1. Single-cell characterization of haematopoietic progenitors and their trajectories in homeostasis and perturbed haematopoiesis.
- Author
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Giladi A, Paul F, Herzog Y, Lubling Y, Weiner A, Yofe I, Jaitin D, Cabezas-Wallscheid N, Dress R, Ginhoux F, Trumpp A, Tanay A, and Amit I
- Subjects
- Animals, CCAAT-Enhancer-Binding Proteins genetics, CCAAT-Enhancer-Binding Proteins metabolism, CRISPR-Cas Systems, Cell Lineage genetics, Cell Proliferation genetics, Cells, Cultured, Cellular Senescence genetics, Erythropoietin pharmacology, Female, Filgrastim pharmacology, Gene Editing, Gene Expression Regulation, Genotype, Hematinics pharmacology, Hematopoiesis drug effects, Hematopoietic Stem Cells drug effects, Hematopoietic Stem Cells metabolism, Homeostasis, Interferon Regulatory Factors genetics, Interferon Regulatory Factors metabolism, Mice, Inbred C57BL, Phenotype, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Recombinant Proteins pharmacology, Time Factors, Trans-Activators genetics, Trans-Activators metabolism, Gene Expression Profiling methods, Hematopoiesis genetics, Hematopoietic Stem Cells physiology, Single-Cell Analysis methods, Transcriptome
- Abstract
The dynamics of haematopoietic stem cell differentiation and the hierarchy of oligopotent stem cells in the bone marrow remain controversial. Here we dissect haematopoietic progenitor populations at single cell resolution, deriving an unbiased reference model of transcriptional states in normal and perturbed murine bone marrow. We define the signature of the naive haematopoietic stem cell and find a continuum of core progenitor states. Core cell populations mix transcription of pre-myeloid and pre-lymphoid programs, but do not mix erythroid or megakaryocyte programs with other fates. CRISP-seq perturbation analysis confirms our models and reveals that Cebpa regulates entry into all myeloid fates, while Irf8 and PU.1 deficiency block later differentiation towards monocyte or granulocyte fates. Our transcriptional map defines a reference network model for blood progenitors and their differentiation trajectories during normal and perturbed haematopoiesis.
- Published
- 2018
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