title: 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 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.
authors.affiliation: Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.|Institute for Systems Biology, Seattle, Washington, United States of America.
authors.forename: Mitra
authors.initials: M
authors.lastname: Mojtahedi
authors.affiliation: Institute for Systems Biology, Seattle, Washington, United States of America.|Luxembourg Centre for Systems Biomedicine, Esch-sur Alzette, Luxembourg.
authors.forename: Alexander
authors.initials: A
authors.lastname: Skupin
authors.affiliation: Institute for Systems Biology, Seattle, Washington, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.|Corporación Parque Explora, Department of innovation and design, Medellin, Colombia.
authors.forename: Ivan G
authors.initials: IG
authors.lastname: Castaño
authors.affiliation: Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Rebecca Y Y
authors.initials: RY
authors.lastname: Leong-Quong
authors.affiliation: 5AM Ventures, Menlo Park, California, United States of America.
authors.forename: Hannah
authors.initials: H
authors.lastname: Chang
authors.affiliation: Institute for Systems Biology, Seattle, Washington, United States of America.
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Trachana
authors.affiliation: Environment and Health Department, Istituto Superiore di Sanità, Roma, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giuliani
authors.affiliation: Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.|Institute for Systems Biology, Seattle, Washington, United States of America.
authors.forename: Sui
authors.initials: S
authors.lastname: Huang
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D020869:Gene Expression Profiling; D059010:Single-Cell Analysis