Hematopoiesis, Differentiation and Maturation of Blood Cells

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Hematopoiesis, Differentiation and Maturation of
Blood Cells

• Dr.Nadjwa Zamalek Dalimoenthe, SpPK-K Department
  of Clinical Pathology RSHS/FKUP Bandung

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Topics to be discuss

• Site of hematopoiesis
• Hematopoietic stem progenitor cells
• Bone marrow stroma
• Hematopoietic growth factor
• Stem cell plasticity
• Apoptosis
• Growth factor receptor and signal transduction
• Adhesion molecules
• Differentiation of blood cells
• Maturation of blood cells

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Reference Books

1. Essential Hematology. AV Hoffbrand, JE Pettit,
   PAH Moss. 4th ed.
2. Denise M Harmening. Hematology and Hemostasis.

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Site of hematopoiesis
AGE SITE
Fetus 0-2 months Yolk sac
2-7 months Liver, spleen
5-9 months Bone marrow
Infants Bone marrow, practically all bones
Adults Vertebrae, ribs, sternum, sacrum and pelvis, proximal ends of femur

• Developing cells situated outside of BM sinuses
  ? mature cells
• released into sinus spaces ? marrow
  microcirculation ? general
• circulation.
• Hematopoiesis starts with pluripotent stem cell

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Hematopoietic Stem Progenitor Cells
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Pluripotent(ial) Hematopoietic Stem Cell

• Give rise to the separate cell lineage
• Exact phenotype unkown ? immunological testing
  CD34, CD38-
• Appearance small/medium size lymphocyte
• Cell differentiation occurs from the stem cell
  down the erythroid, granulocytic and other
  lineages via the committed hematopoietic
  progenitors cells ? restricted in their
  developmental potential.

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• SC has the capability of self-renewal ?
  cellularity remains constant in a normal healthy
  steady state.

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• 1 SC capable of producing 106 mature blood
  cells after 20 cell divisions.
• SC capable of responding to hematopoietic growth
  factors with increased production of one or other
  cell line when the need arises.

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Bone Marrow Stroma

• Suitable environment for SC growth dev.
• Composed of stromal cells microvascular network.

• Extracellular molecules
• Collagen
• Glycoprotein (fibronectin,
• thrombospondin)
• Glycosaminoglycans
• (hyaluronic acid
• chondroitin derivates)
• Growth factors ? for cell
• survival

• Stromal cells
• adipocytes
• Fibroblast
• Reticulum cella
• Endothelial cells
• Macrophages

secrete
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Hemopoietic Growth Factors

• Glycoprotein hormones ? regulate proliferation
  differentiation of HPC function of mature blood
  cells.
• Biological effects of HGF mediated through
  specific receptors on target cells.
• Act
• Locally ? at the site where they are produce ? by
  cell-cell contact.
• Circulate in plasma

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HGF

• May bind to EC matrix ? form niches to which SC
  PHC adhere.
• Major sources (except erythropoietin)
• T-lymphocytes
• Monocytes ( macrophages)
• Stromal cells
• Erythropoietin ? 90 synthesized in kidney
• Thrombopoietin ? largely made in liver

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Leukopoiesis ?also stimulates by endotoxin
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General Characteristics of Myeloid and Lymphoid
Growth Factors

• Glycoprotein that act at very low concentration
• Act hierarchically
• Usually produced by many cell types
• Usually affect more than 1 cell lineage
• Usually active on stem/progenitor cells and on
  functional end cells
• Usually show synergistic or additive interactions
  with other growth factors
• Often act on the neoplastic equivalent of a
  normal cell
• Multiple actions proliferations,
  differentiation, maturation, functional
  activation, prevention of apoptosis.

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Hematopoietic Growth Factor
Site of action HGF
Stromal cell IL-1, TNF
Pluripotential stem cell Stem cell factor (SCF), Flt ligand (Flt-L)
Multipotential progenitor cell IL-3, GM-CSF, IL-6, G-CSF, thrombopoietin
Committed progenitor cell G-CSF, M-CSF, IL-5 (eosinophil-CSF), erythropoietin, thrombopoietin
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Stem Cell Plasticity

• Embryonic SC ? totipotent ? generate all tissues.
• Evidence ? adults SC (in different organs) ?
  pluripotent.
• Bone marrow
• Hematopoietic SC
• Mesenchymal SC ? clinical application ?
  th/mesenchymal disease

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Apoptosis

• Homeostasis
• cell production ? cell destruction
• Regulated process of physiological cell death ?
  triggered to activate intracellular proteins ?
  lead to cell death.
• Morphologically
• Cell shrinkage
• Condensation of nuclear chromatin
• Fragmentation of the nucleus
• Cleavage of intranucleosomal DNA
• Important proses for maintaining tissue
  homeostasis in hematopoiesis lymphocytes
  development

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Pathway of apoptosis
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Growth Factor Receptors Signal Transduction

• Control hematopoiesis by growth factors
• Factors acts on cells expressing the
• corresponding receptors.
• Binding of GF to its receptor activates
• by JAKs ? then phosphorylate STATs
• which translocate to the nucleus and
• activate transcription of specific
• genes

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Adhesion Molecules

• Glycoprotein
• Mediate the attachment of marrow precursors,
  leukocytes and platelet to various components of
  the extracellular matrix to
• Endothelium
• Other surfaces
• Each other
• On leukocyte ? receptors ? interact with ligand
• 3 main families Immunoglobulin, selectins,
  integrin

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Blood Cell Proliferation, Differentiation and
Maturation
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Normal and Abnormal Maturation of Blood Cells
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Normal Cell Maturation

• Changes in cytoplasm
• Changes in nucleus
• Reduction in cell size
• Gradual transformation
• Changes are simultaneous and paralel

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Erythropoiesis
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Changes in Cytoplasma

• Loss of basophilia
• Romanowsky staining (Giemsa)
• The more basophilic cytoplasma, the more immature
  cell
• Cytoplasmic granules in granulocytes
• Azurophil (primary granules)
• Specific (secondary granules)
• Eosinophilic
• Basophilic
• Neutrophilic

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Changes in Cytoplasma

• Elaboration of hemoglobin blue cytoplasm in
  pronormoblast and red cytoplasm in erythrocyte in
  pronormoblast

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Changes in Nucleus

• Nuclear Maturation
• Shape
• Round or oval in blasts
• Striking changes in granulocytes
• Structure delicate netlike or sponge like
• chromatin in blasts
• Chromatin strands become more coarse and clumped
  as the cells matures
• Reduction in the number of nucleoli

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Reduction in Cell Size

• A feature of all cells, except in the
  megakaryocytic series.
• N/C ratio is high in young cells
• and low in mature cells.

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Abnormal Cell Maturation

• Asynchronous maturation of cytoplasma
• and nucleus ? atypical cells.
• Granulocytes
• - agranular
• - persistent primary granules
• - abnormal inclusions
• - Large nucleus
• - Hypersegmentation/hyposegmentation
• Erythrocytes
• persistent basophilia

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Thank You Very Much