The primary function of the mature red cell, which is the end-product of erythropoiesis, is to transport oxygen efficiently through the circulation to the tissues. To achieve this goal, the adult marrow must release approximately 3 × 10⁹ new red cells or reticulocytes per kilo gram per day. This number of reticulocytes represents (1%) of the total red cell mass and is derived from an estimated 5 × 10⁹ erythroid precursors per kilogram. In addition to maintaining homeostasis (i.e., a stable hematocrit), the erythron must be able to respond quickly and appropriately to increased oxygen demands, either acute (e.g., following red cell loss) or chronic (e.g., with hypoxia from pulmonary disease or a right-to-left cardiac shunt). It is well established that EPO is responsible both for maintaining normal erythropoiesis and for increasing red cell production in response to oxygen needs. However, the overall marrow response is complex and requires not only the participation of erythroid cells responsive to EPO but also a structurally intact microenvironment and an optimal iron supply within the marrow.

EPO stimulation elicits two types of measurable responses: changes in proliferative activity (including improved survival) and changes in maturation rates. The first detectable response to increased serum EPO is amplification of CFU-E and erythroid precursors, cells that are extremely sensitive to EPO. Because virtually all these cells are already in cycle, increases in their numbers cannot be achieved by increasing their fraction in cycle. Either additional divisions are involved, or new cells must be recruited to the CFU-E pool (from a pre–CFU-E pool). Additional divisions of CFU-E or precursor cells would increase their transit time within the marrow and potentially delay the delivery of new red cells to the periphery. Because a shortened maturation time has been observed instead and the proliferative potentials of CFU-E and proerythroblasts are finite, high levels of amplification cannot be achieved through this mechanism. Therefore, such needs are met by influx into the CFU-E and precursor pools of newly differentiating cells from earlier progenitor compartments.

Such a surge of newly produced cells has been observed in prior experiments. A rapid influx of fresh cells was particularly notable in polycythemic mice that were experimentally depleted of CFU-E and erythroid precursors at the time the stimulus was applied. Because of the rapidity of response (i.e., within 24 hours in the polycythemic animals), it appeared that the orderly progression from BFU-E to CFU-E to proerythroblast had been compressed. Such acceleration of differentiation is possible through shortened intermitotic intervals, fewer mitotic divisions, or differentiation without divisions. This short-circuiting in differentiation requires high serum levels of EPO and adequate numbers of BFU-E (i.e., these conditions are met in a previously hypertransfused, polycythemic animal stimulated by EPO or in marrow suddenly recovering from acquired pure erythroid aplasia). Once CFU-E and precursors are expanded through this mechanism, most persisting erythropoietic demands can be met through this pool without excess input from pre–CFU-E pools. Thus, acute demand for erythropoiesis is met by influx from pre–CFU-E pools through an accelerated differentiation and maturation sequence. Demonstration of such an event was seen in mice with conditional deletions of integrins using the EPOR-Cre model deleting cells at the post–CFU-E level. In contrast, chronic demands (i.e., demands because of a chronic hemolytic anemia) are mainly satisfied through a greatly amplified late erythroid pool and with a minimum distortion in the differentiation sequence. The fact that the kinetics of erythroid differentiation/maturation are different in acute versus chronic marrow regeneration is supported by differing qualitative changes in the newly formed red cells. An increase in i antigen and HbF expression as well as an increase in cells with higher mean corpuscular volumes is seen with an acute response, whereas these alterations are minimal or less pronounced with chronic responses. When severe anemia persists from birth onward, erythroid production can increase up to 10-fold above baseline. This is possible not only because of maximally expanded erythropoietic pools but also because the sites of active erythropoiesis may extend to include those that support red cell differentiation during fetal life. Thus although the marrow space in axial bones (vertebrae, pelvis, ribs, sternum, clavicles) is sufficient for normal erythropoiesis or for a response to moderate anemia, the femur, humerus, spleen and/or liver, and (rarely) thymus may support red cell production in children with congenital hemolytic anemia (e.g., thalassemia major). Expanded erythropoiesis may lead to skeletal deformities, hepatosplenomegaly, or erythropoiesis in the soft tissues adjacent to bone.

