scholarly journals A composite mouse model of aplastic anemia complicated with iron overload

2017 ◽  
Author(s):  
Dijiong Wu ◽  
Xiaowen Wen ◽  
Wenbin Liu ◽  
Linlong Xu ◽  
Baodong Ye ◽  
...  
Keyword(s):  
Mouse Model ◽  
Iron Overload ◽  
Aplastic Anemia

scholarly journals Comparison of the effects of deferasirox, deferoxamine, and combination of deferasirox and deferoxamine on an aplastic anemia mouse model complicated with iron overload

2018 ◽  
Vol Volume 12 ◽  
pp. 1081-1091 ◽  
Author(s):  
Dijiong Wu ◽  
Xiaowen Wen ◽  
Wenbin Liu ◽  
Huijin Hu ◽  
Baodong Ye ◽  
...  
Keyword(s):  
Mouse Model ◽  
Iron Overload ◽  
Aplastic Anemia

Establishment of a Mouse Model of Aplastic Anemia Complicated By Iron Overload

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4555-4555
Author(s):  
Dijiong Wu ◽  
Xiaowen Wen ◽  
Baodong Ye ◽  
Wenbin Liu ◽  
Yanting Gao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mouse Model ◽  
Iron Overload ◽  
Western Blot ◽  
Aplastic Anemia ◽  
Mrna Expression ◽  
Serum Iron ◽  
Composite Model ◽  
Expression Levels ◽  
Mrna Expression Levels

Abstract Aplastic anemia (AA) is a common hematologic disease characterized by hematopoietic failure of the bone marrow and pancytopenia of the peripheral blood. Some patients with AA suffer from transfusion-induced iron overload secondary to long-term blood transfusions due to moderate and severe anemia. Topics related to iron overload and chelation therapy have recently become important in hematologic diseases, especially in hematopoietic failure. However, no animal model of AA complicated by iron overload has been developed, which affects drug research and development. The purpose of our study is to establish a mouse model of aplastic anemia complicated by iron overload. We firstly controlled the total dose of iron supplements (2.0 *103 mg/kg) and compared how serum iron and ferritin levels varied among different dosage regimens to determine the best dosage and duration for the development of an iron overload model in mice (we finally chose the 200 mg/w/kg * 10 weeks). A composite model of AA was successfully established on the principle of immune-mediated bone marrow failure: DBA/2 mice were euthanized by cervical dislocation and the thymuses were taken out using aseptic techniques for the preparation of cell suspensions of 5 * 106/mL; Balb/c mouse were given whole-body irradiation with 60Co 6.0 Gy at 1 Gy/min, after which 0.2 mL of the prepared cell suspensions was injected into each mouse via the caudal vein within 4 h. We then compared the differences in liver volume, peripheral hemogram, bone marrow pathology, serum iron, serum ferritin, pathological iron deposition in multiple organs (liver, bone marrow, spleen), liver hepcidin, bone morphogenetic protein 6 (BMP6), SMAD family member 4 (SMAD4), transferrin receptor 2 (TfR2) protein, and mRNA expression levels among the Normal Control, AA, Iron Overload, and Composite Model groups to validate the composite model and to explore the pathogenesis and features of iron overload in the composite model. The results indicated significant abnormalities in iron metabolism parameters in mice with AA, which was reflected in the significant decrease of hepcidin expression in the liver (P < 0.01) that basically paralleled the changes in BMP6, SMAD4, and TfR2. Iron Overload Group had a suppressed hepcidin, BMP6, and SMAD4 mRNA expressions in liver, but these parameters were higher than in the AA group (P < 0.01). Association with iron overload would not further downregulate the negative parameters of iron deposition in mice with AA, and SMAD4 and TfR2 protein levels and hepcidin and SMAD4 mRNA expression levels were lower in the AA group than in the Composite Model group (P < 0.01 or P < 0.05). (see Fig.1 and Fig.2) The established model is basically consistent with the clinical manifestations and pathogenesis of AA complicated by transfusion-induced iron overload. This successful establishment will help in the screening of iron chelation drugs and studies on pharmacological mechanisms. Figure 1. Western-blot a nalysis of hepcidin, BMP6, SMAD4 and TfR2 expression among groups Figure 1. Western-blot a nalysis of hepcidin, BMP6, SMAD4 and TfR2 expression among groups Figure 2. Analysis of hepcidin, BMP6, SMAD4 and TfR2 mRNA expression levels among different groups Figure 2. Analysis of hepcidin, BMP6, SMAD4 and TfR2 mRNA expression levels among different groups Disclosures No relevant conflicts of interest to declare.

