Abstract
Cell fate choice during the process of differentiation may obey to deterministic or stochastic rules. In order to discriminate between these two strategies we used time-lapse microscopy of individual murine CD4 + T cells that allows investigating the dynamics of proliferation and fate commitment. We observed highly heterogeneous division and death rates between individual clones resulting in a Pareto-like dominance of a few clones at the end of the experiment. Commitment to the Treg fate was monitored using the expression of a GFP reporter gene under the control of the endogenous Foxp3 promoter. All possible combinations of proliferation and differentiation were observed and resulted in exclusively GFP–, GFP+ or mixed phenotype clones of very different population sizes. We simulated the process of proliferation and differentiation using a simple mathematical model of stochastic decision-making based on the experimentally observed parameters. The simulations show that a stochastic scenario is fully compatible with the observed Pareto-like imbalance in the final population.
Highlights
This substantial proliferation heterogeneity is surprising in a cell population where each cell encounters identical conditions
Variations of cell cycle length and cell death rate are the key factors contributing to the phenotypic heterogeneity of the final cell population
Our observations show that due to the heterogeneity of proliferation and death rate, the final cell population is composed essentially from cells derived from a small number of initial founder cells
Summary
This substantial proliferation heterogeneity is surprising in a cell population where each cell encounters identical conditions. In order to get insight in the origin of this heterogeneous behavior we used a single-cell time-lapse approach coupled to mathematical modeling. We observed substantial heterogeneity in the proliferation, differentiation and death rates leading to an unequal contribution of clonal cell lineages to the final population. Variations of cell cycle length and cell death rate are the key factors contributing to the phenotypic heterogeneity of the final cell population. The initial differences between the cells in the starting population may reinforce this effect but alone is insufficient to fully account for it. Our observations show that due to the heterogeneity of proliferation and death rate, the final cell population is composed essentially from cells derived from a small number of initial founder cells
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