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1.  Transplantation dose alters the differentiation program of hematopoietic stem cells 
Cell reports  2016;15(8):1848-1857.
Hematopoietic stem cell (HSC) transplantation is the most prevalent stem cell therapy, but it remains a risky procedure. To improve this treatment, it is important to understand how transplanted stem cells rebuild the blood and immune systems and how this process is impacted by transplantation variables such as the HSC dose. Here we find that in the long term following transplantation, 70–80% of donor-HSC-derived clones do not produce all measured blood cell types. High HSC doses lead to more clones that exhibit balanced lymphocyte production while low doses produce more T-cell specialized clones. High HSC doses also produce significantly higher proportions of early-differentiating clones compared to low doses. These complex differentiation behaviors uncover the clonal-level regeneration dynamics of hematopoietic regeneration, and suggest that transplantation dose can be exploited to improve stem cell therapy.
PMCID: PMC4880538  PMID: 27184851
2.  mRNA Regulation of Cardiac Iron Transporters and Ferritin Subunits in a Mouse Model of Iron Overload 
Experimental hematology  2014;42(12):1059-1067.
Iron cardiomyopathy is the leading cause of death in iron overload. Men have twice the mortality rate of women, though the cause is unknown. In hemojuvelin-knockout mice, a model of the disease, males load more cardiac iron than females. We postulated that sex differences in cardiac iron import cause differences in cardiac iron concentration. RT-PCR was used to measure mRNA of cardiac iron transporters in hemojuvelin-knockout mice. No sex differences were discovered among putative importers of non-transferrin bound iron (L-type and T-type calcium channels, ZRT/IRT-like protein 14 zinc channels). Transferrin-bound iron transporters were also analyzed; these are controlled by the iron regulatory element/iron regulatory protein (IRE/IRP) system. There was a positive relationship between cardiac iron and ferroportin mRNA in both sexes, but it was significantly steeper in females (p<0.05). Transferrin receptor 1 and divalent metal transporter 1 were more highly expressed in females than males (p<0.01 and p<0.0001, respectively), consistent with their lower cardiac iron levels, as predicted by IRE/IRP regulatory pathways. Light-chain (L) ferritin showed a positive correlation with cardiac iron that was nearly identical in males and females (R2=0.41, p<0.01 and R2=0.56, p<0.05, respectively), while heavy-chain (H) ferritin was constitutively expressed in both sexes. This represents the first report of IRE/IRP regulatory pathways in the heart. Transcriptional regulation of ferroportin was suggested in both sexes, creating a potential mechanism for differential set points for iron export. Constitutive H-ferritin expression suggests a logical limit to cardiac iron buffering capacity at levels known to produce heart failure in humans.
PMCID: PMC4266478  PMID: 25220979
iron overload; heart; ferroportin; ferritin; iron-regulatory proteins
3.  Interdependence of Cardiac Iron and Calcium in a Murine Model of Iron Overload 
Iron cardiomyopathy in β-thalassemia major patients is associated with vitamin D deficiency. Stores of 25-OH-D3 are markedly reduced, while the active metabolite, 1-25-(OH)-D3, is normal or increased. Interestingly, the ratio of 25-OH-D3 to 1-25-(OH)-D3 (a surrogate for parathyroid hormone (PTH)) is the strongest predictor of cardiac iron. Increased PTH and 1-25-OH-D3 levels have been shown to up-regulate L-type voltage-gated calcium channels (LVGCC), the putative channel for cardiac iron uptake. Therefore, we postulate that vitamin D deficiency increases cardiac iron by altering LVGCC regulation. Hemojuvelin knockout mice were calcitriol treated, PTH treated, vitamin D-depleted, or untreated. Half of the animals in each group received the Ca2+-channel blocker verapamil. Mn2+ was infused to determine LVGCC activity. Hearts and livers were harvested for iron, calcium, and manganese measurements as well as histology. Cardiac iron did not differ amongst the treatment groups; however, liver iron was increased in vitamin D-depleted animals (p<0.0003). Cardiac iron levels did not correlate with manganese uptake, but were proportional to cardiac calcium levels (r2 = 0.6, p < 0.0001). Verapamil treatment reduced both cardiac (p <0.02) and hepatic (p < 0.003) iron levels significantly by 34% and 28%. The association between cardiac iron and calcium levels was maintained after verapamil treatment (r2 = 0.3, p < 0.008). Vitamin D-depletion is associated with an increase in liver, but not cardiac, iron accumulation. Cardiac iron uptake was strongly correlated with cardiac calcium stores and was significantly attenuated by verapamil, suggesting that cardiac calcium and iron are related.
PMCID: PMC3073567  PMID: 21256461
b-thalassemia; vitamin D; iron overload; hemojuvelin
4.  Spleen R2 and R2* in Iron-Overloaded Patients With Sickle Cell Disease and Thalassemia Major 
To evaluate the magnetic properties of the spleen in chronically transfused, iron-overloaded patients with sickle cell disease (SCD) and thalassemia major (TM) and to compare splenic iron burdens to those in the liver, heart, pancreas, and kidneys.
Materials and Methods
A retrospective analysis of 63 TM and 46 SCD patients was performed. Spleen R2 and R2* values were calculated from spin-echo and gradient-echo images collected between April 2004 and September 2007.
The spleen showed a different R2–R2* relationship than that previously established for the liver. At high iron concentrations (R2* > 300 Hz), spleen R2 was lower than predicted for liver. The proportion of splenic to hepatic iron content was greater in SCD patients compared with TM patients (23.8% vs. 13.8%). A weak association was found between splenic and liver iron—this association was stronger in SCD patients. Little correlation was found between splenic iron and extrahepatic R2* values.
For spleen and liver tissue with the same R2* value, splenic R2 was significantly lower than hepatic R2, particularly for R2* > ≈300 Hz. Splenic iron levels have little predictive value for R2* values of heart, pancreas, and kidney.
PMCID: PMC2906451  PMID: 19161188
spleen; sickle cell; thalassemia; MRI; iron
5.  Safety and Efficacy of Combined Chelation Therapy with Deferasirox and Deferoxamine in a Gerbil Model of Iron Overload 
Acta haematologica  2008;120(2):123-128.
Combined therapy with deferoxamine (DFO) and deferasirox (DFX) may be performed empirically when DFX monotherapy fails. Given the lack of published data on this therapy, the study goal was to assess the safety and efficacy of combined DFO/DFX therapy in a gerbil model.
Thirty-two female Mongolian gerbils 8–10 weeks old were divided into 4 groups (sham chelated, DFO, DFX, DFO/DFX). Each received 10 weekly injections of 200 mg/kg iron dextran prior to initiation of 12 weeks of chelation. Experimental endpoints were heart and liver weights, iron concentration and histology.
In the heart, there was no significant difference among the treatment groups for wet-to-dry ratio, iron concentration and iron content. DFX-treated animals exhibited lower organ weights relative to sham-chelated animals (less iron-mediated hypertrophy). DFO-treated organs did not differ from sham-chelated organs in any aspects. DFX significantly cleared hepatic iron. No additive effects were observed in the organs of DFO/DFX-treated animals.
Combined DFO/DFX therapy produced no detectable additive effect above DFX monotherapy in either the liver or heart, suggesting competition with spontaneous iron elimination mechanisms for chelatable iron. Combined therapy was well tolerated, but its efficacy could not be proven due to limitations in the animal model.
PMCID: PMC2884393  PMID: 19018129
Deferasirox; Deferoxamine; Iron overload

Results 1-5 (5)