Iron plays an essential role in numerous cellular functions, either as free ion or chelated with porphyrin to form heme, by facilitating the activities of numerous enzymes. In erythroid cells, in addition to cytochromes, heme is a functional element of hemoglobin, the most abundant red cell protein. It is therefore not surprising that iron is at the same time an important regulator and effector of erythropoiesis and that any step of its metabolism in these cells is carefully regulated (uptake, storage, and efflux). Iron affects erythropoiesis directly and indirectly through events that restrict iron avail ability in the body. Erythroid cells, in turn, release feedback messages to modulate iron metabolism.

Iron circulates in the blood complexed with a specific transporter, Tf, and is taken up by the cells through the TfR. TfRs belong to a large group of receptors that internalize their ligand through receptor mediated endocytosis. This cycle allows for reuse both of the ligand, which is released in the blood for re-saturation with iron, and of the receptor, for entering another round of endocytosis.

Iron is so important for erythropoiesis that erythroid progenitors are distinguished from other marrow progenitors by the presence of high levels of TfRs. TfRs are found in characteristic abundance in erythroid cells (300,000 to 800,000 TfRs per cell) and reach peak levels on CFU-E and erythroid precursors and decrease with maturation with the lowest level observed on reticulocytes. After the reticulocyte stage, receptors appear to be shed as small lipid vesicles.

An inverse relationship exists between receptor density and iron availability. Deprivation of iron results in receptor induction, and excess iron results in receptor suppression. However, the mechanisms that regulate the number of TfRs throughout the maturation of pre cursors (even within progenitors) are largely unknown.

Erythroid precursor cells differ from nonerythroid cells not only by requiring a higher number and higher occupancy of TfRs, but also by displaying immunologically distinct receptor isoforms. In addition to TfR1, a TfR2 has been identified. TfR1 and TfR2 are members of a family of genes encoding at least seven different homologous proteins in primates. TfR1 is a type II membrane glycoprotein that, as a cell surface homodimer, binds iron-loaded transferrin as part of the process of iron transfer and uptake. TfR2 is expressed in a membrane (TfR2-α)- and non-membrane (TfR2-β)-bound form, both of which bind transferrin with low affinity. The specific role of TfR2 in hematopoietic cells is unclear. In cells from 67 patients with de novo acute myeloid leukemia (AML), high levels of TfR2-α expression were correlated with an improved prognosis, and higher levels of both TfR2-α and TfR2-β were associated with longer survival, suggesting that TfR independent iron uptake plays a role in in vivo proliferation of AML cells. Recent data in TfR2-deficient mouse models suggest that this receptor may also modulate the erythroblast sensitivity to EPO.

In addition to its direct effect, TfR2 may also play an indirect role in erythropoiesis as the key regulator of iron metabolism in the liver. In fact, maintenance of stable extracellular iron concentrations requires the coordinated regulation of iron transport into plasma from dietary sources in the duodenum, recycled senescent red cells in macrophages, and storage in hepatocytes. The presence of diferric transferrin in the liver is regulated by a complex machinery involving, in addition to TfR2, the product of the hereditary hemochromatosis (HFE) gene (a protein of the major histocompatibility complex class I) and the product of the hemojuvelin (HJV) gene (also known as HFE2). Given that the levels of TfR2 expression are exclusively regulated by holotransferrin, TfR2 expressed by hepatocytes is likely the first element of the iron sensory pathway in the liver. In turn, hepatocytes respond to iron sensing by modulating hepcidin expression and secretion. Hepcidin, a 25-amino acid disulfide-rich peptide, acts as a systemic iron regulatory hormone that regulates both dietary iron absorption by the enterocytes and iron recycling by the macro phages. Because ferroportin shuttles iron from the enterocytes to the macrophages and hepcidin is required for ferroportin internalization and degradation, decreased hepcidin expression blocks iron export in the two cell types. Each gene involved in iron metabolism has a role in regulating the expression of the other genes. In particular, reduced expression of HEF, TfR2, and HJV reduces expression of hepcidin. It is not surprising then that mutations altering the function of all of these genes, including hepcidin, have been found to be associated with hereditary hemochromatosis. In addition to its role in determining the pathobiology of hereditary hemochromatosis, hepcidin plays an important role in determining the anemia of chronic diseases and inflammation. In inflammation, the increased hepcidin synthesis traps iron in macrophages, decreases plasma iron concentrations, and causes iron restricted erythropoiesis characteristic of the anemia of inflammatory states. Hepcidin might inhibit proliferation of erythroid progenitors at low EPO concentrations. On the basis of these data, a hepcidin assay has been proposed as a useful tool for diagnosing iron disorders and monitoring their treatment and hepcidin agonists and antagonists have been suggested as useful therapeutics for treatment of iron disorders and polycythemia vera (PV).