Quantitative assessments of changes in erythroid progenitor cell pools in response to EPO stimulation can be made through cultures of bone marrow cells. Despite sampling errors,117 erythroid cultures can provide rough estimates of relative progenitor abundance within an aspirated marrow specimen and have shown consistent increases in the frequency of CFU-E in proportion to the level of EPO stimulation. Conversely, with increases in the hematocrit or in polycythemic animals, a decrease in CFU-E frequency has been observed. In contrast to CFU-E, the incidence of BFU-E was found to fluctuate less with either acute or chronic expansion of erythropoiesis, probably because a few BFU-E can generate several thousand cells. Furthermore, BFU-E can increase their fraction in cycle and thus increase the number of differentiated progeny without a significant change in their total numbers. Most BFU-E detectable in marrow or blood erythroid cultures probably represent a reservoir of pro genitors not normally participating in day-to-day erythropoiesis. The parameters needed to maintain a healthy or appropriate BFU-E pool in hematopoiesis are not defined. That hematopoietic expansion is curtailed in mice with steel mutations and anemia develops in mice treated with anti-KIT antibody suggests that adequate levels of normal KL may be crucial for early erythropoietic expansion.

The rate of red cell production can also be accurately evaluated by ferrokinetic studies (i.e., study of iron incorporation into developing red cells). In addition, a marrow scan, typically with technetium Tc 99 m, can document the extent of active erythropoiesis. However, these approaches are seldom necessary in clinical practice because estimates of erythropoiesis can be obtained from the reticulocyte index. First, the observed percentage of reticulocytes is normalized to the hematocrit to calculate the total marrow output of reticulocytes. Alternatively, the absolute number of reticulocytes per microliter can be counted directly using fluorescent RNA labeling. However, because younger reticulocytes are prematurely released into the circulation under conditions of acute need, the total number of reticulocytes overestimates the true level of red cell production as measured by iron kinetics. Therefore a second correction is made to account for the maturation of early circulating reticulocytes, or “shift” cells (polychromatophilic red cells), when present in the blood smear. The resulting reticulocyte index provides an excellent estimate of effective red cell production.

Although the presence, density, or both of EPORs on developing erythroid cells determines the responses to EPO, other proper ties (e.g., surface antigens on BFU-E versus CFU-E versus end-stage red cells) may provide the basis for selective suppression of CFU-E versus BFU-E or selective immune destruction of red cells versus erythroblasts. For example, suppression of CFU-E or erythroblasts can occur in acquired pure red cell aplasia or B19 parvovirus infection, respectively, whereas the BFU-E compartment in both these conditions remains largely unperturbed. Thus, the boundary from BFU-E to CFU-E and erythroblast may be biologically important for the pathophysiology of these disease states. Furthermore, in acquired hemolytic anemia, selective destruction at a given stage of maturation (of red cells only or of both erythroblasts and red cells) can be observed depending on the type of antibody produced and the density of its antigen present on maturing erythroid cells.

Detailed knowledge of the structural and functional properties of erythroid cells throughout their differentiation may provide significant insights into the pathogenesis of hematopoietic disorders affecting the red cell lineage. These studies have identified qualitative aberrations in the response of erythroid progenitors to cytokines or EPO that may underlie the abnormalities of congenital erythroid hypo plasia (Diamond-Blackfan syndrome). Analogous qualitative or functional defects can be observed in neoplastic erythropoiesis, because erythroid progenitors from patients with PV and other myeloproliferative neoplasms have altered sensitivities to EPO.

The correlation between the antigenic profiling and the function of erythroid cells described in the section “The Erythroid Compartment” is not maintained under conditions of perturbed or stressed erythropoiesis. Stress activates bone morphologic protein 4 (BMP4)/Hedgehog signaling, which induces the generation of erythroid progenitor cells with a unique phenotype, KITpos, CD71pos, and TER-119pos (TER-119 recognizes the murine equivalent of glycophorin A). The expression on these cells of “true” markers of terminal erythroid maturation suggests that stress-specific erythroid progenitors may be related to the proerythroblasts with extensive proliferative potential generated in mice after EPO treatment or anemia challenge, thereby indicating that stress may uncouple proliferation and differentiation programs during terminal erythroid maturation. Interestingly, human erythroblasts generated in the presence of dexamethasone also express high levels of KIT and acquire self-renewal potential. These observations challenge the notion that erythroblasts are capable of a limited (at most two to four) number of divisions.

