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  • 1
    Abstract: Mechanisms governing stress-induced hematopoietic progenitor cell mobilization are not fully deciphered. We report that during granulocyte colony-stimulating factor-induced mobilization c-Met expression and signaling are up-regulated on immature bone marrow progenitors. Interestingly, stromal cell-derived factor 1/CXC chemokine receptor-4 signaling induced hepatocyte growth factor production and c-Met activation. We found that c-Met inhibition reduced mobilization of both immature progenitors and the more primitive Sca-1(+)/c-Kit(+)/Lin(-) cells and interfered with their enhanced chemotactic migration to stromal cell-derived factor 1. c-Met activation resulted in cellular accumulation of reactive oxygen species by mammalian target of rapamycin inhibition of Forkhead Box, subclass O3a. Blockage of mammalian target of rapamycin inhibition or reactive oxygen species signaling impaired c-Met-mediated mobilization. Our data show dynamic c-Met expression and function in the bone marrow and show that enhanced c-Met signaling is crucial to facilitate stress-induced mobilization of progenitor cells as part of host defense and repair mechanisms.
    Type of Publication: Journal article published
    PubMed ID: 20585044
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  • 2
    Publication Date: 2016-04-14
    Description: Bone marrow endothelial cells (BMECs) form a network of blood vessels that regulate both leukocyte trafficking and haematopoietic stem and progenitor cell (HSPC) maintenance. However, it is not clear how BMECs balance these dual roles, and whether these events occur at the same vascular site. We found that mammalian bone marrow stem cell maintenance and leukocyte trafficking are regulated by distinct blood vessel types with different permeability properties. Less permeable arterial blood vessels maintain haematopoietic stem cells in a low reactive oxygen species (ROS) state, whereas the more permeable sinusoids promote HSPC activation and are the exclusive site for immature and mature leukocyte trafficking to and from the bone marrow. A functional consequence of high permeability of blood vessels is that exposure to blood plasma increases bone marrow HSPC ROS levels, augmenting their migration and differentiation, while compromising their long-term repopulation and survival. These findings may have relevance for clinical haematopoietic stem cell transplantation and mobilization protocols.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Itkin, Tomer -- Gur-Cohen, Shiri -- Spencer, Joel A -- Schajnovitz, Amir -- Ramasamy, Saravana K -- Kusumbe, Anjali P -- Ledergor, Guy -- Jung, Yookyung -- Milo, Idan -- Poulos, Michael G -- Kalinkovich, Alexander -- Ludin, Aya -- Kollet, Orit -- Shakhar, Guy -- Butler, Jason M -- Rafii, Shahin -- Adams, Ralf H -- Scadden, David T -- Lin, Charles P -- Lapidot, Tsvee -- EB017274/EB/NIBIB NIH HHS/ -- HL100402/HL/NHLBI NIH HHS/ -- R01 EB017274/EB/NIBIB NIH HHS/ -- U01 HL100402/HL/NHLBI NIH HHS/ -- England -- Nature. 2016 Apr 21;532(7599):323-8. doi: 10.1038/nature17624. Epub 2016 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel. ; Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. ; Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. ; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; Harvard Stem Cell Institute, Cambridge, Massachusetts 02114, USA. ; Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis and Faculty of Medicine, University of Munster, D-48149 Munster, Germany. ; Internal Medicine Department, Tel-Aviv Sourasky Medical Center, Tel-Aviv 64239, Israel. ; Department of Genetic Medicine, Weill Cornell Medical College, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Ly/metabolism ; Arteries/cytology/physiology ; Blood Vessels/*cytology/*physiology ; Bone Marrow/*blood supply ; Bone Marrow Cells/cytology ; Cell Differentiation ; Cell Movement ; Cell Self Renewal ; Cell Survival ; Chemokine CXCL12/metabolism ; Endothelial Cells/physiology ; Female ; *Hematopoiesis ; Hematopoietic Stem Cell Mobilization ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/cytology ; Leukocytes/cytology ; Male ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Nestin/metabolism ; Pericytes/physiology ; Permeability ; Plasma/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, CXCR4/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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