scholarly journals Effect of Systemic Iron Overload and a Chelation Therapy in a Mouse Model of the Neurodegenerative Disease Hereditary Ferritinopathy

PLoS ONE ◽  
2016 ◽  
Vol 11 (8) ◽  
pp. e0161341 ◽  
Author(s):  
Holly J. Garringer ◽  
Jose M. Irimia ◽  
Wei Li ◽  
Charles B. Goodwin ◽  
Briana Richine ◽  
...  
Keyword(s):  
Mouse Model ◽  
Iron Overload ◽  
Neurodegenerative Disease ◽  
Chelation Therapy

Lentiviral gene transfer regenerates hematopoietic stem cells in a mouse model for Mpl-deficient aplastic anemia

Blood ◽  
2011 ◽  
Vol 117 (14) ◽  
pp. 3737-3747 ◽  
Author(s):  
Dirk Heckl ◽  
Daniel C. Wicke ◽  
Martijn H. Brugman ◽  
Johann Meyer ◽  
Axel Schambach ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mouse Model ◽  
Hematopoietic Stem Cells ◽  
Aplastic Anemia ◽  
Bone Marrow Cells ◽  
Specific Expression ◽  
Hematopoietic Stem ◽  
Egfp Reporter

AbstractThpo/Mpl signaling plays an important role in the maintenance of hematopoietic stem cells (HSCs) in addition to its role in megakaryopoiesis. Patients with inactivating mutations in Mpl develop thrombocytopenia and aplastic anemia because of progressive loss of HSCs. Yet, it is unknown whether this loss of HSCs is an irreversible process. In this study, we used the Mpl knockout (Mpl−/−) mouse model and expressed Mpl from newly developed lentiviral vectors specifically in the physiologic Mpl target populations, namely, HSCs and megakaryocytes. After validating lineage-specific expression in vivo using lentiviral eGFP reporter vectors, we performed bone marrow transplantation of transduced Mpl−/− bone marrow cells into Mpl−/− mice. We show that restoration of Mpl expression from transcriptionally targeted vectors prevents lethal adverse reactions of ectopic Mpl expression, replenishes the HSC pool, restores stem cell properties, and corrects platelet production. In some mice, megakaryocyte counts were atypically high, accompanied by bone neo-formation and marrow fibrosis. Gene-corrected Mpl−/− cells had increased long-term repopulating potential, with a marked increase in lineage−Sca1+cKit+ cells and early progenitor populations in reconstituted mice. Transcriptome analysis of lineage−Sca1+cKit+ cells in Mpl-corrected mice showed functional adjustment of genes involved in HSC self-renewal.

scholarly journals mRNA regulation of cardiac iron transporters and ferritin subunits in a mouse model of iron overload

2014 ◽  
Vol 42 (12) ◽  
pp. 1059-1067 ◽  
Author(s):  
Casey J. Brewer ◽  
Ruth I. Wood ◽  
John C. Wood
Keyword(s):  
Mouse Model ◽  
Iron Overload ◽  
Mrna Regulation ◽  
Cardiac Iron

Iron Stores in Patients with Myelodysplasia and Aplastic Anemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3726-3726
Author(s):  
Peter Nielsen ◽  
Tim H. Bruemmendorf ◽  
Regine Grosse ◽  
Rainer Engelhardt ◽  
Nicolaus Kroeger ◽  
...  
Keyword(s):  
Risk Factor ◽  
Iron Overload ◽  
Aplastic Anemia ◽  
Myelodysplastic Syndromes ◽  
Iron Concentration ◽  
Dry Weight ◽  
Iron Toxicity ◽  
Intervention Threshold ◽  
Liver Iron Concentration ◽  
Liver Iron

Abstract Patients with myelodysplastic syndromes (MDS), osteomyelofibrosis (OMF), or severe aplastic anemia (SAA) suffer from ineffective erythropoiesis due to pancytopenia, which is treated with red blood cell transfusion leading to iron overload. Especially in low-risk patients with mean survival times of > 5 years, potentially toxic levels of liver iron concentration (LIC) can be reached. We hypothesize that the higher morbidity seen in transfused patients may be influenced by iron toxicity. Following a meeting in Nagasaki 2005, a consensus statement on iron overload in myelodysplastic syndromes has been published, however, there is still no common agreement about the initiation of chelation treatment in MDS patients. In the present study, a total of 67 transfused patients with MDS (n = 20, age: 17 – 75 y), OMF (n = 4, age: 48 – 68 y), SAA (n = 43, age: 5 – 64 y) were measured by SQUID biomagnetic liver susceptometry (BLS) and their liver and spleen volumes were scanned by ultrasound at the Hamburg biosusceptometer. Less than 50 % were treated with DFO. LIC (μg/g-liver wet weight, conversion factor of about 6 for μg/g-dry weight) and volume data were retrospectively analyzed in comparison to ferritin values. Additionally, 15 patients (age: 8 – 55 y) between 1 and 78 months after hematopoietic cell transplantation (HCT) were measured and analyzed. LIC values ranged from 149 to 8404 with a median value of 2705 μg/g-liver, while serum ferritin (SF) concentrations were between 500 and 10396 μg/l with a median ratio of SF/LIC = 0.9 [(μg/l)/(μg/g-liver)] (range: 0.4 to 5.2). The Spearman rank correlation between SF and LIC was found to be highly significant (RS = 0.80, p < 0.0001), however, prediction by the linear regression LIC = (0.83± 0.08)·SF was poor (R2 = 0.5) as found also in other iron overload diseases. Although iron toxicity is a long-term risk factor, progression of hepatic fibrosis has been observed for LIC > 16 mg/g dry weight or 2667 μg/g-liver (Angelucci et al. Blood2002; 100:17–21) within 60 months and significant cardiac iron levels have been observed for LIC > 350 μmol/g or 3258 μg/g-liver (Jensen et al. Blood2003; 101:4632-9). The Angelucci threshold of hepatic fibrosis progression was exceeded by 51 % of our patients, while 39 % were exceeding the Jensen threshold of potential risk of cardiac iron toxicity. The total body iron burden is even higher as more than 50 % of the patients had hepatomegaly (median liver enlargement factor 1.2 of normal). A liver iron concentration of about 3000 μg/g-liver or 18 mg/g-dry weight has to be seen as latest intervention threshold for chelation treatment as MDS patients are affected by more than one risk factor. A more secure intervention threshold would be a LIC of 1000 μg/g-liver or 4 – 6 mg/g-dry weight, corresponding with a ferritin level of 900 μg/l for transfused MDS patients. Such a LIC value is not exceeded by most subjects with heterozygous HFE-associated hemochromatosis and is well tolerated without treatment during life-time. Non-invasive liver iron quantification offers a more reliable information on the individual range of iron loading in MDS which is also important for a more rational indication for a chelation treatment in a given patient.

RNAi-Mediated Inhibition of Tmprss6 Ameliorates Anemia and Secondary Iron Overload in a Mouse Model of β-Thalassemia Intermedia and Decreases Iron Overload in Hfe−/− Mice

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1018-1018
Author(s):  
Paul J Schmidt ◽  
Anoop K Sendamarai ◽  
Ivanka Toudjarska ◽  
Tim Racie ◽  
Jim S Butler ◽  
...  
Keyword(s):  
Mouse Model ◽  
Iron Overload ◽  
Iron Absorption ◽  
Disease Phenotype ◽  
Ineffective Erythropoiesis ◽  
Employment Equity ◽  
Liver Iron ◽  
Secondary Iron Overload ◽  
Equity Ownership ◽  
Low Levels

Abstract Abstract 1018 β-Thalassemia intermedia (TI), an inherited hemoglobinopathy caused by partial loss of β-globin synthesis, is characterized by anemia, extramedullary hematopoiesis and ineffective erythropoiesis as well as secondary iron overload. Hereditary hemochromatosis (HH) is most frequently caused by mutations in HFE and is marked by excess uptake of dietary iron with concomitant tissue iron overload. In both diseases, increased iron absorption is due to inappropriately low levels of the liver hormone, hepcidin (encoded by Hamp1). The membrane serine protease Matriptase-2 (encoded by Tmprss6) attenuates BMP-mediated Hamp1 induction by cleaving the BMP co-receptor, hemojuvelin. Previously, it has been shown that elevating Hamp1 expression by genetic inactivation of Tmprss6 reduces disease severity in the Hbbth3/+ mouse model of TI and prevents iron overload in Hfe−/− mice. Therefore, a therapeutic approach comprising specific inhibition of Tmprss6 could prove efficacious in TI and HH. Here we show that systemic administration of a potent lipid nanoparticle (LNP) formulated siRNA directed against Tmprss6 leads to >80% inhibition of Tmprss6 mRNA in the livers of Hbbth3/+ and Hfe−/− mice with concomitant >2-fold elevation in Hamp1 expression. In the TI model, Tmprss6 silencing leads to ∼30% reductions in serum iron and non-heme liver iron. In Hfe−/− mice, serum iron and non-heme liver iron are similarly reduced, and Perls staining of peri-portal iron is diminished. Remarkably, the partial iron restriction induced by Tmprss6 inhibition in Hbbth3/+ mice leads to dramatic improvements in the hematological aspects of the disease phenotype: the severity of the anemia is decreased as evidenced by an approximately 1 g/dL increase in total hemoglobin and a 50% decrease in circulating erythropoietin levels. As in the human disease, Hbbth3/+ mice exhibit the hallmarks of ineffective erythropoiesis including splenomegaly, decreased erythrocyte survival and marked reticulocytosis. Treatment with LNP formulated Tmprss6 siRNA leads to a dramatic 2–3 fold decrease in spleen size, a 3–4 fold decrease in reticulocyte counts and a >7-day increase in RBC half-life. Histological analysis of spleens from Tmprss6 siRNA treated animals demonstrates restoration of normal splenic architecture, as well as a reduction in the number of Tfr1-positive erythrocyte precursors in the spleen. Furthermore, as evidenced by the near normalization of blood smears, the overall quality of erythropoiesis in treated animals is vastly improved. Taken together, these data demonstrate that RNAi-mediated silencing of liver Tmprss6 elevates Hamp1 expression and reduces iron overload in both TI and HH model mice. More significantly, Tmprss6 siRNA treatment ameliorates all aspects of the disease phenotype in the TI mouse model. These results support the development of an RNAi therapeutic targeting TMPRSS6 for the treatment of TI, HH and potentially other disorders characterized by excess iron absorption due to physiologically inappropriately low levels of hepcidin. Disclosures: Racie: Alnylam Pharmaceuticals: Employment. Butler:Alnylam Pharmaceuticals, Inc.: Employment, Equity Ownership. Bumcrot:Alnylam Pharmaceuticals, Inc.: Employment, Equity Ownership.

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