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      Distinct bone marrow blood vessels differentially regulate hematopoiesis

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          Abstract

          Bone marrow (BM) endothelial cells (BMECs) form a network of blood vessels (BVs) which regulate both leukocyte trafficking and hematopoietic stem and progenitor cell (HSPC) maintenance. However, it is not clear how BMECs balance these dual roles and if these events occur at the same vascular site. We found that BM stem cell maintenance and leukocyte trafficking are regulated by distinct BV types with different permeability properties. Less permeable arterial BVs maintain HSCs 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 BM. A functional consequence of high BVs permeability is that exposure to blood plasma increases BM HSPC ROS levels, augmenting their migration capacity while compromising their long term repopulation and survival potential. These findings may have relevance for clinical hematopoietic stem cell transplantation and mobilization protocols.

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          Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone.

          Anjali P. Kusumbe, Saravana K. Ramasamy, Ralf H. Adams (2014)
          The mammalian skeletal system harbours a hierarchical system of mesenchymal stem cells, osteoprogenitors and osteoblasts sustaining lifelong bone formation. Osteogenesis is indispensable for the homeostatic renewal of bone as well as regenerative fracture healing, but these processes frequently decline in ageing organisms, leading to loss of bone mass and increased fracture incidence. Evidence indicates that the growth of blood vessels in bone and osteogenesis are coupled, but relatively little is known about the underlying cellular and molecular mechanisms. Here we identify a new capillary subtype in the murine skeletal system with distinct morphological, molecular and functional properties. These vessels are found in specific locations, mediate growth of the bone vasculature, generate distinct metabolic and molecular microenvironments, maintain perivascular osteoprogenitors and couple angiogenesis to osteogenesis. The abundance of these vessels and associated osteoprogenitors was strongly reduced in bone from aged animals, and pharmacological reversal of this decline allowed the restoration of bone mass.
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            Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche.

            Fumio Arai, Atsushi Hirao, Masako Ohmura … (2004)
            The quiescent state is thought to be an indispensable property for the maintenance of hematopoietic stem cells (HSCs). Interaction of HSCs with their particular microenvironments, known as the stem cell niches, is critical for adult hematopoiesis in the bone marrow (BM). Here, we demonstrate that HSCs expressing the receptor tyrosine kinase Tie2 are quiescent and antiapoptotic, and comprise a side-population (SP) of HSCs, which adhere to osteoblasts (OBs) in the BM niche. The interaction of Tie2 with its ligand Angiopoietin-1 (Ang-1) induced cobblestone formation of HSCs in vitro and maintained in vivo long-term repopulating activity of HSCs. Furthermore, Ang-1 enhanced the ability of HSCs to become quiescent and induced adhesion to bone, resulting in protection of the HSC compartment from myelosuppressive stress. These data suggest that the Tie2/Ang-1 signaling pathway plays a critical role in the maintenance of HSCs in a quiescent state in the BM niche.
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              Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells.

              Keisuke Ito, Atsushi Hirao, Fumio Arai … (2006)
              Hematopoietic stem cells (HSCs) undergo self-renewing cell divisions and maintain blood production for their lifetime. Appropriate control of HSC self-renewal is crucial for the maintenance of hematopoietic homeostasis. Here we show that activation of p38 MAPK in response to increasing levels of reactive oxygen species (ROS) limits the lifespan of HSCs in vivo. In Atm(-/-) mice, elevation of ROS levels induces HSC-specific phosphorylation of p38 MAPK accompanied by a defect in the maintenance of HSC quiescence. Inhibition of p38 MAPK rescued ROS-induced defects in HSC repopulating capacity and in the maintenance of HSC quiescence, indicating that the ROS-p38 MAPK pathway contributes to exhaustion of the stem cell population. Furthermore, prolonged treatment with an antioxidant or an inhibitor of p38 MAPK extended the lifespan of HSCs from wild-type mice in serial transplantation experiments. These data show that inactivation of p38 MAPK protects HSCs against loss of self-renewal capacity. Our characterization of molecular mechanisms that limit HSC lifespan may lead to beneficial therapies for human disease.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 0410462
                Journal ID (pubmed-jr-id): 6011
                Journal ID (nlm-ta): Nature
                Journal ID (iso-abbrev): Nature
                Title: Nature
                ISSN (Print): 0028-0836
                ISSN (Electronic): 1476-4687
                Publication date Nihms-submitted: 11 May 2016
                Publication date (Electronic): 13 April 2016
                Publication date (Print): 21 April 2016
                Publication date PMC-release: 05 April 2019
                Volume: 532
                Issue: 7599
                Pages: 323-328
                Affiliations
                [1 ]Department of Immunology, The Weizmann Institute of Science, Rehovot, 76100, Israel;
                [2 ]Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA;
                [3 ]Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA;
                [4 ]Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA;
                [5 ]Harvard Stem Cell Institute, Cambridge, MA 02114, USA;
                [6 ]Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA;
                [7 ]Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis and Faculty of Medicine, University of Münster, D-48149 Münster, Germany;
                [8 ]Internal Medicine Department, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel;
                [9 ]Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, 10065, USA
                Author notes

                AUTHOR CONTRIBUTIONS:

                T.I. designed and performed experiments, analyzed data and wrote the manuscript; S.G.C. helped in the design and execution of experiments and analyzed data; J.A.S., A.S., and J.Y. designed and performed intravital related experiment, analyzed data and helped writing the manuscript; S.K.R and A.P.K. designed and performed confocal related experiments and analyzed data; G.L., I.M., M.G.P., A.K., A.L., and O.K. helped with experiments; G.S. helped and guided in some intravital related experiments; J.M.B. and S.R. helped in design of endothelial related studies; R.H.A helped and guided in design of confocal and in vivo endothelial related experiments; D.T.S. helped and guided in design of in vivo intravital live imaging experiments and wrote the manuscript; and T.L. and C.P.L. guided and designed the research and wrote the manuscript.

                [# ] Correspondence should be addressed to: Tsvee Lapidot, Department of Immunology, Weizmann Institute of Science, Rehovot, 76100, Israel. Tel: +972-8-934-2481 Tsvee.Lapidot@ 123456weizmann.ac.il , Charles P. Lin, Wellman Center for Photomedicine and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Tel: +1-617-643-3531 charles_lin@ 123456hms.harvard.edu
                Article
                Manuscript ID: NIHMS763942
                DOI: 10.1038/nature17624
                PMC ID: 6450701
                PubMed ID: 27074509
                SO-VID: d88b43e2-4279-41d3-b01b-2409640b5f59
                License:

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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