title: The bone marrow hematopoietic microenvironment is impaired in iron-overloaded mice.
abstract: OBJECTIVE
  Increasing numbers of reports have described hematopoietic improvement after iron chelation therapy in iron-overloaded patients. These observations indicate that excess iron could affect hematopoiesis unfavorably. To investigate how excess iron affects hematopoiesis in vivo, we generated iron-overloaded mice and examined hematopoietic parameters in these mice.
  
  
  METHODS
  We generated iron-overloaded mice by injecting 200 mg of iron dextran into C57BL/6J mice, and immature hematopoietic cells in the bone marrow were evaluated by flow cytometric analyses, colony-forming assays, and bone marrow transplantation analyses. We also examined changes in molecular profiles of the hematopoietic microenvironment.
  
  
  CONCLUSIONS
  Iron-overloaded (IO) mice did not show significant defects in the hematopoietic data of the peripheral blood. Myeloid progenitor cells in the bone marrow were increased in IO mice, but the number and function of the erythroid progenitors and hematopoietic stem cells were not significantly affected. However, bone marrow transplantation from normal donors to IO recipients showed delayed hematopoietic reconstitution, which indicates that excess iron impacts the hematopoietic microenvironment negatively. Microarray and quantitative RT-PCR analyses on the bone marrow stromal cells demonstrated remarkably reduced expression of CXCL12, VCAM-1, Kit-ligand, and IGF-1 in the iron-overloaded mice. In addition, erythropoietin and thrombopoietin levels were significantly suppressed, and increased oxidative stress was observed in the IO bone marrow and liver. Consequently, our findings indicate that excess iron can damage bone marrow stromal cells and other vital organs, disrupting hematopoiesis presumably by increased oxidative stress.
authors.affiliation: Division of Hematology, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okabe
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Eisuke
authors.initials: E
authors.lastname: Uehara
authors.forename: Masuzu
authors.initials: M
authors.lastname: Ueda
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nagai
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D060833:Cellular Microenvironment / Q000235:genetics*; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D019190:Iron Overload / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007505:Iron-Dextran Complex; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D018384:Oxidative Stress; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism; D013926:Thrombopoietin / Q000235:genetics / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019089:Stem Cell Factor; D019010:Vascular Cell Adhesion Molecule-1; D004921:Erythropoietin; D007334:Insulin-Like Growth Factor I; D007505:Iron-Dextran Complex; D013926:Thrombopoietin
keywords: bone marrow microenvironment; erythropoietin; hematopoiesis; hematopoietic stem cell; iron overload; reactive oxygen species; thrombopoietin