Free iron catalyzes oxidative damage to hematopoietic cells/mesenchymal stem cells<i>in vitro</i>and suppresses hematopoiesis in iron overload patients

Lu, Wenyi; Zhao, Mingfeng; Rajbhandary, Sajin; Xie, Fang; Chai, Xiangping; Mu, Juan; Meng, Jiayuan; Liu, Y; Jiang, Yan; Xing, Xu; Meng, Aimin

doi:10.1111/ejh.12159

Cited by 82 publications

(84 citation statements)

References 34 publications

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“…Furthermore, iron overload in bone marrow-derived MSCs result in increased apoptosis. This is similar to our results in osteoblasts and also consistent with previous reports (Chai et al, 2015; Zhang et al, 2015; Lu et al, 2013). To explore the effect of iron-overload on the osteogenic differentiation of bone marrow-derived MSCs, we estimated the change of ALP activity.…”

Section: Discussionsupporting

confidence: 94%

Iron overload induced death of osteoblasts in vitro: involvement of the mitochondrial apoptotic pathway

Tian

Dai

et al. 2016

PeerJ

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BackgroundIron overload is recognized as a new pathogenfor osteoporosis. Various studies demonstrated that iron overload could induce apoptosis in osteoblasts and osteoporosis in vivo. However, the exact molecular mechanisms involved in the iron overload-mediated induction of apoptosis in osteoblasts has not been explored.PurposeIn this study, we attempted to determine whether the mitochondrial apoptotic pathway is involved in iron-induced osteoblastic cell death and to investigate the beneficial effect of N-acetyl-cysteine (NAC) in iron-induced cytotoxicity.MethodsThe MC3T3-E1 osteoblastic cell line was treated with various concentrations of ferric ion in the absence or presence of NAC, and intracellular iron, cell viability, reactive oxygen species, functionand morphology changes of mitochondria and mitochondrial apoptosis related key indicators were detected by commercial kits. In addition, to further explain potential mechanisms underlying iron overload-related osteoporosis, we also assessed cell viability, apoptosis, and osteogenic differentiation potential in bone marrow-derived mesenchymal stemcells(MSCs) by commercial kits.ResultsFerric ion demonstrated concentration-dependent cytotoxic effects on osteoblasts. After incubation with iron, an elevation of intracelluar labile iron levels and a concomitant over-generation of reactive oxygen species (ROS) were detected by flow cytometry in osteoblasts. Nox4 (NADPH oxidase 4), an important ROS producer, was also evaluated by western blot. Apoptosis, which was evaluated by Annexin V/propidium iodide staining, Hoechst 33258 staining, and the activation of caspase-3, was detected after exposure to iron. Iron contributed to the permeabilizatio of mitochondria, leading to the release of cytochrome C (cyto C), which, in turn, induced mitochondrial apoptosis in osteoblasts via activation of Caspase-3, up-regulation of Bax, and down-regulation of Bcl-2. NAC could reverse iron-mediated mitochondrial dysfunction and blocked the apoptotic events through inhibit the generation of ROS. In addition, iron could significantly promote apoptosis and suppress osteogenic differentiation and mineralization in bone marrow-derived MSCs.ConclusionsThese findings firstly demonstrate that the mitochondrial apoptotic pathway involved in iron-induced osteoblast apoptosis. NAC could relieved the oxidative stress and shielded osteoblasts from apoptosis casused by iron-overload. We also reveal that iron overload in bone marrow-derived MSCs results in increased apoptosis and the impairment of osteogenesis and mineralization.

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Section: Discussionsupporting

confidence: 94%

Iron overload induced death of osteoblasts in vitro: involvement of the mitochondrial apoptotic pathway

Tian

Dai

et al. 2016

PeerJ

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“…Similar improvements in marrow function have been seen in other patients with myelodysplastic syndrome [205–210], with aplastic anemia [211, 212] and dyserythropoietic anemia [213]. These effects have been attributed to oxidant-mediated damage to marrow precursors [179, 207, 214–217]. At least in some patients, the improvement in marrow function started within two months of initiating chelation therapy [205], well before the ferritin starts to drop.…”

Section: Iron Toxicitysupporting

confidence: 52%

Physiology and pathophysiology of iron in hemoglobin-associated diseases

Coates

2014

Free Radical Biology and Medicine

153

118

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Iron overload and iron toxicity, whether because of increased absorption or iron loading from repeated transfusions, can be major causes of morbidity and mortality in a number of chronic anemias. Significant advances have been made in our understanding of iron homeostasis over the past decade. At the same time, advances in magnetic resonance imaging have allowed clinicians to monitor and quantify iron concentrations non-invasively in specific organs. Furthermore, effective iron chelators are now available, including preparations that can be taken orally. This has resulted in substantial improvement in mortality and morbidity for patients with severe chronic iron overload. This paper reviews the key points of iron homeostasis and attempts to place clinical observations in patients with transfusional iron overload in context with the current understanding of iron homeostasis in humans.

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“…MDS patients show increased levels of oxidative stress, which is further aggravated by iron overload [14][15][16][17][18][19][20][21]. The resulting oxidative DNA damage, worsened by iron overload [22], may contribute to mutagenesis in the bone marrow.…”

Section: Iron Overload and Bone Marrow Functionmentioning

confidence: 99%

Iron overload in myelodysplastic syndromes (MDS)

Gattermann

2017

Int J Hematol

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Iron overload (IOL) starts to develop in MDS patients before they become transfusion-dependent because ineffective erythropoiesis suppresses hepcidin production in the liver and thus leads to unrestrained intestinal iron uptake. However, the most important cause of iron overload in MDS is chronic transfusion therapy. While transfusion dependency by itself is a negative prognostic factor reflecting poor bone marrow function, the ensuing transfusional iron overload has an additional dose-dependent negative impact on the survival of patients with lower risk MDS. Cardiac dysfunction appears to be important in this context, as a consequence of chronic anemia, age-related cardiac comorbidity, and iron overload. Another potential problem is iron-related endothelial dysfunction. There is some evidence that with increasing age, high circulating iron levels worsen the atherosclerotic phenotype. Transfusional IOL also appears to aggravate bone marrow failure in MDS, through unfavorable effects on mesenchymal stromal cells as well a hematopoietic cells, particularly erythroid precursors. Patient series and clinical trials have shown that the iron chelators deferoxamine and deferasirox can improve hematopoiesis in a minority of transfusion-dependent patients. Analyses of registry data suggest that iron chelation provides a survival benefit for patients with MDS, but data from a prospective randomized clinical trial are still lacking.

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Free iron catalyzes oxidative damage to hematopoietic cells/mesenchymal stem cellsin vitroand suppresses hematopoiesis in iron overload patients

Abstract: Our study shows that iron overload injures the hematopoiesis by damaging hematopoietic cell and hematopoietic microenvironment, which is mediated by ROS-related signaling proteins.

Cited by 82 publications

References 34 publications

Iron overload induced death of osteoblasts in vitro: involvement of the mitochondrial apoptotic pathway

Iron overload induced death of osteoblasts in vitro: involvement of the mitochondrial apoptotic pathway

Physiology and pathophysiology of iron in hemoglobin-associated diseases

Iron overload in myelodysplastic syndromes (MDS)

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