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Endothelial Cell-Selective Adhesion Molecule Expression in Hematopoietic Stem/Progenitor Cells Is Essential for Erythropoiesis Recovery after Bone Marrow Injury

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      Abstract

      Numerous red blood cells are generated every second from proliferative progenitor cells under a homeostatic state. Increased erythropoietic activity is required after myelo-suppression as a result of chemo-radio therapies. Our previous study revealed that the endothelial cell-selective adhesion molecule (ESAM), an authentic hematopoietic stem cell marker, plays essential roles in stress-induced hematopoiesis. To determine the physiological importance of ESAM in erythroid recovery, ESAM-knockout (KO) mice were treated with the anti-cancer drug, 5-fluorouracil (5-FU). ESAM-KO mice experienced severe and prolonged anemia after 5-FU treatment compared to wild-type (WT) mice. Eight days after the 5-FU injection, compared to WT mice, ESAM-KO mice showed reduced numbers of erythroid progenitors in bone marrow (BM) and spleen, and reticulocytes in peripheral blood. Megakaryocyte-erythrocyte progenitors (MEPs) from the BM of 5-FU-treated ESAM-KO mice showed reduced burst forming unit-erythrocyte (BFU-E) capacities than those from WT mice. BM transplantation revealed that hematopoietic stem/progenitor cells from ESAM-KO donors were more sensitive to 5-FU treatment than that from WT donors in the WT host mice. However, hematopoietic cells from WT donors transplanted into ESAM-KO host mice could normally reconstitute the erythroid lineage after a BM injury. These results suggested that ESAM expression in hematopoietic cells, but not environmental cells, is critical for hematopoietic recovery. We also found that 5-FU treatment induces the up-regulation of ESAM in primitive erythroid progenitors and macrophages that do not express ESAM under homeostatic conditions. The phenotypic change seen in macrophages might be functionally involved in the interaction between erythroid progenitors and their niche components during stress-induced acute erythropoiesis. Microarray analyses of primitive erythroid progenitors from 5-FU-treated WT and ESAM-KO mice revealed that various signaling pathways, including the GATA1 system, were impaired in ESAM-KO mice. Thus, our data demonstrate that ESAM expression in hematopoietic progenitors is essential for erythroid recovery after a BM injury.

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      Most cited references 37

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      A clonogenic common myeloid progenitor that gives rise to all myeloid lineages.

      Haematopoietic stem cells give rise to progeny that progressively lose self-renewal capacity and become restricted to one lineage. The points at which haematopoietic stem cell-derived progenitors commit to each of the various lineages remain mostly unknown. We have identified a clonogenic common lymphoid progenitor that can differentiate into T, B and natural killer cells but not myeloid cells. Here we report the prospective identification, purification and characterization, using cell-surface markers and flow cytometry, of a complementary clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Common myeloid progenitors give rise to either megakaryocyte/erythrocyte or granulocyte/macrophage progenitors. Purified progenitors were used to provide a first-pass expression profile of various haematopoiesis-related genes. We propose that the common lymphoid progenitor and common myeloid progenitor populations reflect the earliest branch points between the lymphoid and myeloid lineages, and that the commitment of common myeloid progenitors to either the megakaryocyte/erythrocyte or the granulocyte/macrophage lineages are mutually exclusive events.
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        Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche

        Hematopoietic stem cells (HSCs) reside in specialized bone marrow (BM) niches regulated by the sympathetic nervous system (SNS). Here, we have examined whether mononuclear phagocytes modulate the HSC niche. We defined three populations of BM mononuclear phagocytes that include Gr-1hi monocytes (MOs), Gr-1lo MOs, and macrophages (MΦ) based on differential expression of Gr-1, CD115, F4/80, and CD169. Using MO and MΦ conditional depletion models, we found that reductions in BM mononuclear phagocytes led to reduced BM CXCL12 levels, the selective down-regulation of HSC retention genes in Nestin+ niche cells, and egress of HSCs/progenitors to the bloodstream. Furthermore, specific depletion of CD169+ MΦ, which spares BM MOs, was sufficient to induce HSC/progenitor egress. MΦ depletion also enhanced mobilization induced by a CXCR4 antagonist or granulocyte colony-stimulating factor. These results highlight two antagonistic, tightly balanced pathways that regulate maintenance of HSCs/progenitors in the niche during homeostasis, in which MΦ cross talk with the Nestin+ niche cell promotes retention, and in contrast, SNS signals enhance egress. Thus, strategies that target BM MΦ hold the potential to augment stem cell yields in patients that mobilize HSCs/progenitors poorly.
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          Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy.

