Cell Fate Decision as High-Dimensional Critical State Transition

Mitra Mojtahedi, Alexander Skupin, Joseph Zhou, Ivan G Castaño, Rebecca Y Y Leong-Quong, Hannah Chang, Kalliopi Trachana, Alessandro Giuliani and Sui Huang

PLOS Biology, 2016, vol. 14, issue 12, 1-28

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.Author Summary: A 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 diversified, manifesting the predicted flattening of an attractor’s potential well, which allows the increasingly vacillating progenitor cells to “spill” into adjacent potential wells corresponding to either lineage—myeloid or erythroid. This destabilization of an old stable state until suddenly opening access to new stable states is consistent with a critical transition (tipping point). We propose and demonstrate a new type of early warning signal that precedes critical transitions: an index IC based on a change in the high-dimensional cell population structure obtained from single-cell resolution measurements. This index may be used to predict imminent tipping point–like transitions in multicell systems, e.g., before pathological changes in tissues.

Date: 2016
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pbio00:2000640

DOI: 10.1371/journal.pbio.2000640

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