The stringent need for iron during erythroid maturation led Dr. Clement Finch to first hypothesize the existence of signals released by mature erythroid cells that controls iron metabolism. This hypothesis has been recently confirmed by the identification of erythroferrone (ERFE), a protein released by erythroid cells that suppresses hepcidin expression in mice under conditions of stress.113 ERFE-deficient mice fail to suppress hepcidin after hemorrhage and exhibit a delayed recovery after blood loss. Data from additional mouse models suggest that ERFE also contributes to recovery from anemia after inflammation.

Synthesis of heme appears to be coordinated with synthesis of globins throughout erythroid maturation so that functional hemoglobin tetramers are formed rapidly and spontaneously after release of newly synthesized globins from polysomes. Information about the accumulation of heme and its synthetic intermediaries has been provided by crude biochemical approaches. However, now that the genes for several enzymes in the heme synthetic pathway (e.g., δ-5aminolevulinic acid synthase, porphobilinogen deaminase, ferrochelatase) have been cloned, further information about their regulation is available.

At the early stages of differentiation when globin chain synthesis is scanty, upregulation of heme biosynthesis is restrained by specific iron effluxers, such as the export proteins first identified as the receptor for the feline leukemia virus, which restrict iron availability in the cytoplasm. As maturation progresses, an important role in coordinating heme and globin chain assembly during hemoglobin production is exerted by AHSP. AHSP is a protein abundantly expressed in erythroid cells whose function is to bind free α-chains, stabilizing their structure and limiting their ability to participate in chemical reactions that generate ROS. In addition, AHSP binding increases the affinity of α-chains for β-chains, accelerating the formation of Hb tetramers. The essential role exerted by this gene in erythroid development has been demonstrated by the fact that its deletion in normal mice impairs red cell production. The red cells from AHSPnull mice have a decreased half-life, contain Hb precipitates, and exhibit signs of oxidative damage. The observation that double AHSP−/− b-thalassemic mutant mice have an exacerbated phenotype suggests that AHSP is a gene modifier that, like the HPFH mutations, may ameliorate the phenotype of thalassemic patients. However, gene mapping, direct genomic sequencing, and extended haplotype analysis have not revealed any mutations or specific association between haplotypes of AHSP in 120 β-thalassemic patients. On the other hand, a polymorphism in the putative AHSP promoter leading to a threefold higher expression of the gene in reticulocytes has been observed in the normal population, but the clinical consequences of this observation are unknown.

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المزيد

الآخبار الصحية

العلاج بالماء البارد.. باحثون يكشفون فوائده الصحية

من دون صالة رياضية.. عادة بسيطة لتحسين الصحة وخسارة الوزن

لصحة القلب وتفادي السرطان.. استهلك هذا النوع من الطعام

دراسة تحذر من خطر شرب القهوة في أكواب البلاستيك

المزيد

الآخبار التكنلوجية

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اليابان.. مراحيض توفر فحص للحالة الصحية عبر "تحليل البراز" !

اختراق واسع لمنصة "إنستغرام".. ونشر بيانات على "الدارك ويب"

علماء يحذرون: هكذا سيفنى كوكب الأرض

المزيد

مواضيع ذات صلة

Ontogeny of Erythropoiesis

Cellular Dynamics in Erythropoiesis: Steady State and Stress Erythropoiesis

Hematopoietic Microenvironment

Intrinsic Control of Erythropoiesis:Erythropoietin

Nuclear Organization

Unfolded Protein Response

Autophagy

Nonapoptotic forms of cell death

The Cell Division Cycle

Stem Cells

Proliferation and the Cell Cycle

Growth Factors and Receptors