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      Population Snapshots Predict Early Hematopoietic and Erythroid Hierarchies

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          Abstract

          Red cell formation begins with the differentiation of multipotent hematopoietic progenitors. Reconstructing the steps of differentiation represents a stereotypical challenge in stem cell biology. Combining single-cell transcriptomics, fate assays, and theory for predicting fate from population snapshots, we inferred a continuous, hierarchical structure of murine hematopoietic progenitors committing to seven blood lineages. We uncovered coupling between erythroid and basophil/mast cell fates, a global hematopoietic response to erythroid stress, and novel growth factor receptor regulators of erythropoiesis. We also defined a new flow-cytometric sorting strategy to purify progressive early stages of erythroid differentiation, completely isolating classically-defined burst-forming (BFU-e) and colony-forming progenitors (CFU-e). Intriguingly, profound remodeling of the cell cycle is intimately entwined with erythroid development and with a sharp transcriptional switch that extinguishes the CFU-e stage and activates terminal differentiation. Our work showcases the utility of theory linking transcriptomic data to predictive fate models, providing insights into lineage development in vivo.

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          Most cited references49

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            Identification of clonogenic common lymphoid progenitors in mouse bone marrow.

            The existence of a common lymphoid progenitor that can only give rise to T cells, B cells, and natural killer (NK) cells remains controversial and constitutes an important gap in the hematopoietic lineage maps. Here, we report that the Lin(-)IL-7R(+)Thy-1(-)Sca-1loc-Kit(lo) population from adult mouse bone marrow possessed a rapid lymphoid-restricted (T, B, and NK) reconstitution capacity in vivo but completely lacked myeloid differentiation potential either in vivo or in vitro. A single Lin(-)IL-7R(+)Thy-1(-)Sca-1loc-Kit(lo) cell could generate at least both T and B cells. These data provide direct evidence for the existence of common lymphoid progenitors in sites of early hematopoiesis.
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              Single-Cell RNA-Seq with Waterfall Reveals Molecular Cascades underlying Adult Neurogenesis.

              Somatic stem cells contribute to tissue ontogenesis, homeostasis, and regeneration through sequential processes. Systematic molecular analysis of stem cell behavior is challenging because classic approaches cannot resolve cellular heterogeneity or capture developmental dynamics. Here we provide a comprehensive resource of single-cell transcriptomes of adult hippocampal quiescent neural stem cells (qNSCs) and their immediate progeny. We further developed Waterfall, a bioinformatic pipeline, to statistically quantify singe-cell gene expression along a de novo reconstructed continuous developmental trajectory. Our study reveals molecular signatures of adult qNSCs, characterized by active niche signaling integration and low protein translation capacity. Our analyses further delineate molecular cascades underlying qNSC activation and neurogenesis initiation, exemplified by decreased extrinsic signaling capacity, primed translational machinery, and regulatory switches in transcription factors, metabolism, and energy sources. Our study reveals the molecular continuum underlying adult neurogenesis and illustrates how Waterfall can be used for single-cell omics analyses of various continuous biological processes.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                16 March 2018
                21 February 2018
                01 March 2018
                21 August 2018
                : 555
                : 7694
                : 54-60
                Affiliations
                [1 ]Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA
                [2 ]Department of Systems Biology, Harvard Medical School, Boston, MA
                [3 ]Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
                [4 ]Division of Immunology, Department of Microbiology and Immunobiology and Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA
                Author notes
                [# ]Corresponding authors: Merav Socolovsky, Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, 364 Plantation Street, LRB Room 405, Worcester, MA 01605, USA, Office: (508) 856 3743, lab: (508) 856 3704, cell: (617) 797 1633, fax: (508) 856 1310, merav.socolovsky@ 123456umassmed.edu ; Allon M. Klein, Department of Systems Biology, Harvard Medical School, Boston, MA, Office: (617) 432 7147, cell: (617) 792 5601, allon_klein@ 123456hms.harvard.edu
                [*]

                Contributed equally to this work

                Article
                NIHMS934423
                10.1038/nature25741
                5899604
                29466336
                7cbf00b6-6d2c-4154-8573-297b68360db8

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