Murine models have been developed to address phenotype-function cell relationships during recovery from acute and chronic erythroid stress. A model for acute stress is represented by the hemolytic anemia induced by phenylhydrazine treatment. Recovery from this acute anemia involves recruitment of the spleen as an additional erythropoietic site and is dependent on EPO. The amount of 3H-thymidine incorporated by splenic erythroblasts produced in response to this stress initially represented the biologic assay for EPO. Genetic evidence indicates that recovery from this hemolytic anemia is controlled by a receptor complex formed between the EPOR and a truncated version of the Stk receptor encoded by Fv2s, a locus that also determines strain susceptibility to Friend virus infection. An additional control on the response to acute erythroid stress in mice is exerted by the GR, because mice in which this receptor is targeted recover poorly from phenylhydrazine treatment. On the other hand, experimentally induced mutations in genes involved in the regulation of erythroid differentiation, such as STAT5null119 and GATA1LOW, or an inability to respond to ROS challenge (i.e., Foxo3 deficiency) increase the rate of erythroblast apoptosis.

Although clinical observations indicating that the GR ligand such as dexamethasone stimulates erythropoiesis have been available since 1961, the precise role of GR in human erythropoiesis is still unclear. GR activation increases the erythroid output by inducing BFU-E-self replication (this effect is mediated by ZFP36L2 in cooperation with PARP) and by blocking the terminal maturation of proerythro blasts which proliferate for longer period of time. This later effect requires the chaperone protein, calreticulin (CALR), which retains GR in the cytoplasm restoring EPOR signaling.

Great individual variability in the response to glucocorticoids exists in the human population. In fact, the murine GR is not polymorphic, whereas the human GR (GR/NR3C1 located in the 5q31-32 region of chromosome 5 and deleted in 5q-syndrome) contains several SNPs. Because of this genetic diversity, human cells may express more than 260 isoforms with slightly or greatly different biologic activities. The most studied isoform is GRα, an isoform similar to the murine GR. Alternative splicing between exon 3 and 4 generates GRγ, an isoform containing an additional arginine in the DNA-binding domain that reduces the transactivation potential by half. An alternative splicing of exon 9 generates mRNA encoding the dominant-negative GRβ isoform. It is generally accepted that responses to GR ligands depend on the signal transduction potential of the GR isoforms expressed by different cells and tissues. Studies in human non-erythroid cell types have identified that GR isoform expression predicts the variegation of cellular response to dexamethasone in vitro. Recently, clinicians have established important correlations between GR haplotype and variability in patients’ responses to glucocorticoids and in the development of glucocorticoid resistance in several disorders. GR poly morphism and/or epigenetic changes are emerging as the leading cause for dexamethasone unresponsiveness or for development of dexamethasone resistance in patients with inflammatory and autoimmune diseases (i.e., Crohn disease, systemic lupus) and in chronic depression. The frequency of the rs6198 SNP is also greater than normal in patients with the Philadelphia-negative myeloproliferative neoplasm PV (55%, P = .0028) and primary myelofibrosis and with DBA (43%, P = .03), suggesting that genetic conditions favoring GRβ expression may represent host genetic modifiers in diseases with altered terminal erythroid differentiation.

Additional functions of the red cells are starting to emerge: RBCs are thought to initiate clotting by binding to the endothelial cells and trapping platelets to the binding site. Since they express high levels of lipoprotein receptors, RBCs have been proposed to function as lipid scavengers that regulate the lipid content in blood and may affect the onset of atherosclerosis and stroke. In addition, the similarity between the amino acid sequence of the blood group antigens and that of proteins present on the surface of bacteria and the increased frequency of certain blood group antigens in regions with a high incidence of malaria suggest that the blood group antigens present on red cells may facilitate development of innate immunoreactivity toward opportunistic infections.

اخر الاخبار

اخبار العتبة العباسية المقدسة

استعدادًا لافتتاحه.. المشرف على قسم الشؤون الطبية يجري جولة في مركز السيد جعفر الحلي للخدمات الطبية.

الهيأة العليا لإحياء التراث تقيم الدورة العلمية التخصصية لكتاب في رحاب العقيدة

سماحة السيد الصافي يؤكد ضرورة تنمية الموارد المالية لدائرة التقاعد الوطنية وتعظيمها

بالتزامن مع اليوم الوطني للقرآن الكريم المَجمَع العلميّ ينظم دورة تطويرية لأساتذة مشروع حفظ القرآن الكريم في كربلاء

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

إنجاز طبي تاريخي.. جراحة قلب بلا شق في الصدر

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

Erythropoiesis and Iron Regulation

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