As discussed in Chapter 27, the mature RBC is the product of a com plex and orderly set of differentiation and maturation steps beginning with the pluripotent stem cell. By complex partially understood mechanisms involving hierarchic networks of cytokines, a portion of these cells becomes committed to differentiate along the erythroid pathway. Commitment to erythropoiesis provokes a progressively increasing sensitivity to the stimulatory actions of the hormone erythropoietin. As differentiation proceeds, there is preprogramming of certain genes whose expression at high levels will be required during the maturation phase of erythropoiesis. Genes coding for molecules defining the RBC phenotype (e.g., globin) are poised for activation at later maturation steps.

Intermediate progenitor cells arising during differentiation have been characterized experimentally, including the burst-forming unit erythroid (BFU-E) and the colony-forming unit-erythroid (CFU-E) stages. BFU-Es are progenitor cells that in culture produce bursts or clusters of erythroid colonies, are relatively less sensitive to erythropoietin, and are more plastic with respect to important gene expression parameters, such as the synthesis of adult or fetal Hb (HbF) by their descendants. CFU-Es produce single colonies, exhibit considerably higher sensitivity to erythropoietin, and appear to be more fixed in their potential to express a particular subset of globin genes. CFU-Es give rise to the first morphologically recognizable erythroid cells, the proerythroblasts. At this “primitive” morphologic stage, the program of erythroid cell expression has already been essentially pre-determined. The cell is predestined to undergo only a limited additional number of cell divisions, culminating in the formation of the enucleate reticulocyte. The terminal maturation stages are morpho logically recognizable as erythroblasts exhibiting progressive hemoglobinization of the cytoplasm, condensation, and eventual ejection of the nucleus and remodeling of the plasma membrane. The actual expression of the preprogrammed genes occurs during the 5- to 7-day period of erythroblast maturation.

As discussed in Chapters 9 and 27, the actual reconfiguration of chromatin for activation of the genes and activation itself appears to require the concerted and complex interaction of a diverse but limited group of transcription factors and associated epigenetic regulators. These regulatory proteins recognize a specific array of promoter and enhancer sequences that are embedded as recurrent motifs in and around the appropriate target genes. Even though an enormous amount of information has been gathered about sequences such as the GATA enhancers and their cognate transcription factors (e.g., GATA, FOG, ETS), the precise means by which these sequences and fac tors cause erythroid differentiation remains under investigation. At this time, this information is of limited clinical relevance to anemias or polycythemias. Major changes in the balance of post transcriptional regulatory molecules such as pre-mRNA splicing factors, mRNA stabilization factors, and translation factors also occur during maturation. Some of these, notably certain splicing factors, are proving to be relevant to myelodysplastic and myeloproliferative disorders (see Chapters 61 and 70). The orderly 14- to 21-day sequence of differentiation and maturation becomes progressively influenced by the levels of erythropoietin available to the progenitor cells, possibly because of increasing density and affinity of erythropoietin receptors on their cell surfaces. Within 24 hours after enucleation, the reticulocyte traverses the bone marrow–blood barrier membrane and enters the circulation as an immature erythrocyte. These cells retain remnants of nucleated precursors in the form of a relatively small number of polyribosomes actively translating messenger ribonucleic acid (RNA) (greater than 90% of which is globin messenger RNA), a cell membrane that retains some molecules and structures reminiscent of its earlier stages of differentiation, and the complement of enzymes, phospholipids, and cytoskeletal proteins that the cell will possess throughout its remaining life span.

During its first 24 hours in the circulation, the reticulocyte spends considerable amounts of time in the spleen, during which its mem brane is “polished.” This is a poorly understood remodeling process by which some lipids and proteins, including adhesive molecules such as fibronectin, are removed. The content of polyribosomes and other nucleic acids progressively declines so that stainability with methylene blue is lost by the end of the first day. At this time, the RBC is regarded as a mature erythrocyte, and it circulates relatively unchanged for the remainder of its 120-day life span.

Perhaps the most remarkable feature of the human RBC is its durability, given that it is an enucleated cell devoid of organelles that are critical for the survival and function of most other cell types. The RBC has no mitochondria available for efficient oxidative metabolism; no ribosomes for regeneration of lost or damaged proteins; a very limited metabolic repertoire that largely precludes de novo synthesis of lipids; and no nucleus to direct regenerative processes, adaptation to circulatory stresses, or cell division to replenish itself. Given these handicaps, the 120-day survival of these cells is even more striking considering the multiple and often exceedingly hostile environments they must traverse. Mechanical stresses of the circulation include high hydrostatic pressure and turbulence and the shear stresses inherent in a microcirculation networked with many capillaries having diameters only one-third to one-half that of the normal RBC. Biochemical stresses include osmotic and redox fluxes associated with travel through the collecting system of the kidney; the sluggish vascular beds of the spleen, muscle, and bone; and the rapid changes in ambient oxygen pressures occurring in the lungs. All con spire to damage RBCs. Their 4-month survival is truly remarkable.

The ability of the RBC to persist in the circulation depends on its simple but exquisitely adaptive membrane structures; its pathways of intermediary energy metabolism and redox regulation; and its ability to maintain its largest cytoplasmic component, Hb, in a soluble and non-oxidized state. The membrane and enzymes of the RBC appear to be exquisitely crafted to protect the cell from the external ravages of the circulation and the potential internal assaults of the massive amount of iron-rich and potentially oxidizing protein represented by its complement of Hb molecules. For these reasons, a few basic features of these membrane and enzyme systems merit comment before considering the Hb molecule itself.

اخر الاخبار

اخبار العتبة العباسية المقدسة

العتبة العباسية المقدسة تشهد تشييع جثمان المحقق الشيخ محمد رضا المامقاني

قسم الشؤون الفكرية يختتم برنامج (فتية سيد الماء) لرعاية الأيتام بنسخته الثانية

لتطوير المهارات الإدارية.. العتبة العباسية المقدسة تطلق الدورة التعليمية الأولى لمسؤولي وحداتها

قسم التطوير يقيم دورة تدريبية عن الظهور الإعلامي لملاكاته

المزيد

الآخبار الصحية

دراسة تكشف "السبب الخفي" وراء ترك التمارين الرياضية

كشف التوقيت "المثالي" لتغيير فرشاة الأسنان

بلاستيك في أنسجة بشرية.. دراسة تكشف مفاجأة طبية

دراسة تحذر من الإفراط في ممارسة الرياضة.. كيف يضر دماءك؟

المزيد

الآخبار التكنلوجية

"ديب سيك" تحجب أحدث نماذجها عن شركات الرقائق الأميركية

"سامسونغ" تطلق سلسلة هواتف "غالاكسي إس 26"

حملات سرية ورسائل تشويه.. كيف يتم استغلال "تشات جي بي تي"؟

أثر نفسي غير متوقع للرياضة.. مرتبط بالغضب

المزيد

مواضيع ذات صلة

sentinel lymph node biopsy (SLNB, Lymphoscintigraphy)

salivary gland nuclear imaging (Parotid gland nuclear imaging)

pulmonary angiography (Pulmonary arteriography)

Fever of Unknown Origin

Biological Markers of Mental Illness

New Biomarkers of Bone Remodeling : Sclerostin

New Biomarkers of Bone Remodeling : RANK-RANKL-OPG

Splenic Abscesses

Liver Abscesses

Intraperitoneal Abscesses

Prions

Periprosthetic Joint Infection