Symmetric vs. Asymmetric Stem Cell Divisions: An Adaptation against Cancer?

Leili Shahriyari,Natalia L Komarova

doi:10.1371/journal.pone.0076195

Leili Shahriyari, Natalia L Komarova

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https://doi.org/10.1371/journal.pone.0076195

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Journal: PLoS ONE	Publication Date: Oct 29, 2013
Citations: 122	License type: CC BY 4.0

Affiliation: University of California, Irvine

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Traditionally, it has been held that a central characteristic of stem cells is their ability to divide asymmetrically. Recent advances in inducible genetic labeling provided ample evidence that symmetric stem cell divisions play an important role in adult mammalian homeostasis. It is well understood that the two types of cell divisions differ in terms of the stem cells' flexibility to expand when needed. On the contrary, the implications of symmetric and asymmetric divisions for mutation accumulation are still poorly understood. In this paper we study a stochastic model of a renewing tissue, and address the optimization problem of tissue architecture in the context of mutant production. Specifically, we study the process of tumor suppressor gene inactivation which usually takes place as a consequence of two “hits”, and which is one of the most common patterns in carcinogenesis. We compare and contrast symmetric and asymmetric (and mixed) stem cell divisions, and focus on the rate at which double-hit mutants are generated. It turns out that symmetrically-dividing cells generate such mutants at a rate which is significantly lower than that of asymmetrically-dividing cells. This result holds whether single-hit (intermediate) mutants are disadvantageous, neutral, or advantageous. It is also independent on whether the carcinogenic double-hit mutants are produced only among the stem cells or also among more specialized cells. We argue that symmetric stem cell divisions in mammals could be an adaptation which helps delay the onset of cancers. We further investigate the question of the optimal fraction of stem cells in the tissue, and quantify the contribution of non-stem cells in mutant production. Our work provides a hypothesis to explain the observation that in mammalian cells, symmetric patterns of stem cell division seem to be very common.

Highlights

The ability of stem cells to divide asymmetrically to produce one stem and one non-stem daughter cell is often considered to be one of the defining characteristics of stemness
Tunneling rates While the detailed temporal dynamics of double-mutant production is given in the Methods Section, here we present the results for the so-called ‘‘tunneling rates’’ - the rates at which the stem cell system of a given size produces double-hit mutants
In this paper we found that symmetrically dividing stem cells are characterized by a significantly lower rate of two-hit mutant generation, compared to asymmetrically-dividing cells

Summary

Introduction

The ability of stem cells to divide asymmetrically to produce one stem and one non-stem daughter cell is often considered to be one of the defining characteristics of stemness. There is ample evidence suggesting that adult stem cell can and do divide symmetrically [1,2]. The asymmetric model suggests that the homeostatic control of the stem cell pool is maintained at the level of single cells, whereby each stem cell produces a copy of itself plus one differentiated cell [4,5,6]. An obvious disadvantage is its inability to replenish the stem cell pool in case of injury. This problem is naturally solved by the symmetric model, which maintains homeostatic control at the population level, rather than at the individual cell level.

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