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      From single cells to tissue self‐organization

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          Abstract

          Self‐organization is a process by which interacting cells organize and arrange themselves in higher order structures and patterns. To achieve this, cells must have molecular mechanisms to sense their complex local environment and interpret it to respond accordingly. A combination of cell‐intrinsic and cell‐extrinsic cues are decoded by the single cells dictating their behaviour, their differentiation and symmetry‐breaking potential driving development, tissue remodeling and regenerative processes. A unifying property of these self‐organized pattern‐forming systems is the importance of fluctuations, cell‐to‐cell variability, or noise. Cell‐to‐cell variability is an inherent and emergent property of populations of cells that maximize the population performance instead of the individual cell, providing tissues the flexibility to develop and maintain homeostasis in diverse environments. In this review, we will explore the role of self‐organization and cell‐to‐cell variability as fundamental properties of multicellularity—and the requisite of single‐cell resolution for its understanding. Moreover, we will analyze how single cells generate emergent multicellular dynamics observed at the tissue level ‘travelling’ across different scales: spatial, temporal and functional.

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          Most cited references146

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          Reconstruction of zebrafish early embryonic development by scanned light sheet microscopy.

          A long-standing goal of biology is to map the behavior of all cells during vertebrate embryogenesis. We developed digital scanned laser light sheet fluorescence microscopy and recorded nuclei localization and movement in entire wild-type and mutant zebrafish embryos over the first 24 hours of development. Multiview in vivo imaging at 1.5 billion voxels per minute provides "digital embryos," that is, comprehensive databases of cell positions, divisions, and migratory tracks. Our analysis of global cell division patterns reveals a maternally defined initial morphodynamic symmetry break, which identifies the embryonic body axis. We further derive a model of germ layer formation and show that the mesendoderm forms from one-third of the embryo's cells in a single event. Our digital embryos, with 55 million nucleus entries, are provided as a resource.
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            Transcriptome-wide noise controls lineage choice in mammalian progenitor cells.

            Phenotypic cell-to-cell variability within clonal populations may be a manifestation of 'gene expression noise', or it may reflect stable phenotypic variants. Such 'non-genetic cell individuality' can arise from the slow fluctuations of protein levels in mammalian cells. These fluctuations produce persistent cell individuality, thereby rendering a clonal population heterogeneous. However, it remains unknown whether this heterogeneity may account for the stochasticity of cell fate decisions in stem cells. Here we show that in clonal populations of mouse haematopoietic progenitor cells, spontaneous 'outlier' cells with either extremely high or low expression levels of the stem cell marker Sca-1 (also known as Ly6a; ref. 9) reconstitute the parental distribution of Sca-1 but do so only after more than one week. This slow relaxation is described by a gaussian mixture model that incorporates noise-driven transitions between discrete subpopulations, suggesting hidden multi-stability within one cell type. Despite clonality, the Sca-1 outliers had distinct transcriptomes. Although their unique gene expression profiles eventually reverted to that of the median cells, revealing an attractor state, they lasted long enough to confer a greatly different proclivity for choosing either the erythroid or the myeloid lineage. Preference in lineage choice was associated with increased expression of lineage-specific transcription factors, such as a >200-fold increase in Gata1 (ref. 10) among the erythroid-prone cells, or a >15-fold increased PU.1 (Sfpi1) (ref. 11) expression among myeloid-prone cells. Thus, clonal heterogeneity of gene expression level is not due to independent noise in the expression of individual genes, but reflects metastable states of a slowly fluctuating transcriptome that is distinct in individual cells and may govern the reversible, stochastic priming of multipotent progenitor cells in cell fate decision.
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              Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture.

              Mouse embryonic stem (ES) cells are competent for production of all fetal and adult cell types. However, the utility of ES cells as a developmental model or as a source of defined cell populations for pharmaceutical screening or transplantation is compromised because their differentiation in vitro is poorly controlled. Specification of primary lineages is not understood and consequently differentiation protocols are empirical, yielding variable and heterogeneous outcomes. Here we report that neither multicellular aggregation nor coculture is necessary for ES cells to commit efficiently to a neural fate. In adherent monoculture, elimination of inductive signals for alternative fates is sufficient for ES cells to develop into neural precursors. This process is not a simple default pathway, however, but requires autocrine fibroblast growth factor (FGF). Using flow cytometry quantitation and recording of individual colonies, we establish that the bulk of ES cells undergo neural conversion. The neural precursors can be purified to homogeneity by fluorescence activated cell sorting (FACS) or drug selection. This system provides a platform for defining the molecular machinery of neural commitment and optimizing the efficiency of neuronal and glial cell production from pluripotent mammalian stem cells.
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                Author and article information

                Contributors
                prisca.liberali@fmi.ch
                Journal
                FEBS J
                FEBS J
                10.1111/(ISSN)1742-4658
                FEBS
                The Febs Journal
                John Wiley and Sons Inc. (Hoboken )
                1742-464X
                1742-4658
                19 November 2018
                April 2019
                : 286
                : 8 , Focus Issue: Single‐cell analyses ( doiID: 10.1111/febs.2019.286.issue-8 )
                : 1495-1513
                Affiliations
                [ 1 ] Friedrich Miescher Institute for Biomedical Research (FMI) Basel Switzerland
                [ 2 ] University of Basel Switzerland
                Author notes
                [*] [* ] Correspondence

                P. Liberali, Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, 4058 Basel, Switzerland

                Fax: +41 61 69 73976

                Tel: +41 61 69 76651

                E‐mail: prisca.liberali@ 123456fmi.ch

                Article
                FEBS14694
                10.1111/febs.14694
                6519261
                30390414
                fa33403c-9d67-44fb-87e3-a7c281d6998e
                © 2018 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 27 July 2018
                : 10 October 2018
                : 02 November 2018
                Page count
                Figures: 3, Tables: 0, Pages: 19, Words: 13530
                Funding
                Funded by: Swiss initiative in Systems Biology, Systemsx.ch
                Funded by: Swiss National Science Foundation
                Award ID: POOP3_157531
                Award ID: PMPD3_171365
                Funded by: European Research Council (ERC) under the European Union's Horizon 2020
                Award ID: 758617
                Categories
                Review Article
                Review Articles
                Custom metadata
                2.0
                febs14694
                April 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:15.05.2019

                Molecular biology
                cell‐to‐cell variability,crossing‐scales technologies,development,emergent properties,multicellularity,organoids,pattern formation,regeneration,self‐organization,symmetry‐breaking

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