Graudenzi Alex, Caravagna Giulio, De Matteis Giovanni, Antoniotti Marco
Dept. of Informatics, Systems and Communication, University of Milan-Bicocca, Milan, Italy.
Department of Mathematics and Information Sciences, Northumbria University, Newcastle, United Kingdom.
PLoS One. 2014 May 28;9(5):e97272. doi: 10.1371/journal.pone.0097272. eCollection 2014.
Colorectal tumors originate and develop within intestinal crypts. Even though some of the essential phenomena that characterize crypt structure and dynamics have been effectively described in the past, the relation between the differentiation process and the overall crypt homeostasis is still only partially understood. We here investigate this relation and other important biological phenomena by introducing a novel multiscale model that combines a morphological description of the crypt with a gene regulation model: the emergent dynamical behavior of the underlying gene regulatory network drives cell growth and differentiation processes, linking the two distinct spatio-temporal levels. The model relies on a few a priori assumptions, yet accounting for several key processes related to crypt functioning, such as: dynamic gene activation patterns, stochastic differentiation, signaling pathways ruling cell adhesion properties, cell displacement, cell growth, mitosis, apoptosis and the presence of biological noise. We show that this modeling approach captures the major dynamical phenomena that characterize the regular physiology of crypts, such as cell sorting, coordinate migration, dynamic turnover, stem cell niche correct positioning and clonal expansion. All in all, the model suggests that the process of stochastic differentiation might be sufficient to drive the crypt to homeostasis, under certain crypt configurations. Besides, our approach allows to make precise quantitative inferences that, when possible, were matched to the current biological knowledge and it permits to investigate the role of gene-level perturbations, with reference to cancer development. We also remark the theoretical framework is general and may be applied to different tissues, organs or organisms.
结直肠肿瘤起源并发展于肠隐窝内。尽管过去已经有效地描述了一些表征隐窝结构和动态的基本现象，但分化过程与整体隐窝稳态之间的关系仍仅被部分理解。我们在此通过引入一种新颖的多尺度模型来研究这种关系以及其他重要的生物学现象，该模型将隐窝的形态学描述与基因调控模型相结合：潜在基因调控网络的涌现动态行为驱动细胞生长和分化过程，将两个不同的时空层次联系起来。该模型依赖于一些先验假设，但考虑了与隐窝功能相关的几个关键过程，例如：动态基因激活模式、随机分化、调节细胞黏附特性的信号通路、细胞位移、细胞生长、有丝分裂、细胞凋亡以及生物噪声的存在。我们表明，这种建模方法捕捉到了表征隐窝正常生理学的主要动态现象，如细胞分选、协调迁移、动态更新、干细胞微环境的正确定位和克隆扩增。总而言之，该模型表明，在某些隐窝构型下，随机分化过程可能足以驱动隐窝达到稳态。此外，我们的方法允许进行精确的定量推断，在可能的情况下，这些推断与当前的生物学知识相匹配，并且它允许研究基因水平扰动在癌症发展中的作用。我们还指出，该理论框架具有通用性，可应用于不同的组织、器官或生物体。
