Theoretical study of the impact of adaptation on cell-fate heterogeneity and fractional killing

Julien Hurbain,Darka Labavić,Benjamin Pfeuty,Quentin Thommen

doi:10.1038/s41598-020-74238-y

Abstract

Fractional killing illustrates the cell propensity to display a heterogeneous fate response over a wide range of stimuli. The interplay between the nonlinear and stochastic dynamics of biochemical networks plays a fundamental role in shaping this probabilistic response and in reconciling requirements for heterogeneity and controllability of cell-fate decisions. The stress-induced fate choice between life and death depends on an early adaptation response which may contribute to fractional killing by amplifying small differences between cells. To test this hypothesis, we consider a stochastic modeling framework suited for comprehensive sensitivity analysis of dose response curve through the computation of a fractionality index. Combining bifurcation analysis and Langevin simulation, we show that adaptation dynamics enhances noise-induced cell-fate heterogeneity by shifting from a saddle-node to a saddle-collision transition scenario. The generality of this result is further assessed by a computational analysis of a detailed regulatory network model of apoptosis initiation and by a theoretical analysis of stochastic bifurcation mechanisms. Overall, the present study identifies a cooperative interplay between stochastic, adaptation and decision intracellular processes that could promote cell-fate heterogeneity in many contexts.

Highlights

Fractional killing illustrates the cell propensity to display a heterogeneous fate response over a wide range of stimuli
Fractional killing can be defined as the population-level property by which isogenic cells exposed to increasing doses of death-inducing stimuli will tend to display a fraction of surviving cells and dying cells, with increasing probability of death
The present modeling study deciphers the role of adaptation dynamics in promoting cell-fate heterogeneity associated for instance with the fractional killing behavior

Summary

Introduction

Fractional killing illustrates the cell propensity to display a heterogeneous fate response over a wide range of stimuli. An attractive case study is the stochastic fate decision between life and death, commonly termed fractional killing, for which the systematic measure of probabilistic dose-response curves coupled with single-cell analysis of stochastic and dynamical signatures are possible[19]. On this issue, several modelling studies have been devoted to identify which sources of fluctuations and which parts of the apoptotic network could contribute the most to the variability of decision time and o utcomes[20,21,22,23], while the impact of the transient dynamics has been seldomly addressed[24]. Killing raise the more general question of the role of adaptation dynamics in shaping the timing and probabilities of stochastic fate decisions

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