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Abstract
Iron overload is the accumulation of excess iron in the body that may occur as a result of various genetic disorders or as a consequence of repeated blood transfusions. The surplus iron is then stored in the liver, pancreas, heart and other organs, which may lead to chronic liver disease or cirrhosis, diabetes and heart disease, respectively. In addition, excessive iron may impair hematopoiesis, although the mechanisms of this deleterious effect is not entirely known. In this study, we found that ferrous ammonium sulfate (FeAS), induced growth arrest and apoptosis in immature hematopoietic cells, which was mediated via reactive oxygen species (ROS) activation of p38MAPK and JNK pathways. In in vitro hematopoiesis derived from embryonic stem cells (ES cells), FeAS enhanced the development of dysplastic erythroblasts but inhibited their terminal differentiation; in contrast, it had little effect on the development of granulocytes, megakaryocytes, and B lymphocytes. In addition to its directs effects on hematopoietic cells, iron overload altered the expression of several adhesion molecules on stromal cells and impaired the cytokine production profile of these cells. Therefore, excessive iron would affect whole hematopoiesis by inflicting vicious effects on both immature hematopoietic cells and stromal cells.
Highlights
IntroductionIron is an essential component of numerous proteins and enzymes that are involved in oxygen transport and storage (hemoglobin, myoglobin), electron transfer and drug metabolism (cytochrome c), and signal transduction (nitric oxide synthases) [1,2]
Iron is an essential component of numerous proteins and enzymes that are involved in oxygen transport and storage, electron transfer and drug metabolism, and signal transduction [1,2]
Toblocked examine effects of iron overload on hematopoiesis, we first cultured cellstowith support the culture of Lineage− Sca1+ c-Kit+ (LSK) cells, with more severe inhibitory effects observed when the culture several cytokines in the presence of 2 mM ascorbic acid and two medium was supplemented with FCS lot 1502 (Figure 1A)
Summary
Iron is an essential component of numerous proteins and enzymes that are involved in oxygen transport and storage (hemoglobin, myoglobin), electron transfer and drug metabolism (cytochrome c), and signal transduction (nitric oxide synthases) [1,2]. Excessive concentrations of iron are toxic to cells, almost all organisms have developed tightly regulated mechanisms to maintain iron homeostasis [1,3]. As mammals lack an active system for iron excretion, iron homeostasis is maintained by regulating intestinal iron absorption [4]. The liver hormone hepcidin binds to ferroportin transmembrane protein during states of excess iron or inflammation reducing the amount of iron released into the circulation by enterocytes and macrophages controlling iron absorption, recycling, and storage [5].
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