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C. Casu et al.
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Figure 7. Improved iron parameters and splenomegaly in Hbbth1/th2-BMC mice treated with minihepcidin and blood transfusion. (A) Hepcidin (HAMP) levels increased in the group given blood transfusions (Bl.Tr.) with or without high-dose minihepcidin (MH-H). (B) Transferrin saturation levels were not statistically different in treated or untreated animals. (C) Serum iron levels were decreased in the animals given blood transfusions compared to animals treated with vehicle (V) alone and were similar to those in animals treated with MH-H. (D) Liver iron content was decreased in animals given blood trans- fusions (with or without MH_H) when compared to animals treated with vehicle and sim- ilar to those treated with MH_H alone. (E, F) Total iron content in the heart (E) and spleen (F) was decreased. (G) Spleen weight was almost normalized in MH_H- treated mice, transfused or not. Bars represent the standard deviation. ****P≤0.001, ***P≤0.005, **P≤0.01; *P≤0.05.
(Figure 7F, Online Supplementary Figure S7) and splenomegaly (Figure 7G), reaching levels similar to those in WT mice. Therefore, administration of minihepcidins may also be beneficial in reducing or preventing splenomegaly and organ-associated iron overload in the presence of blood transfusion.
Discussion
We crossed models of NTDT Hbbth1/th1 with Hbbth2/+ to generate a combination of mutations that decreased syn- thesis of mouse β-globin genes to mimic TDT. These models exhibit severe anemia, high erythroferrone and
low hepcidin levels in the serum, iron overload and suc- cumbed to death due to anemia 4 months after transplan- tation, mimicking the most severe form of thalassemia in humans. This relatively slow progression to fatal anemia enables this model to be used to study drugs, such as minihepcidins, with the potential to modulate ineffective erythropoiesis in the presence and absence of transfu- sions.
The administration of a minihepicidin improved RBC morphology, hemichrome formation, and thus the quali- ty of RBC, and reversed splenomegaly, ineffective ery- thropoiesis, and anemia in Hbbth1/th2BMC mice, our new model of TDT. Furthermore, iron parameters, such as serum, liver, and spleen iron concentration, were
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haematologica | 2020; 105(7)