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    Mapping normal and stress hematopoiesis at a single cell resolution

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    Séminaire de l'Institut Cochin

    Jeudi 14 juin 2018 - 12h00 - Salle de conférence Rosalind Franklin, 2ème étage

     


    Ioannis Aifantis

    Pathology Department of NYU Langone Medical Center,
    New York, USA

     

     invité par Julie Chaumeil

    Institut Cochin, 22 rue Méchain, 75014 Paris

     

    Résumé

    Despite the importance of the bone marrow (BM) microenvironment for the regulation of normal and leukemic hematopoiesis, the molecular complexity of the BM niche is incompletely understood. Here we map the transcriptional landscape of the BM vascular, perivascular, and osteoblast niche populations at a single cell resolution in homeostasis and under stress hematopoiesis. This analysis revealed a previously unappreciated level of cellular heterogeneity, identified novel cellular fractions, and resolved cellular sources of pro-hematopoietic growth factors, chemokines, and membrane-bound ligands. Under conditions of stress (including inflammation and irradiation), our studies identified a dramatic transcriptional remodeling of these niche elements accompanying the myeloid skewing that typifies emergency hematopoiesis. Among the stress-induced changes, a Notch ligand DLL4 was significantly downregulated in the vascular endothelium. Fluorescent reporters confirmed vascular distribution of DLL4 and vascular-specific deletion resulted in a significant loss of lymphocytes and skewing towards the myeloid lineage, indicating that the BM vascular niche can directly impact fate choices. These findings refine our understanding of the cellular architecture of the BM niche and reveal a dynamic molecular landscape that is highly sensitive to stress. They also translate single cell transcriptomic data to critical mechanistic insights into regulation of HSCs differentiation by discrete niche subpopulations. Finally, single cell RNA-Sequencing of hematopoietic stem and progenitor populations help us draw direct connections between blood cells and their putative micro-environments.

     

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