          The major myeloid blood cell lineages are generated from hematopoietic stem cells by differentiation through a series of increasingly committed progenitor cells. Precise characterization of intermediate progenitors is important for understanding fundamental differentiation processes and a variety of disease states, including leukemia. Here, we evaluated the functional in vitro and in vivo potentials of a range of prospectively isolated myeloid precursors with differential expression of CD150, Endoglin, and CD41. Our studies revealed a hierarchy of myeloerythroid progenitors with distinct lineage potentials. The global gene expression signatures of these subsets were consistent with their functional capacities, and hierarchical clustering analysis suggested likely lineage relationships. These studies provide valuable tools for understanding myeloid lineage commitment, including isolation of an early erythroid-restricted precursor, and add to existing models of hematopoietic differentiation by suggesting that progenitors of the innate and adaptive immune system can separate late, following the divergence of megakaryocytic/erythroid potential.
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            Author and article information

            Affiliations
            [1 ]Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
            [2 ]DNA Chip Development Center, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
            B.C. Cancer Agency, CANADA
            Author notes

            Competing Interests: The authors have declared that no competing interests exist.

            Conceived and designed the experiments: TS TY KO YK. Performed the experiments: TS TU TY MI T. Ishibashi T. Isono YH. Analyzed the data: TS DO. Wrote the paper: TS TY.

            Contributors
            Role: Editor
            Journal
            PLoS One
            PLoS ONE
            plos
            plosone
            PLoS ONE
            Public Library of Science (San Francisco, CA USA )
            1932-6203
            25 April 2016
            2016
            : 11
            : 4
            27111450 4844162 10.1371/journal.pone.0154189 PONE-D-15-48949
            © 2016 Sudo et al

            This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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            Figures: 6, Tables: 0, Pages: 20
            Product
            Funding
            Funded by: funder-id http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
            Award ID: 25461416
            Award Recipient :
            Funded by: funder-id http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
            Award ID: 15K09475
            Award Recipient :
            This work was supported by Grants-in-Aid for Scientific Research (JSPS KAKENHI) Grant Number 25461416. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Categories
            Research Article
            Biology and Life Sciences
            Physiology
            Immune Physiology
            Spleen
            Medicine and Health Sciences
            Physiology
            Immune Physiology
            Spleen
            Biology and Life Sciences
            Physiology
            Physiological Processes
            Erythropoiesis
            Medicine and Health Sciences
            Physiology
            Physiological Processes
            Erythropoiesis
            Biology and Life Sciences
            Genetics
            Gene Expression
            Biology and Life Sciences
            Cell Biology
            Cellular Types
            Animal Cells
            Blood Cells
            White Blood Cells
            Macrophages
            Biology and Life Sciences
            Cell Biology
            Cellular Types
            Animal Cells
            Immune Cells
            White Blood Cells
            Macrophages
            Biology and Life Sciences
            Immunology
            Immune Cells
            White Blood Cells
            Macrophages
            Medicine and Health Sciences
            Immunology
            Immune Cells
            White Blood Cells
            Macrophages
            Medicine and Health Sciences
            Hematology
            Anemia
            Biology and Life Sciences
            Cell Biology
            Cellular Types
            Animal Cells
            Bone Marrow Cells
            Erythroblasts
            Biology and Life Sciences
            Cell Biology
            Cellular Types
            Animal Cells
            Blood Cells
            Red Blood Cells
            Erythroblasts
            Biology and Life Sciences
            Physiology
            Physiological Processes
            Homeostasis
            Medicine and Health Sciences
            Physiology
            Physiological Processes
            Homeostasis
            Medicine and Health Sciences
            Oncology
            Cancer Treatment
            Custom metadata
            Access to microarray data concerning this study can be found under GEO experiment accession number (GSE 73496). Other data are within the paper and its Supporting Information files.

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