Computer simulation of neutral drift among limbal epithelial stem cells of mosaic mice

John D West,Richard L Mort,Robert E Hill,Steven D Morley,J Martin Collinson

doi:10.1016/j.scr.2018.05.003

Abstract

The use of mice that are mosaic for reporter gene expression underlies many lineage-tracing studies in stem cell biology. For example, using mosaic LacZ reporter mice, it was shown that limbal epithelial stem cells (LESCs) around the periphery of the cornea maintain radial sectors of the corneal epithelium and that radial stripe numbers declined with age. Originally, the corneal results were interpreted as progressive, age-related loss or irreversible inactivation of some LESC clones. In this study we used computer simulations to show that these results could also be explained by stochastic replacement of LESCs by neighbouring LESCs, leading to neutral drift of LESC populations. This was shown to reduce the number of coherent clones of LESCs and hence would coarsen the mosaic pattern in the corneal epithelium without reducing the absolute number of LESCs. Simulations also showed that corrected stripe numbers declined more slowly when LESCs were grouped non-randomly and that mosaicism was rarely lost unless simulated LESC numbers were unrealistically low. Possible reasons why age-related changes differ between mosaic corneal epithelia and other systems, such as adrenal cortices and intestinal crypts, are discussed.

Highlights

Two related types of observations with chimaeric or mosaic mice, or from lineage-tracing experiments, suggest that, in some tissues, progressive changes in the pattern of variegation result from stem cells being lost, irreversibly inactivated or replaced
Larger array sizes were used for simulations where limbal epithelial stem cells (LESCs) were in ‘clumped arrays’ to maintain a similar LESC coherent clone number and, a similar predicted corrected stripe number in the corneal epithelium
Our main conclusion is that the computer model supports the hypothesis that stochastic LESC replacement by neighbouring LESC lineages, leading to neutral drift, without changing the number of active LESCs, could account for the age-related changes demonstrated for corneal epithelial stripe patterns in mosaic and chimaeric mice (Collinson et al, 2002; Mort et al, 2009)

Summary

Introduction

Two related types of observations with chimaeric or mosaic mice, or from lineage-tracing experiments, suggest that, in some tissues, progressive changes in the pattern of variegation result from stem cells being lost, irreversibly inactivated or replaced. The first observation involved the loss of one of two cell populations, from intestinal crypts of chimaeric mice (Ponder et al, 1985; Schmidt et al, 1988) This loss of mosaicism occurred between birth and adulthood and was termed ‘crypt purification’ by the authors. The second type of observation is exemplified by the age-related coarsening of variegated patterns in corneal epithelia of adult chimaeric and mosaic mice, comprising two genetically distinct cell populations (Collinson et al, 2002; Mort et al, 2009). Equivalent results have been reported recently, using tamoxifen-inducible lineage tracing to label K14positive progenitor cells with the multi-coloured, R26-confetti marker at 6 weeks (Richardson et al, 2017)

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