Bases Moleculares Hematopoyesis
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Transcript of Bases Moleculares Hematopoyesis
Hematopoyesis
• Producción diaria de células hemáticas:– GR 200.000 millones– GB 70.000 millones
• Sin embargo es inefeciente sólo un 5% alcanzan el estadío final de maduración
• Vida Media de las células hemáticas:– GR 120 días– Granulocito6-8 horas– Plaqueta 7-10 días
Índices
• Hematocrito (Ht)– 47 5 %– 42 5 %
• Hemoglobina (Hb)– 13-15,5 g/dL– 12,5-14 g/dL
• Velocidad de Sedimentación Globular (VSG)
– 2-8 mm/h– 2-10 mm/h
•Hemoglobina Corpuscular Media (HCM)HCM = Hb(g/L)/nº de eritrocitos (cel/L)HCM = 150 g/L/5 x 10 12 cel./L =30 x 10- 12 g/cel
•Concentración Media de Hemoglobina Corpuscular (CMHC)CMHC = Hb(g/L)/HtCMHC = 150 g/L/0,45 = 333 g/L, 33 %.
•Volumen Corpuscular Medio (VCM)VCM = Ht/nº de eirtrocitos VCM = 0,45 / 5 x 10 12 cel./L = 90 fL
Un eritrocito tiene un diametro aprox. 7,5 , un volumen de 90 fL y contiene 30 pg de Hb que ocupan el 33 % del volumen celular
Normal Hematopoiesis
Modified from Dick: ASH Education Program Book, 2001
CD34+, CD38-
( ) SCID-Repopulating Cell
c-kit+, Thy1+, CD71+, HLA-DR+, IL3R-
( ) Hematopoietic Stem Cell
Disminución del tamaño celularDisminución del número de organelas
Condensación nuclearAumento del contenido de Hb
ProeritroblastoCélulas grandes (20-25 mm)Citoplasma pequeñoAbundante mRNA
Eritroblasto basófiloCélulas grandes (16-18 mm)Aumento relación citoplasma/núcleosíntesis de Hb
Eritroblasto policromatófiloCélulas pequeñas (8-12 mm)Citoplasma grandeAbundante Hb Eritroblasto ortocromático
Células pequeñas (10 mm)Citoplasma grandeAbundante HbAl perder el núcleo se transformaen reticulocito (restos de organelas)
ERITROPOYESIS
Figure 19-01
Copyright © 2005 Elsevier Inc. (USA) All rights reserved.
Figure 19-02
Copyright © 2005 Elsevier Inc. (USA) All rights reserved.
Table 19-02
Copyright © 2005 Elsevier Inc. (USA) All rights reserved.
Figure 19-03
Copyright © 2005 Elsevier Inc. (USA) All rights reserved.
Figure 19-04
Copyright © 2005 Elsevier Inc. (USA) All rights reserved.
FACTOR TARGET CELLS PRODUCING CELLS RECEPTORS
Erythropoietin CFC-E kidney cells cytokine family
Interleukin 3 (IL-3) multipotent stem cell, most progenitor cells, many terminally differentiated cells
T lymphocytes, epidermal cells
cytokine family
Granulocyte/ macrophage CSF (GM-CSF)
GM progenitor cells T lymphocytes, endothelial cells, fibroblasts
cytokine family
Granulocyte CSF (G-CSF)
GM progenitor cells and neutrophils macrophages, fibroblasts cytokine family
Macrophage CSF (M-CSF)
GM progenitor cells and macrophages fibroblasts, macrophages, endothelial cells
receptor tyrosine kinase family
Steel factor (stem cell factor)
hemopoietic stem cells stromal cells in bone marrow and many other cells
receptor tyrosine kinase family
Total Blood Total Body Pool
Circulating Pool
Half-Life in Circulation
Percentage of Volume Replaced Daily in Healthy Adult
Red blood cell (× 1010/kg)
33 33 50 65 days 0.8
Neutrophil (× 107/kg)
70 (14 160) 31 (11 46) 6.7 (4 10) hour
Lymphocyte (× 107/kg)
133 266 8 12 1 hour 1,500 days
230.0
Platelet (× 1010/kg)
2.8 (2.1 3.8)
2.1 (1.6 2.9)
4 5 days 10.0
Type Characteristics Receptor Examples
Type 1 cytokine receptor
Does not possess intrinsic kinase acivity. IL-1, -2, -3, -4, -5, -6, -7, -9, -13, -18, - 21;GM-CSF; G-CSF; EPO; TPO; leukemia inhibitory factor; interferon and IL-10; fms (M-CSF receptor); flt3; c-kit (SCF receptor); PDGFR
Receptor acts as docking site for adaptor molecules, which leads to phosphorylation of cellular substrates.
