Maximum entropy and population heterogeneity in continuous cell cultures

PLoS Computational Biology
Jorge Fernandez-de-Cossio-Diaz, Roberto Mulet

Abstract

Continuous cultures of mammalian cells are complex systems displaying hallmark phenomena of nonlinear dynamics, such as multi-stability, hysteresis, as well as sharp transitions between different metabolic states. In this context mathematical models may suggest control strategies to steer the system towards desired states. Although even clonal populations are known to exhibit cell-to-cell variability, most of the currently studied models assume that the population is homogeneous. To overcome this limitation, we use the maximum entropy principle to model the phenotypic distribution of cells in a chemostat as a function of the dilution rate. We consider the coupling between cell metabolism and extracellular variables describing the state of the bioreactor and take into account the impact of toxic byproduct accumulation on cell viability. We present a formal solution for the stationary state of the chemostat and show how to apply it in two examples. First, a simplified model of cell metabolism where the exact solution is tractable, and then a genome-scale metabolic network of the Chinese hamster ovary (CHO) cell line. Along the way we discuss several consequences of heterogeneity, such as: qualitative changes in the dynamical land...Continue Reading

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Citations

May 20, 2020·Journal of Mathematical Biology·David S Tourigny
May 20, 2020·Physical Review. E·Jorge Fernandez-de-Cossio-Diaz, Roberto Mulet
Oct 12, 2020·Biotechnology Letters·Hamideh FouladihaNathan E Lewis
Dec 5, 2020·PloS One·Marcelo Rivas-Astroza, Raúl Conejeros
Jan 23, 2021·Journal of Mathematical Biology·David S Tourigny
Feb 20, 2021·Genome Biology·David B BernsteinDaniel Segrè

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Software Mentioned

MaxEnt
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