The major stages of differentiation in human erythropoiesis are depicted in Figure 1. The commitment of multipotent hemopoietic stem cells to erythroid progenitors is driven by several growth factors, such as stem cell factor, thrombopoietin, and interleukin IL -3[ 2 ]. The most immature stage of committed erythroid progenitors is the burst-forming unit-erythroid, which differentiates into colony-forming unit-erythroid CFU-E in approximately 7 d, with declining proliferative potential as the progenitors approach CFU-Es. Each CFU-E develops a single cluster of mature erythroblasts within 7 d, after several differentiation stages pro-erythroblast, basophilic erythroblast, polychromatic erythroblast, and orthochromatic erythroblast.
Orthochromatic erythroblasts do not divide but they enucleate, and form nascent RBCs, called reticulocytes, which are release into the bloodstream. After 1 d of circulation in the peripheral blood, reticulocytes mature into RBCs[ 3 ]. The normal proliferation and differentiation of erythroid progenitor cells require several essential nutrients, such as iron, folate, and vitamin B12, the interaction with the stromal cells in the bone marrow, and stimulation by erythropoietin EPO [ 3 ]. For a kg male individual, total body iron is about 3.
The remaining body iron is stored in the liver mg , macrophages of the reticuloendothelial system RES; mg , and bone marrow mg. In premenopausal women, total body iron especially the stored fraction, mg is lower than in men.
This is balanced with losses via sloughed intestinal mucosal cells, menstruation and other blood losses. On the other hand, the body has no effective means of excreting iron and thus the regulation of absorption of dietary iron from the duodenum plays a critical role in iron homeostasis in the body[ 5 ]. This is extremely important as iron is essential for cellular metabolism and aerobic respiration, whilst cellular iron overload leads to toxicity and cell death via free radical formation and lipid peroxidation, thus, iron homeostasis requires tight regulation[ 3 , 4 , 6 ].
A summary of proteins involved in iron homeostasis, as well as their most frequently used acronyms, is given in Table 1. Nearly all absorption of dietary iron occurs in the duodenum. Several steps are involved, including the reduction of iron to a ferrous state, apical uptake, intracellular storage or transcellular trafficking, and basolateral release Figure 2. There is also a siderophore-like iron uptake pathway mediated by lipocalin-2 that seems to exert an innate immune response to bacterial infection by sequestrating iron but its physiological role is not fully worked out.
The absorption of non-heme can be diminished by co-administration of tetracyclines, proton pump inhibitors and antacid medication, phytates high-fiber diets , calcium, and phenolic compounds coffee and tea.
In addition, infection with Helicobacter pylori H pylori produces gastric atrophy that, even in the absence of significant bleeding, can lead to profound iron-deficiency anemia IDA. As expected, this anemia is poorly responsive to oral iron therapy, but can be corrected by eradication of H pylori infection[ 7 ]. Heme iron is absorbed into enterocytes by a putative, not totally identified heme carrier protein 1, which is a membrane protein found in the proximal intestine, where heme absorption is greatest[ 8 ].
Once internalized in the enterocytes, it is likely that most dietary heme iron is released as ferrous iron by heme oxygenase to enter a common pathway with dietary non-heme iron before it leaves the enterocytes[ 3 , 4 ] Figure 2. If this does occur, the subsequent disposition of plasma heme is unknown. In addition, it is not yet known whether heme carrier protein 1 has physiological roles in tissues other than the intestine. The protein is also expressed in the kidneys and liver, which suggests that it may act at those sites. It might, for example, scavenge free heme or mediate cellular uptake of heme from its circulating carrier protein, hemopexin[ 9 ].
Once inside the intestinal epithelial cell, iron may either remains in the cell for use or storage this iron is never absorbed into the body; rather, it is lost when enterocytes senesce and are sloughed into the gut lumen or exported across the basolateral membrane of the enterocyte into the circulation absorbed iron. Ferroportin 1 is the only putative iron exporter identified to date.
Ferrous iron once exported across the basal membrane by ferroportin 1, is then oxidized by a multi-copper oxidase protein called hephaestin an enzymatic protein similar to plasma ceruloplasmin before being bound by plasma transferrin. Ferroportin 1 is also the putative iron exporter in macrophages and hepatocytes Figure 2 [ 3 , 4 ]. Two models have been proposed to explain how the absorption of iron is regulated: the crypt programming model and the hepcidin model.
The crypt programming model: This model proposes that enterocytes in the crypts of the duodenum take up iron from the plasma. The crypt cells express both transferrin receptor 1 TfR1 and TfR2, which mediate the cellular uptake of transferrin-bound iron from plasma[ 3 , 5 ]. TfR1 is expressed ubiquitously and transferrin mediated iron uptake is thought to occur in most cell types.
Its role in the regulation of TfR1-mediated transferrin-bound iron uptake remains unclear, but it seems to enhance transferrin-bound iron uptake from the plasma into crypt cells via TfR1, and may also inhibit the release of iron from the cell via ferroportin 1. In contrast, TfR2 is restricted to hepatocytes, duodenal crypt cells and erythroid cells, which suggests a more specialized role in iron metabolism. Thus, a high IRP binding activity reflects low body iron stores and results in upregulation of these proteins in the duodenum and increased dietary iron absorption.
Thus, ferritin levels are regulated reciprocally - being increased in iron-replete states and decreased in iron-deplete states[ 3 ].