Type II cytokine receptor
Contains extracellular fibronectin III type domain
Receptors with tyrosine kinase domains (type) III
Large extracellular immunoglobulin-like domain, single transmembrane spinning region, and a cytoplasmic tyrosine kinase domain(s)
Chemokine receptor Seven transmembrane-spanning G protein-linke regions
IL-8
Tumor necrosis factor family
Cysteine-rich repeats in the extracellular domain, and cytoplasmic 80-amino acid "death domain"
Tumor necrosis factor and Fas
EPO = erythropoietin; G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; IL = interleukin; M-CSF = macrophage colony-stimulating factor; SCF = stem cell factor; TPO = thrombopoietin.
Some Cytokines Using Subunit Receptor Subunit Shared
IL-3, IL-5, and GM-CSF subunit
IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 IL-2 receptor c chain
IL-2 and IL-15 chain of IL-2 receptor
IL-4 and IL-13 IL-4R and IL-13R1
IL-6, oncostatin M, leukemia inhibitory factor, and IL-11 gp130
IL10, IL-22 IL-10R
IL-19, IL-20, IL-24 IL-20R, IL-20R
IL-20, IL-22, IL-24 IL-22R
IL-12, IL-23 IL-12R1
GM-CSF = granulocyte macrophage colony-stimulating factor; IL = interleukin.
Characteristic27 38 Stem Cell Factor Comment
Chromosomal localization
12q22 12q24
Natural forms of SCF
Transmembrane and soluble Both forms are biologically active
Major sites of production
Marrow stroma IL-1 and TNF increase stromal SCF reproduction
Hematopoietic cells
Gut epithelial cells
Central nervous system, thymus
Skin keratinocytes
Selected biologic activities
Promotes hematopoiesis at multiple levels; migration during embryonic life; Influences primordial germ cell and melanocyte
Affects immunoregulatory cells (B and T cells, mast cells, NK cells, dendritic cells);
Influences hematopoietic cell adhesive properties
Receptor c-kit Also known as CD117: encoded on 4q11 q13 (piebald locus)
Natural antagonists
Soluble c-kit receptor Kit is mutated in gastrointestinal stromal tumors
Major clinical trials Peripheral blood progenitor mobilization (SCF + G-CSF better than SCF alone);
Aplastic anemia (trilineage responses seen after SCF) STI571 (Gleevec) targets the activated Kit kinase activity and produces striking responses in gastrointestinal stromal tumors with Kit mutations
Causes of Anemia, Thrombocytopenia, and Leukopenia in Cancer
Bone marrow replacement by primary tumor (eg, leukemia)
Bone marrow involvement by metastatic tumor (eg, breast, prostate)
Derangement of normal physiology
Nutritional (eg, folate, iron, negative nitrogen balance)
Abnormal feedback (eg, stimulation/inhibition of hematopoiesis)
Bone marrow reaction (eg, fibrosis)
Peripheral destruction (eg, immune hemolysis, diffuse intravascular coagulation, splenomegaly)
Blood loss
Myelosuppression by chemotherapy or radiotherapy
Summary
The many types of blood cells, including erythrocytes, lymphocytes, granulocytes, and macrophages, all derive from a common multipotent stem cell. In the adult, hemopoietic
stem cells are found mainly in bone marrow, and they depend on contact-mediated signals from the marrow stromal (connective-tissue) cells to maintain their stem-cell
character. The stem cells normally divide infrequently to produce more stem cells (self-renewal) and various committed progenitor cells (transit amplifying cells), each able to
give rise to only one or a few types of blood cells. The committed progenitor cells divide extensively under the influence of various protein signal molecules (colony-stimulating
factors, or CSFs) and then terminally differentiate into mature blood cells, which usually die after several days or weeks.
Studies of hemopoiesis have been greatly aided by in vitro assays in which stem cells or committed progenitor cells form clonal colonies when cultured in a semisolid matrix. The
progeny of stem cells seem to make their choices between alternative developmental pathways in a partly random manner. Cell death by apoptosis, controlled by the
availability of CSFs, also plays a central part in regulating the numbers of mature differentiated blood cells.