Abstract
BackgroundColon and intestinal crypts serve as an important model system for adult stem cell proliferation and differentiation. We develop a spatial stochastic model to study the rate of somatic evolution in a normal crypt, focusing on the production of two-hit mutants that inactivate a tumor suppressor gene. We investigate the effect of cell division pattern along the crypt on mutant production, assuming that the division rate of each cell depends on its location.ResultsWe find that higher probability of division at the bottom of the crypt, where the stem cells are located, leads to a higher rate of double-hit mutant production. The optimal case for delaying mutations occurs when most of the cell divisions happen at the top of the crypt. We further consider an optimization problem where the “evolutionary” penalty for double-hit mutant generation is complemented with a “functional” penalty that assures that fully differentiated cells at the top of the crypt cannot divide.ConclusionThe trade-off between the two types of objectives leads to the selection of an intermediate division pattern, where the cells in the middle of the crypt divide with the highest rate. This matches the pattern of cell divisions obtained experimentally in murine crypts.ReviewersThis article was reviewed by David Axelrod (nominated by an Editorial Board member, Marek Kimmel), Yang Kuang and Anna Marciniak-Czochra. For the full reviews, please go to the Reviewers’ comments section.Electronic supplementary materialThe online version of this article (doi:10.1186/s13062-016-0141-6) contains supplementary material, which is available to authorized users.
Highlights
Colon and intestinal crypts serve as an important model system for adult stem cell proliferation and differentiation
We investigate the role of spatial structure on two-hit mutant production in a stochastic model of the colon/intestinal crypt, in the context of symmetric and asymmetric divisions patterns
Probability of 2-hit mutant generation is minimized when most cell divisions occur at the top of the crypt We have examined the probability of 2-hit mutant generation under different division probability distribution functions (Fig. 3)
Summary
Colon and intestinal crypts serve as an important model system for adult stem cell proliferation and differentiation. Dividing stem cell populations face multiple performance objectives, such as steady state robustness (low sensitivity to parameter variation) [8, 9], minimizing fluctuations in the population size (low variance) [10, 11], rapid regeneration of population following injury [12], Shahriyari et al Biology Direct (2016) 11:42 and delaying the onset of cancer [13, 14]. Dividing tissues, such as epithelial cells of intestinal crypts, are sensitive to somatic mutation accumulation, which can lead to cancer. The rationale is that symmetric division producing two progenitors flushes out mutations in the stem cell lineage, if progenitor turnover is fast [19, 20, 22, 24]
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