4.1.-Erythropoiesis-RBC-Maturation.pdf
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Blood Cell Formation, Maturation and Differentiation ERYTHROPOIESIS It takes about 18-21 days to produce an RBC from stimulation of the earliest erythroid progenitor to release from the BM. Criteria for the identification of the erythroid precursors ...
Blood Cell Formation, Maturation and Differentiation ERYTHROPOIESIS It takes about 18-21 days to produce an RBC from stimulation of the earliest erythroid progenitor to release from the BM. Criteria for the identification of the erythroid precursors Nuclear chromatin pattern Nuclear diameter N:C ratio Presence/absence of nucleoli Cytoplasmic color Rules (as the cell matures) Diameter of the cell decreases. N:C ratio decreases. Nuclear chromatin becomes coarser, clumped and condensed. Nucleoli disappear. Cytoplasm changes from blue to gray-blue to salmon-pink. Basophilia or blueness is due to acidic components that attract the basic stain (methylene blue). The degree of cytoplasmic basophilia correlates with the amount of ribosomal RNA. Pinkness called eosinophilia or acidophilia is due to the accumulation of more basic components that attract the acid stain, eosin. N:C ratio – visual estimate of what area of the cell is occupied by the nucleus compared with the cytoplasm RBC Maturation Series (pronormoblastic/rubriblastic/erythroblastic nomenclature) 1. PRONORMOBLAST RUBRIBLAST PROERYTHROBLAST a. Earliest morphologically recognizable erythrocyte precursor b. 1% in the BM c. 12-20 um d. N:C ratio = 8:1 e. 1-3 nucleoli f. Chromatin (purple-red) is fine and uniform. g. Deep/dark blue cytoplasm (ribosomes) with no granules 2. BASOPHILIC NORMOBLAST PRORUBRICYTE BASOPHILIC ERYTHROBLAST a. 1-4% in the BM b. 10-15 um c. N:C ratio = 6:1 Blood Cell Formation, Maturation and Differentiation d. Centrally located nucleus with 0-1 nucleoli e. Chromatin (deep purple-red) is coarsening/begins to condense. f. Cytoplasm is less blue but intensely basophilic. 3. POLYCHROMATOPHILIC NORMOBLAST RUBRICYTE POLYCHROMATOPHILIC ERYTHROBLAST a. 10-20% in the BM b. 10-12 um c. N:C ratio = 4:1 d. Eccentric nucleus with no nucleoli e. Chromatin shows significant clumping. f. Last stage capable of cell division g. Begins to produce hemoglobin, resulting in murky gray-blue cytoplasm (mixture of pink and blue;; polychromatic = many colors) 4. ORTHOCHROMATOPHILIC NORMOBLAST METARUBRICYTE ORTHOCHROMATOPHILIC ERYTHROBLAST a. 5-10% in the BM b. 8-10 um c. N:C ratio = 1:2 d. Eccentric nucleus with small, fully condensed (pyknotic) nucleus e. No nucleoli f. Pale blue to salmon-pink cytoplasm g. Hemoglobin synthesis decreases h. Last stage with nucleus (moves to the periphery and is ejected from the cell -> Howell-Jolly bodies 5. RETICULOCYTE a. 1% in the BM b. 8-10 um c. No nucleus d. Salmon-pink cytoplasm e. Last stage to synthesize hemoglobin f. Last stage in the bone marrow prior to release to the peripheral blood g. Can be best seen using supravital stains 6. MATURE ERYTHROCYTE a. 6-8 um (ave 7.2 um) b. Round, biconcave discocyte c. Salmon-pink with central pallor Blood Cell Formation, Maturation and Differentiation ERYTHROKINETICS (dynamics of RBC production and destruction) Erythron – collection of all stages of erythrocytes throughout the body;; entirety of erythroid cells in the body RBC mass – refers ONLY to cells in the circulation Hypoxia – stimulus to RBC production;; too little tissue oxygen;; detected by the peritubular cells of the kidneys which will produce EPO Erythropoietin (EPO) mol wt. = 34 000 Daltons MAJOR stimulatory cytokine (growth factor) for RBC production amount is regulated to sufficiently replace RBCs that undergo senescence (death due to old age) trauma, increased RBC destruction and diminished O2-carrying capacity influence EPO production signal transduction: sends intracellular messages to RBCs (binds to receptor on the surface of cells ad creates a cascade or “program” that will lead to cell division, maturation and more RBCs entering the circulation JAK2 signal transducer (Janus-activated tyrosine kinase 2) three major effects: early release of reticulocytes from the BM, prevents apoptosis, reduced time needed for cells to mature in the BM puts more RBCs into the circulation at a faster rate than without its stimulation Early release of reticulocytes EPO induces changes in the adventitial cell layer to increase the width of the spaces to allow for movement of RBCs (held in the marrow because they contain receptors for adhesive molecules -> EPO downregulates or suppress these receptors for RBCs to be loosened from adhesion, allowing early exit -> shift reticulocytes) Limited in effectiveness: precursors in the BM (storage pool) become depleted Inhibition of apoptosis Increasing the number of cells that will mature into circulating erythrocytes Apoptosis – programmed cell death;; intentional cell wasting When there is a steady-state demand for RBCs, early progenitors are allowed to die, but in cases of increased demand, RBC progenitors are given a head-start, preventing apoptosis or death. EPO indirectly removes the apoptosis induction signal. o Fas – death receptor found on the membrane of progenitor cells;; ligand: FasL (present on more mature cells) o When EPO levels are low, so is cell production because hypoxia is not present;; thus;; early precursors are allowed to undergo apoptosis. This happened when FasL-bearing precursors cross-link with Fas-marked immature precursors which are stimulated to undergo cell death. As long as Blood Cell Formation, Maturation and Differentiation more mature cells with FasL are present in the marrow, erythropoiesis is subdued. If FasL-bearing cells are depleted, EPO is produced and younger Fas+ precursor are allowed to develop which increases RBC output by the marrow. Direct EPO rescue from apoptosis o When EPO binds to its receptor on the CFU-E, one of the effects is to reduce production of Fas ligand;; thus, younger cells avoid the apoptotic signal from the older cells. Reduced marrow transit time Increasing the rate at which surviving precursors can enter the circulation o Increased rate of cellular processes o Decreased cell cycle times = reduced time for cells to mature;; fewer mitotic divisions Increased hemoglobin production Bone marrow egress = loss of adhesive molecules Cessation of division = cell division takes time, delay in the entry of cells to the circulation Stress reticulocytes – due to early marrow exit Other stimuli to erythropoiesis: hormones (testosterone, pituitary and thyroid hormones) Erythrocyte Destruction RBC life span: 120 days Senescence (old age or cellular aging) – brought about by loss of glycolytic enzymes (RBC lacks mitochondria) Macrophage-Mediated Hemolysis (Extravascular Hemolysis) Deteriorating glycolytic processes = reduced ATP production;; low glucose Oxidation of membrane lipids and proteins Imbalance between intracellular and extracellular ions – effect on the membrane’s selective permeability (water enters the cell, losing its discoid shape) Spherical RBCs are rigid and cannot squeeze though narrow vessels, trapped and ingested or salvaged by macrophages. Macrophages are able to recognize senescent cells and distinguish them from younger cells. Iron is removed and stored as ferritin. Mechanical Hemolysis (Fragmentation or Intravascular Hemolysis) Mechanical or traumatic stress – rupture of cell membrane while the cell is in the peripheral circulation (inside the blood vessels)
