Cell fate-decision as high-dimensional critical state transition

Cell fate choice and commitment of multipotent progenitor cells to a differentiated lineage requires broad changes of their gene expression profile. However, how progenitor cells overcome the stability of their robust gene expression configuration (attractor) and exit their state remains elusive. Here we show that commitment of blood progenitor cells to the erythroid or the myeloid lineage is preceded by the destabilization of their high-dimensional attractor state and that 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: decrease of correlation between cells with concomitant increase of correlation between genes as cells approach a tipping point. The detection of \"rebellious cells\" which enter the fate opposite to the one intended corroborates the model of preceding destabilization of the progenitor state. Thus, \"early-warning signals\" associated with critical transitions can be detected in statistical ensembles of high-dimensional systems, offering a formal tool for analyzing single-cells molecular profiles that goes beyond computational pattern recognition but is based on dynamical systems theory and can predict impending major shifts in cell populations in development and disease.