Cell fate-decision as high-dimensional critical state transition

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 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. Author SummaryA certain type of multipotent progenitor cell of the blood can commit to either the white (myeloid) or the red (erythroid) blood cell lineage, thus making a discrete binary cell fate decision. To test a theory on fundamental principles of cell fate dynamics (as opposed to the usually studied molecular mechanisms), we monitored such a fate decision in vitro using single-cell resolution gene expression analysis. 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. Cell states hereby PLOS Biology |

Cell population structure prior to bifurcation predicts efficiency of directed differentiation in human induced pluripotent cells

“…population at a tipping point is characterized by increased gene to gene correlations-suggesting a coordination between the functionally related nodes of the GRN as recently shown (11). Thus, sampling longitudinally, even before the bifurcation, can reveal the pair of genes that increases their coordination and could serve as markers for the upcoming cell fate transition.…”

“…The signature of a critical state transition that can be identified by single-cell resolution analysis of cell populations consists of (i) a decrease of overall cell to cell correlation with respect to gene expression and (ii) a concomitant increase in overall gene to gene correlation across the cells (11). The first one manifests an increase in cell diversity as the attractor destabilizing and allowing access to new GRN states (lineage priming).…”

“…2 and Fig. S3) (11). These changes can be summarized by the critical transition index I C (t) computed for each measured time point t ( Fig.…”

“…The associated sudden qualitative system changes are known to produce the phenomenological signatures of a critical state transition ("tipping point") (9,10). As the cell population approaches a tipping point, we expect to observe two changes that can only be revealed by analyzing gene expression patterns at single-cell resolution: (i) increased cell population diversity because of the destabilization of the attractor and diminished "attracting force" and simultaneously, (ii) a higher coordination of gene expression across the cells as they move on a trajectory along which the attractor transition takes place (11,12).…”

“…1 A and B). A destabilization of an attractor until it vanishes formally represents a bifurcation event (11,12). The associated sudden qualitative system changes are known to produce the phenomenological signatures of a critical state transition ("tipping point") (9,10).…”