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 – Granulocito 6-8 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)/Ht CMHC = 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 µ, un volumen de 90 fL y contiene 30 pg de Hb que ocupan el 33 % del volumen celular

Normal Hematopoiesis CD34+, CD38(

) Hematopoietic Stem Cell

c-kit+, Thy1+, CD71+, HLA-DR+, IL3Rα-

( ) SCID-Repopulating Cell

Modified from Dick: ASH Education Program Book, 2001

ERITROPOYESIS

Proeritroblasto

Células grandes (20-25 mm) Citoplasma pequeño Abundante mRNA

Eritroblasto policromatófilo

Células pequeñas (8-12 mm) Citoplasma grande Abundante Hb Eritroblasto ortocromático Células pequeñas (10 mm) Citoplasma grande Eritroblasto basófilo Abundante Hb Células grandes (16-18 mm) Al perder el núcleo se transforma Aumento relación citoplasma/núcleo en reticulocito (restos de síntesis de Hb organelas)

Disminución del tamaño celular Disminución del número de organelas Condensación nuclear Aumento del contenido de Hb

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

RECEPTOR S

Erythropoietin

CFC-E

kidney cells

Interleukin 3 (IL-3)

multipotent stem cell, most progenitor cells, many terminally differentiated cells GM progenitor cells

T lymphocytes, epidermal cells

cytokine family cytokine

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

Steel factor (stem cell factor)

hemopoietic stem cells

stromal cells in bone marrow and many other cells

receptor tyrosine kinase family receptor

Granulocyte/ macrophage CSF (GM-CSF)

family

tyrosine kinase

Total Blood

Total Body Pool

Red blood cell (× 1010/kg) Neutrophil (× 107/kg) Lymphocyte (× 107/kg) Platelet (× 1010/kg)

Circulatin Half-Life in g Pool Circulation

33

33

50  65 days

70 (14  160)

31 (11  46)

6.7 (4  10) hour

133  266

8  12

1 hour  1,500 days

 

 

 

 

 

 

Percentage of Volume Replaced Daily in Health Adult 0.8

 

   

230.0

 

2.8 (2.1  3.8)  

2.1 (1.6  2.9)  

4  5 days  

10.0

Type

Characteristics

Type 1 cytokine receptor

Does not possess intrinsic kinase acivity.

Receptors with tyrosine kinase domains (type) III

Large extracellular immunoglobulin-like domain, single transmembrane spinning region, and a cytoplasmic tyrosine kinase Seven transmembranedomain(s) spanning G protein-linke

Receptor Examples

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 acts as docking site receptor); flt3; c-kit (SCF for adaptor molecules, which receptor); PDGFR leads to phosphorylation of Type II cytokine cellular Containssubstrates. extracellular receptor fibronectin III type domain

Chemokine receptor

IL-8

regions Cysteine-rich repeats in the Tumor necrosis factor and extracellular domain, and Fas cytoplasmic 80-amino acid EPO = erythropoietin; G-CSF = granulocyte colony-stimulating factor; GM-CSF "death domain" = granulocyte-macrophage colony-stimulating factor; IL = interleukin; M-CSF = macrophage colony-stimulating factor; SCF = stem cell factor; TPO = Tumor necrosis factor family

Some Cytokines Using Subunit

Receptor Subunit Shared

IL-3, IL-5, and GM-CSF

β subunit

IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21

IL-2 receptor γc chain

IL-2 and IL-15

βchain of IL-2 receptor

IL-4 and IL-13

IL-4Rα and IL-13Rα1

IL-6, oncostatin M, leukemia inhibitory factor, and IL-11

gp130

IL10, IL-22

IL-10Rβ

IL-19, IL-20, IL-24

IL-20Rα, IL-20Rβ

IL-20, IL-22, IL-24

IL-22Rα

IL-12, IL-23

IL-12Rβ1

GM-CSF = granulocyte macrophage colony-stimulating factor; IL = interleukin.

Characteristic27

   38

Stem Cell Factor

Comment

Chromosoma l 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);

Receptor

Influences hematopoietic cell adhesive properties c-kit

Natural antagonists

Soluble c-kit receptor

Major clinical trials

Peripheral blood progenitor mobilization (SCF + G-CSF better than SCF alone); Aplastic anemia (trilineage responses seen after SCF)

Also known as CD117: encoded on 4q11  q13 (piebald locus) Kit is mutated in gastrointestinal stromal tumors

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 (selfrenewal) 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.