title: Wild-type macrophages reverse disease in heme oxygenase 1-deficient mice.
abstract: Loss-of-function mutation in the heme oxygenase 1 (Hmox1) gene causes a rare and lethal disease in children, characterized by severe anemia and intravascular hemolysis, with damage to endothelia and kidneys. Previously, we found that macrophages engaged in recycling of red cells were depleted from the tissues of Hmox1(-/-) mice, which resulted in intravascular hemolysis and severe damage to the endothelial system, kidneys, and other organs. Here, we report that subablative bone marrow transplantation (BMT) has a curative effect for disease in Hmox1(-/-) animals as a result of restoration of heme recycling by repopulation of the tissues with wild-type macrophages. Although engraftment was transient, BMT reversed anemia, normalized blood chemistries and iron metabolism parameters, and prevented renal damage. The largest proportion of donor-derived cells was observed in the livers of transplanted animals. These cells, identified as Kupffer cells with high levels of Hmox1 expression, persisted months after transient engraftment of the donor bone marrow and were responsible for the full restoration of heme-recycling ability in Hmox1(-/-) mice and reversing Hmox1-deficient phenotype. Our findings suggest that BMT or the development of specific cell therapies to repopulate patients' tissues with wild-type or reengineered macrophages represent promising approaches for HMOX1 deficiency treatment in humans.
authors: Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD;
authors: Gennadiy
authors: G
authors: Kovtunovych
authors: Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD;
authors: Manik C
authors: MC
authors: Ghosh
authors: Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD;
authors: Wade
authors: W
authors: Ollivierre
authors: Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD;
authors: R Patrick
authors: RP
authors: Weitzel
authors: Division of Veterinary Resources, Office of Research Services, Office of the Director, National Institutes of Health, Bethesda, MD; and.
authors: Michael A
authors: MA
authors: Eckhaus
authors: Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD;
authors: John F
authors: JF
authors: Tisdale
authors: Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
authors: Akihiro
authors: A
authors: Yachie
authors: Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD;
authors: Tracey A
authors: TA
authors: Rouault
mesh_terms: D000745:Anemia, Hemolytic, Congenital / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D000818:Animals; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D005260:Female; D006418:Heme / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007728:Kupffer Cells / Q000378:metabolism* / Q000637:transplantation; D008264:Macrophages / Q000378:metabolism* / Q000637:transplantation; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress
chemical_list: D008565:Membrane Proteins; D006418:Heme; D007501:Iron; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse