Abstract
Iron overload, caused by hereditary hemochromatosis or repeated blood transfusions in some diseases, such as beta thalassemia, bone marrow failure and myelodysplastic syndrome, can significantly induce injured bone marrow (BM) function as well as parenchyma organ dysfunctions. However, the effect of iron overload and its mechanism remain elusive. In this study, we investigated the effects of iron overload on the hematopoietic stem and progenitor cells (HSPCs) from a mouse model. Our results showed that iron overload markedly decreased the ratio and clonogenic function of murine HSPCs by the elevation of reactive oxygen species (ROS). This finding is supported by the results of NAC or DFX treatment, which reduced ROS level by inhibiting NOX4 and p38MAPK and improved the long-term and multi-lineage engrafment of iron overload HSCs after transplantation. Therefore, all of these data demonstrate that iron overload injures the hematopoiesis of BM by enhancing ROS through NOX4 and p38MAPK. This will be helpful for the treatment of iron overload in patients with hematopoietic dysfunction.
Highlights
Patients and that iron chelation therapy could improve this situation[6,7]
An iron overload mouse model was established by intraperitoneally injecting with different doses (12.5, 25 or 50 mg/ml) of iron dextran every three days for various durations (2 w, 4 w, 8 w)
To confirm the establishment of the iron overload mouse model, the labile iron pool (LIPs) of the bone marrow mononuclear cells (BMMNCs) were dynamically detected, while the hepatic, splenic and bone marrow (BM) iron deposits were assessed at the fourth week
Summary
The BMMNCs were flushed from the bones as described previously[9,10] and were counted using the hematology analyzer. CFC assays were performed by culturing BMMNCs in MethoCult GF M3434 methylcellulose medium (Stem Cell Technologies, Vancouver, BC). Competitive repopulation assays were performed using the Ly45 congenic mice to analyze hematopoietic stem reconstitution capacity, as described previously[10]. Donor BMMNCs were harvested from the Ly45.2 mice after they were given different treatments. These cells (1 × 106 BMMNCs) were mixed with competitive cells (1 × 106 BMMNCs) from the Ly45.1/45.2 hybrid mice. Peripheral blood was obtained from all of the recipients at two months and four months after transplantation and was analyzed using a BD FACS Aria III, as described previously[10].
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