title: Inferring Cell-State Transition Dynamics from Lineage Trees and Endpoint Single-Cell Measurements.
abstract: As they proliferate, living cells undergo transitions between specific molecularly and developmentally distinct states. Despite the functional centrality of these transitions in multicellular organisms, it has remained challenging to determine which transitions occur and at what rates without perturbations and cell engineering. Here, we introduce kin correlation analysis (KCA) and show that quantitative cell-state transition dynamics can be inferred, without direct observation, from the clustering of cell states on pedigrees (lineage trees). Combining KCA with pedigrees obtained from time-lapse imaging and endpoint single-molecule RNA-fluorescence in situ hybridization (RNA-FISH) measurements of gene expression, we determined the cell-state transition network of mouse embryonic stem (ES) cells. This analysis revealed that mouse ES cells exhibit stochastic and reversible transitions along a linear chain of states ranging from 2C-like to epiblast-like. Our approach is broadly applicable and may be applied to systems with irreversible transitions and non-stationary dynamics, such as in cancer and development.
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Kavli Institute for Theoretical Physics, University of California, Santa Barbara, CA 93106, USA.
authors.forename: Sahand
authors.initials: S
authors.lastname: Hormoz
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Zakary S
authors.initials: ZS
authors.lastname: Singer
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Linton
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Yaron E
authors.initials: YE
authors.lastname: Antebi
authors.affiliation: Kavli Institute for Theoretical Physics, University of California, Santa Barbara, CA 93106, USA. Electronic address: shraiman@kitp.ucsb.edu.
authors.forename: Boris I
authors.initials: BI
authors.lastname: Shraiman
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Howard Hughes Medical Institute (HHMI) and Department of Applied Physics, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: melowitz@caltech.edu.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Elowitz
mesh_terms: D000818:Animals; D019070:Cell Lineage; D053595:Embryonic Stem Cells; D018507:Gene Expression Regulation, Developmental; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008954:Models, Biological; D000066450:Mouse Embryonic Stem Cells; D059010:Single-Cell Analysis
keywords: cell state transition; dynamics; heterogeneity; inference; lineage; single cell; single-molecule FISH; stem cells; stochasticity; time-lapse microscopy