Dynamics of living cells in a cytomorphological state space

Cells are non-equilibrium systems that rely on a continuous exchange of matter and energy with the environment to sustain their metabolic needs. The non-equilibrium nature of this system presents considerable challenges to developing a general theory describing its behavior; however, studies have demonstrated that when studied at appropriate spatiotemporal scales, the behavior of ensembles of non-equilibrium systems can resemble that of system at equilibrium. Here we apply this principle to a population of cells within a cytomorphological state space and demonstrate that cellular transition dynamics within this space can be suitably described using equilibrium dynamics formalisms. We use this framework to map the effective energy landscape underlying the cytomorphological state space of a population of mouse embryonic fibroblasts (MEFs) and identify topographical non-uniformity in this space, indicating non-uniform occupation of cytomorphological states within an isogenic population. The introduction of exogenous apoptotic agents altered this energy landscape, inducing formation of additional energy minima that correlated directly with changes in sensitivity to apoptotic induction. The measured application of equilibrium dynamics formalism allows us to accurately capture and these findings suggest that though cells are complex non-equilibrium systems, the application of formalisms derived from equilibrium thermodynamics can provide insight into the basis of non-genetic heterogeneities as well as the relationship between morphological and functional heterogeneity.