The hepcidin model: Liver hepcidin is a amino-acid cysteine-rich peptide with antimicrobial properties, which is regulated by a number of factors such as liver iron levels, inflammation, hypoxia and anemia. The hepcidin model proposes that hepcidin is secreted into the blood and interacts with villous enterocytes to regulate the rate of iron absorption, by controlling the expression of ferroportin 1 at their basolateral membranes.
The binding of hepcidin to ferroportin 1 results in internalization of ferroportin 1 and loss of its function. Ferroportin 1 molecules present in macrophages and liver are also targets for hepcidin. In contrast, when hepcidin levels are reduced, as in iron deficiency ID , anemia or hypoxia, it is likely that ferroportin 1 expression and iron release from intestinal cells, liver and cells of reticuloendothelial system is increased[ 10 ].
In contrast, a mutation in the ferroportin 1 gene is responsible for type IV hemochromatosis. There is evidence to support both models and it is possible that both control mechanisms may contribute to the regulation of iron absorption. In this regard, there is emerging evidence that hepcidin may act directly on mature villous enterocytes rather than crypt enterocytes.
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There are several situations e. Iron released into the circulation binds to transferrin and is transported to sites of use and storage. Transferrin has two binding sites, binding one iron atom each thus three forms can be found in plasma: apo-transferrin which contains no iron, monoferric-transferrin and diferric-transferrin.
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Thus, transferrin-bound iron is about 4 mg, but this is the most import dynamic iron pool[ 11 ]. Transferrin-bound iron enters target cells - mainly erythroid cells, but also immune and hepatic cells- through a process of receptor-mediated endocytosis Figure 3. As diferric-transferrin has a much higher affinity for TfR than does monoferric-transferrin, it binds to the TfR at the plasma membrane, and patches of cell-surface membrane that carry receptor-ligand complexes invaginate to form clathrin-coated endosomes siderosomes [ 11 ].
Production of hemoglobin by the erythron accounts for most iron use. High-level expression of TfR1 in erythroid precursors ensures the uptake of iron into this compartment. To make heme, iron must again cross an ion-impermeable membrane to enter the mitochondria. The mitochondrial iron importer was recently identified as mitoferrin also known as SLC25A37 , a transmembrane protein that plays a crucial role in supplying iron to ferrochelatase for insertion into protoporphyrin IX to form heme[ 12 ] Figure 3. Thus, when increased iron uptake is needed, the expression of TfR1 and DMT-1 is increased, whereas the synthesis of ferritin is halted[ 3 ].
In addition, there is evidence that EPO activates IRP-1, leading to upregulation of TfR1 expression in the erythroid precursors, which is maintained along with the differentiation process, and DMT-1 and hephaestin gene expression in the duodenum[ 13 ]. To date, three patients have been reported with DMT-1 mutations that cause microcytic hypochromic anemia, as a result of decreased erythroid iron utilization, but lead to increased liver iron storage[ 14 ]. A truncated form of the TfR can be detected in human serum. The serum concentration of this soluble form of TfR sTfR; normal median concentration: 1.
Increased sTfR concentrations indicate ID even during the anemia of chronic disease ACD , as well as increased erythropoietic activity without ID, whereas lower sTfR concentrations may reflect decreased numbers of erythroid progenitors[ 3 , 15 ]. Hemoglobin iron has substantial turnover, as senescent erythrocytes undergo phagocytosis by RES macrophages. Within the phagocytic vesicles, heme is metabolized by heme oxygenase and the released iron is exported to the cytoplasm through the action of natural resistance-associated macrophage protein-1, a transport protein similar to DMT-1 Figure 4.
Macrophages can also obtain iron from bacteria and apoptotic cells, from plasma through the action of DMT-1 and TfR1, and from other sources Figure 4. Within the cell, iron can be stored in two forms: in the cytosol as ferritin and, after breakdown of ferritin within the lysosomes, as hemosiderin. Hemosiderin represents a very small fraction of normal body iron stores, mostly in macrophages, but increases dramatically in iron overload[ 11 ]. Iron export from macrophages to transferrin is accomplished primarily by ferroportin 1, the same iron-export protein expressed in duodenal enterocytes, and hephaestin[ 3 ] Figure 4.
The amount of iron required for daily production of billion RBCs mg is provided mostly by recycling iron by macrophages[ 4 ]. Importantly, iron storage at the macrophages is safe, as it does not lead to oxidative damage.
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EPO reduces iron retention in macrophages by decreasing DMT-1 and increasing ferroportin 1 expression[ 16 ]. The liver is the other main storage organ for iron. In iron overload, free radical formation and generation of lipid peroxidation products may result in progressive tissue injury and eventually cirrhosis or hepatocellular carcinoma[ 17 ]. Iron is sequestrated in hepatocytes predominantly in the form of ferritin or hemosiderin.
Frontiers | Iron Metabolism and Brain Development in Premature Infants | Physiology
In iron overload, TfR1 is downregulated in hepatocytes[ 5 ]. TfR2 is expressed highly in human liver and is likely to play an important role in liver iron loading in iron overload states. The volume contains more than detailed tables and informative figures and up-to-date references that provide the reader with excellent sources of information about the critical role of iron nutrition, optimal iron status and the adverse clinical consequences of altered iron homeostasis.
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