等人（2009）Nature 459，262-265]成功地建立了长期肠培养物，证明表达Lgr 5基因的细胞可以产生具有类似于体内发现的隐窝样结构域的类器官。在这些培养物中，潘氏细胞提供支持干细胞功能的基本信号。我们最近开发了一种基于单个细胞的肠组织计算模型[Buske，P.，Galle，J.，Barker，N.，Aust，G.，Clevers，H. & Loeffler，M.（2011）PLoS Comput Biol 7，e1001045]。该模型能够定量地再现一组关于肠细胞组织的全面实验数据。在这里，我们提出了一个显着的扩展这个模型，允许模拟肠道类器官的形成在硅片上。为了这个目的，我们引入了一个灵活的基膜，分配一个弯曲模量的类器官表面。该膜可能会被附着在其上的细胞重新组织，具体取决于它们的分化状态。因此，上皮的形态是自组织的。我们假设局部组织弯曲是通过控制潘氏细胞特化而在肠组织中干细胞组织化的关键调节因子。在模拟研究中，我们的模型非常类似于肠道类器官的时空组织。根据我们的研究结果，增殖诱导的形状波动足以诱导隐窝样结构域，潘氏细胞诱导的自发组织曲率可以控制细胞数量比。因此，类器官中的干细胞扩增敏感地取决于其生物力学。我们提出了一些实验，这将使新的见解在肠道中的机械转导，并建议在腺体形成领域的模型扩展。
In vitro culture of intestinal tissue has been attempted for decades. Only recently did Sato et al. [Sato, T., Vries, R. G., Snippert, H. J., van de Wetering, M., Barker, N., Stange, D. E., van Es, J. H., Abo, A., Kujala, P., Peters, P. J., et al. (2009) Nature 459, 262-265] succeed in establishing long-term intestinal culture, demonstrating that cells expressing the Lgr5 gene can give rise to organoids with crypt-like domains similar to those found in vivo. In these cultures, Paneth cells provide essential signals supporting stem cell function. We have recently developed an individual cell-based computational model of the intestinal tissue [Buske, P., Galle, J., Barker, N., Aust, G., Clevers, H. & Loeffler, M. (2011) PLoS Comput Biol 7, e1001045]. The model is capable of quantitatively reproducing a comprehensive set of experimental data on intestinal cell organization. Here, we present a significant extension of this model that allows simulation of intestinal organoid formation in silico. For this purpose, we introduce a flexible basal membrane that assigns a bending modulus to the organoid surface. This membrane may be re-organized by cells attached to it depending on their differentiation status. Accordingly, the morphology of the epithelium is self-organized. We hypothesize that local tissue curvature is a key regulatory factor in stem cell organization in the intestinal tissue by controlling Paneth cell specification. In simulation studies, our model closely resembles the spatio-temporal organization of intestinal organoids. According to our results, proliferation-induced shape fluctuations are sufficient to induce crypt-like domains, and spontaneous tissue curvature induced by Paneth cells can control cell number ratios. Thus, stem cell expansion in an organoid depends sensitively on its biomechanics. We suggest a number of experiments that will enable new insights into mechano-transduction in the intestine, and suggest model extensions in the field of gland formation.