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  • 1
    Keywords: EXPRESSION ; IN-VITRO ; ACTIVATION ; mechanisms ; BONE-MARROW ; MIGRATION ; STEM-CELLS ; OXIDATIVE STRESS ; COLONY-STIMULATING FACTOR ; SDF-1 ; HEPATOCYTE GROWTH-FACTOR ; MARROW STROMAL CELLS ; Niche ; SCATTER-FACTOR
    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
    Keywords: INVASION ; PATHWAY ; GROWTH-FACTOR RECEPTOR ; endocytosis ; CELL-MIGRATION ; TUMOR-METASTASIS ; ACTIN ; SRC ; INVADOPODIA FORMATION ; PODOSOMES
    Abstract: Amplified HER2, which encodes a member of the epidermal growth factor receptor (EGFR) family, is a target of effective therapies against breast cancer. In search for similarly targetable genomic aberrations, we identified copy number gains in SYNJ2, which encodes the 5'-inositol lipid phosphatase synaptojanin 2, as well as overexpression in a small fraction of human breast tumors. Copy gain and overexpression correlated with shorter patient survival and a low abundance of the tumor suppressor microRNA miR-31. SYNJ2 promoted cell migration and invasion in culture and lung metastasis of breast tumor xenografts in mice. Knocking down SYNJ2 impaired the endocytic recycling of EGFR and the formation of cellular lamellipodia and invadopodia. Screening compound libraries identified SYNJ2-specific inhibitors that prevented cell migration but did not affect the related neural protein SYNJ1, suggesting that SYNJ2 is a potentially druggable target to block cancer cell migration.
    Type of Publication: Journal article published
    PubMed ID: 25605973
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  • 3
    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="http://www.ncbi.nlm.nih.gov/pubmed/27074509" 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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  • 4
    Publication Date: 2016-04-14
    Description: Blood vessels define local microenvironments in the skeletal system, play crucial roles in osteogenesis and provide niches for haematopoietic stem cells. The properties of niche-forming vessels and their changes in the ageing organism remain incompletely understood. Here we show that Notch signalling in endothelial cells leads to the expansion of haematopoietic stem cell niches in bone, which involves increases in CD31-positive capillaries and platelet-derived growth factor receptor-beta (PDGFRbeta)-positive perivascular cells, arteriole formation and elevated levels of cellular stem cell factor. Although endothelial hypoxia-inducible factor signalling promotes some of these changes, it fails to enhance vascular niche function because of a lack of arterialization and expansion of PDGFRbeta-positive cells. In ageing mice, niche-forming vessels in the skeletal system are strongly reduced but can be restored by activation of endothelial Notch signalling. These findings indicate that vascular niches for haematopoietic stem cells are part of complex, age-dependent microenvironments involving multiple cell populations and vessel subtypes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kusumbe, Anjali P -- Ramasamy, Saravana K -- Itkin, Tomer -- Mae, Maarja Andaloussi -- Langen, Urs H -- Betsholtz, Christer -- Lapidot, Tsvee -- Adams, Ralf H -- England -- Nature. 2016 Apr 21;532(7599):380-4. doi: 10.1038/nature17638. Epub 2016 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Munster, Faculty of Medicine, D-48149 Munster, Germany. ; Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel. ; Vascular Biology Program, Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden. ; Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Scheeles vag 2, SE-171 77 Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27074508" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/*physiology ; Animals ; Antigens, CD31/metabolism ; Arterioles/cytology/*physiology ; Bone and Bones/*blood supply/cytology/metabolism ; Capillaries/cytology/*physiology ; Cell Count ; Endothelial Cells/metabolism ; Hematopoietic Stem Cells/*cytology ; Hypoxia-Inducible Factor 1/metabolism ; Male ; Mice ; Osteogenesis ; Receptor, Platelet-Derived Growth Factor beta/metabolism ; Receptors, Notch/metabolism ; Signal Transduction ; Stem Cell Factor/metabolism ; *Stem Cell Niche
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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