Investigating the relation between Stochastic Differentiation, Homeostasis and Clonal Expansion in Intestinal Crypts via Multiscale Modeling

Graudenzi, Alex, Caravagna, Giulio, De Matteis, Giovanni and Antoniotti, Marco (2014) Investigating the relation between Stochastic Differentiation, Homeostasis and Clonal Expansion in Intestinal Crypts via Multiscale Modeling. PLoS ONE, 9 (5). e97272. ISSN 1932-6203

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Official URL: http://dx.doi.org/10.1371/journal.pone.0097272

Abstract

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.

Item Type: Article
Uncontrolled Keywords: cell differentiation, stem cells, genetic networks
Subjects: C100 Biology
G100 Mathematics
Department: Faculties > Engineering and Environment > Mathematics, Physics and Electrical Engineering
Depositing User: Ay Okpokam
Date Deposited: 03 Jun 2014 09:23
Last Modified: 19 May 2017 04:28
URI: http://nrl.northumbria.ac.uk/id/eprint/16500

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