HEMATOPOIESIS

Erythropoiesis

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  Maintenance of an adequate number of cells through these
functions:
 Proliferation
 Differentiation
 Death (apoptosis)

TISSUE HOMEOSTASIS

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 CELL CYCLE
 G1 S G2 M
 S phase - DNA synthesis
 M phase – mitosis

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 Necrosis: cell death by lethal chemical, biological or physical
events

 Apoptosis : programmed cell death regulated by genetic material

of cell

APOPTOSIS VS NECROSIS

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 HEMATOPOIESIS

▪ Blood cell formation – production and development

▪ Occurs bone marrow, liver, spleen, lymph nodes, thymus
▪ Bone marrow – sole site of effective hematopoiesis in normal adults
▪ 6 billion cells/kg of body weight per day
▪ 2.5 billion red cells
▪ 2.5 billion platelets
▪ 1.0 billion white cells
▪ Rate adjusted to need, vary from nearly zero to many times the normal
▪ Constant turnover of cells

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 1. Totipotential stem cells. These cells are present in the first few
hours after an ovum is fertilized. Totipotential stem cells, the most
versatile type of stem cell, can develop into any human cell type,
including development from embryo into fetus.
 2. Pluripotential stem cells. These cells are present several days
after fertilization. Pluripotent stem cells can develop into any cell
type, except they cannot develop into a fetus.
 3. Multipotential stem cells. These cells are derived from pluripotent
stem cells. They can be found in adults, but they are limited to
specific types of cells to form tissues. For example, bone marrow
stem cells can produce all types of blood cells, bone cartilage,
and adipose (fat) cells.

TYPES OF HUMAN STEM CELLS

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 Development of different cell lineages in blood
 Differentiation
 Appearance of different properties in cells
 Commitment
 Cells derived from common precursors take separate
routes
 Maturation occurs from commitment to fully developed
cell

DEFINITION OF HEMATOPOIESIS

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Yolksac > fetal liver/spleen > BM
Three developmental periods
Mesoblastic
Hepatic
Myeloid

ONTOGENY OF HEMATOPOEISIS

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 Blood islands of yolk sac
 Primarily RBC production
 Embryonic hemoglobin produced

MESOBLASTIC

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 At 6 weeks cell production in liver
 Fetal hemoglobin produced
 Spleen, thymus, lymph nodes also active production

HEPATIC

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 At 5th month Bone Marrow becomes site of cell
production
 Liver & spleen now Extramedullary
 Hemoglobin A (22)

MYELOID

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 Stem cells
 Progenitor cells
 Maturing cells

HEMATOPOIETIC PRECURSOR CELLS

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 Hematopoietic growth factors
Growth Factors Function: stimulate
progenitor of the followings:
GM-CSF (granulocyte- Granulocyte-monocyte
macrophage CSF)
G-CSF (granulocyte CSF) Granulocyte

M-CSF (macrophage CSF) Monocyte

EPO (Erythropoietin) Erythrocyte

IL-1,3,6 (Interleukin-3, 1, 6) Myeloid lineage

TPO (Thrombopoietin) Platelet

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 ▪ Very small group of cells
▪ Multipotential cells that give rise to all lineages of blood cells
▪ High self-renewal ability
▪ Not morphologically distinguishable
▪ Identified by flow cytometry with marker CD34
▪ Supporting research

STEM CELLS

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 Committed cells to differentiation into cell lines
 Described as colony-forming units (CFU)
 CFU-GEMM
 CFU-GM
 CFU-Meg
 Population amplified by proliferation

PROGENITOR CELLS

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 Majority of precursor cells
 Recognizable morphologic characteristics
 Nomenclature unique for each cell line

MATURING CELLS

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▪ Cytokines
▪ Govern precursor cell survival, self-renewal, proliferation,
differentiation
▪ Growth factor control
▪ Interleukins numbered according to discovery
▪ Growth factors promote cell survival by suppressing
apoptosis
▪ Growth factors promote proliferation

CYTOKINES & GROWTH

FACTORS
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 Erythropoiesis
 BFU-E
 CFU-E dependent on EPO
 Granulopoiesis and Monopoiesis
 CFU-GM supported by IL-3
 Megakaryocytopoiesis
 CFU-Meg induced by IL-11 and TPO
 Lymphopoiesis
 Multiple GF in development of T & B cells

LINEAGE SPECIFIC CYTOKINES

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BONE MARROW

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 Bone marrow/ medullary hematopoiesis
 Major hematopoietic organ
 Blood forming tissue located between
trabeculae
 Bonemarrow stroma is supporting tissue for
hematopoietic cells
 Red marrow/yellow marrow

BONE MARROW

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 Lymphopoietic organ in upper mediastinum
 Cortex densely packed with small lymphocytes
 Primary purpose
 Compartment for maturation of T lymphocytes
 Precursor T cells leave the bone marrow and enter the
thymus

THYMUS

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 Upper left quadrant of abdomen
 Richly supplied with blood
 Functions include
 culling; filtering and destruction of old or damaged RBCs
 Pitting: pluck our particles from RBCs
 immune defense
 storage: hold 1/3 of platelets

SPLEEN

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 Lymph nodes and lymphatic vessels

 Nodes remove foreign particles from lymph

 Functions
 Immune defense
B cell production in germinal centers

LYMPHATIC SYSTEM

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 ERYTHROPOIESIS

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 Total population
of erythrocytes and precursors in peripheral
blood and bone marrow
 RBC production
 RBC release
 RBC destruction
 Primary signal regulating RBC production is oxygen tension
  tissue oxygenation due to anemia or pulmonary insufficiency

