Abstract
Cell fate choice and commitment of multipotent progenitor cells to a differentiated lineage requires broad changes of their gene expression profile. But how progenitor cells overcome the stability of their gene expression configuration (attractor) to exit the attractor in one direction remains elusive. Here we show that commitment of blood progenitor cells to the erythroid or myeloid lineage is preceded by the destabilization of their high-dimensional attractor state, such that differentiating cells undergo a critical state transition. Single-cell resolution analysis of gene expression in populations of differentiating cells affords a new quantitative index for predicting critical transitions in a high-dimensional state space based on decrease of correlation between cells and concomitant increase of correlation between genes as cells approach a tipping point. The detection of “rebellious cells” that enter the fate opposite to the one intended corroborates the model of preceding destabilization of a progenitor attractor. Thus, early warning signals associated with critical transitions can be detected in statistical ensembles of high-dimensional systems, offering a formal theory-based approach for analyzing single-cell molecular profiles that goes beyond current computational pattern recognition, does not require knowledge of specific pathways, and could be used to predict impending major shifts in development and disease.
Highlights
A multipotent stem cell or a progenitor cell is in a state that poises it to be able to commit to one of multiple available options of predestined cell lineages and to differentiate
Early warning signals associated with critical transitions can be detected in statistical ensembles of high-dimensional systems, offering a formal theorybased approach for analyzing single-cell molecular profiles that goes beyond current computational pattern recognition, does not require knowledge of specific pathways, and could be used to predict impending major shifts in development and disease
We found that blood progenitor cells undergoing a fate decision to commit to either lineage after treatment with fate-determining cytokines, according to theory, first destabilized their original state
Summary
A multipotent stem cell or a progenitor cell is in a state that poises it to be able to commit to one of multiple available options of predestined cell lineages and to differentiate. The high-dimensional attractor guarantees that the state-characteristic genome-wide gene expression pattern is self-stabilizing, withstanding the stochastic molecular fluctuations. As cells differentiate and alter their gene expression pattern in a coordinated manner to implement the expression pattern of the new cell type, they must first overcome this stabilization of the progenitor ground state imposed by the GRN. Individual multipotent progenitor cells can, due to the stochastic gene expression fluctuations, temporarily and by chance, approach the border of the basin of attraction of their attractor and thereby be transiently primed to exit the progenitor state in a random direction, giving rise to the occasionally observed spontaneous, apparently stochastic differentiation into one of a set of alternative lineages. Once in the new basin, the cell will robustly establish the new gene expression pattern of the respective destination cell type as it enters the new attractor state [2]
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