Chaotic expression dynamics implies pluripotency: when theory and experiment meet

BACKGROUND:During normal development, cells undergo a unidirectional course of differentiation that progressively decreases the number of cell types they can potentially become. Pluripotent stem cells can differentiate into several types of cells, but terminally differentiated cells cannot differentiate any further. A fundamental problem in stem cell biology is the characterization of the difference in cellular states, e.g., gene expression profiles, between pluripotent stem cells and terminally differentiated cells.PRESENTATION OF THE HYPOTHESIS:To address the problem, we developed a dynamical systems model of cells with intracellular protein expression dynamics and interactions with each other. According to extensive simulations, cells with irregular (chaotic) oscillations in gene expression dynamics have the potential to differentiate into other cell types. During development, such complex oscillations are lost successively, leading to a loss of pluripotency. These simulation results, together with recent single-cell-level measurements in stem cells, led us to the following hypothesis regarding pluripotency: Chaotic oscillation in the expression of some genes leads to cell pluripotency and affords cellular state heterogeneity, which is supported by itinerancy over quasi-stable states. Differentiation stabilizes these states, leading to a loss of pluripotency.TESTING THE HYPOTHESIS:To test the hypothesis, it is crucial to measure the time course of gene expression levels at the single-cell level by fluorescence microscopy and fluorescence-activated cell sorting (FACS) analysis. By analyzing the time series of single-cell-level expression data, one can distinguish whether the variation in protein expression level over time is due only to stochasticity in expression dynamics or originates from the chaotic dynamics inherent to cells, as our hypothesis predicts. By further analyzing the expression in differentiated cell types, one can examine whether the loss of pluripotency is accompanied by a loss of oscillation.IMPLICATIONS OF THE HYPOTHESIS:Recovery of pluripotency from determined cells is a long-standing aspiration, from both scientific and clinical perspectives. Our hypothesis suggests a feasible route to recover the potential to differentiate, i.e., by increasing the variety of expressed genes to restore chaotic expression dynamics, as is consistent with the recent generation of induced pluripotent stem (iPS) cells.REVIEWERS:This article was reviewed by David Krakauer, Jeroen van Zon (nominated by Rob de Boer), and Williams S. Hlavacek.