ERYTHRON

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 Stimulated by Erythropoietin (EPO), a glycoprotein hormone
produced in the kidney
 EPO accelerates commitment of pluripotent stem cell to CFU-E
and erythroid development

ERYTHROPOIESIS

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 Cells accumulate hemoglobin
 Lose their protein-synthesizing apparatus
 Nuclear chromatin pattern changes
 cells become smaller
 Nucleus to cytoplasm ratio decreases

MATURATION CHARACTERISTICS

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 Pronormoblast

 Basophilic normoblast
 Polychromatic normoblast
 Orthochromic normoblast
 Reticulocyte

 Erythrocyte

SEQUENCE OF RBCS MATURATION

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ALL STAGES OF ERYTHROPOEISIS

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PROERYTHROBLAST

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BASOPHILIC ERYTHROBLAST

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POLYCHROMATIC ERYTHROBLAST

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ORTHOCHROMATIC ERYTHROBLAST

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RETICULOCYTE/POLYCHROMATIC RBC

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RED BLOOD CELLS

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latin American-english
normoblastic rubriblastic Erythroblastic
pronormoblastic Rubriblast proerythroblast

NOMENCLATURE FOR RBC PRECURSORS

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RBC STRUCTURE AND FUNCTION
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RBC MEMBRANE COMPOSITION

 Proteins
 Trilaminar structure
 integral: Extend from outer
 outer hydrophilic surface to inner
 central hydrophobic  peripheral: cytoplasmic
 inner hydrophilic surface beneath lipid
bilayer

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SCHEMATIC OF RBC MEMBRANE
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RBC MEMBRANE LIPIDS

 95% of lipid content

 Unesterified Cholesterol
 Phospholipid bilayer
 Remaining 5%
 Glycolipids
 Antigenic properties of the membrane

 Free fatty acids

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 Integral
 Glycophorin A,B,C
 Carry RBC antigens and give the RBC it’s negative charge

 Band 3
 Functions as anion exchange protein

MEMBRANE PROTEINS: INTEGRAL

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 Peripheral (form membrane “skeleton”)

 Contribute to cell shape,membrane

stability, deformability and gives it the
viscoelastic properties

MEMBRANE PROTEINS: PERIPHERAL

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 RBC DEFORMABILITY

Flexibility
of the RBC to squeeze through
capillaries
Increased conc of hgb or decreased
fluidity = decreased deformability.
Accumulation of membrane calcium
result in rigid, shrunken cells & reduced
deformability
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Freely permeable to H2O, Cl-,
Cationpump regulates
balance of Na+and K+

RBC PERMEABILITY

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 Limited
because of absence of nucleus,
mitochondria, and other organelles
 Pathways described contribute energy to
maintain :
 high intracellular K+, low intracellular Na+, very low
intracellular Ca++
 Hemoglobin in reduced form
 Membrane integrity and deformability

RBC METABOLISM

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1- Embden-Meyerhof Pathway
2- Hexose Monophosphate Shunt
3-Methemoglobin reductase
4-Rapoport- Luebering Shunt

PATHWAYS:

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90-95% of rbc glucose consumption
 Glucose enters cell by diffusion and metabolized to
lactate
 net gain of two moles of ATP/mole of glucose
 Key enzymes: pyruvate kinase, phosphofructokinase
 Key
role: ATP necessary for RBC shape, flexibility and
membrane integrity

PATHWAYS: EMBDEN-MEYERHOF
PATHWAY
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GYLCOLYSIS IN RBCS

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 produces reduced NADPH and reduced
glutathione(GSH)
 Functionally dependent on G6PD
 GSH protects cell from permanent oxidant
damage
 Key enzymes:glutathione reductase, G6PD
 Key role:maintain reduced GSH and reduced
NADP

HEXOSE MONOPHOSPHATE SHUNT

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DIAGRAM OF HMS

http://www.uq.edu.au/vdu/HexoseMonophosphateShunt.gif
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  Pathway that maintains heme iron in reduced ferrous (Fe 2+)
 Hgb in ferric state is methemoglobin(Fe3+)
 Key enzyme: methemoglobin reductase
 Key role: prevent hypoxia

METHEMOGLOBIN REDUCTASE

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 causes accumulation of 2,3 DPG thus
regulating oxygen delivery to the tissues.
 Key enzyme:DPG-synthetase
 Key role: affects oxygen affinity of hemoglobin

RAPOPORT- LUEBERING SHUNT

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 RBC begins to undergo senescence

 Reticuloendothelial
System (RES) daily removes 1%
of old RBCs via macrophages

 AsRBC ages, glycolytic enzymes decrease activity

resulting in less energy and less deformability

ERYTHROCYTE DESTRUCTION

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 Occurs in RES macrophages
 90% of RBC destruction
 iron returned to erythroid precursors
 globin amino acids returned to AA pool
 heme protoporphyrin ring disassembled .
Balances RBC number with
production and use

EXTRAVASCULAR HEMOLYSIS

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 5-10% rbc destruction(within blood
vessel)
Free hemoglobin in the blood
Iron bound to transferrin
Released Hgb complexed to
haptoglobin therefore decreased
haptoglobin in the plasma

INTRAVASCULAR HEMOLYSIS

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