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Control of Haemopoiesis

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Control of Haemopoiesis Control of Haemopoiesis Presentation Transcript

  • CONTROL OF HAEMOPOIESIS Denise Pegnall
  • AIM
    • Demonstrate an understanding of the haemopoietic process
    • Where haemopoiesis takes place
    • When haemopoiesis takes place
    • Stem cells
    • Stromal microenvironment
    • Cell Cycle
  • HAEMOPOIESIS
    • The formation of blood cells
    • High level turnover, need 10 13 new cells daily
    • Bone Marrow contains only 10 12
    • During 70 years, average 70kg human will produce 7 tons of blood cells
    • Blood cells for lifelong haemopoiesis cannot be preformed on the body
    • Renewable source
  • STEM CELLS
    • Mesenchymal
      • osteoblasts, chondrocytes , adipocytes
    • Neural, Muscle, In the crypt of the gut,
    • Hair follicle stem cells
    • Haemopoietic stem cells (HSC)
      • Erythrocytes, platelets, monocytes, neutrophils, eosinophils, basophils, lymphocytes , natural killer cells
    • Transcription factors commit HSC’s to cell lineages
      • PU-1
      • GATA-1
  • STEM CELLS
    • Important cells for haemopoietic production
    • Haemopoietic stem cells, HSC’s
    • Capable of self renewal
      • maintain stem cell pool
    • Differentiation
      • progenitor cells of each blood lineage
    • Regulation of Haemopoiesis starts with stem cell division
      • One to self renew, One to differentiate
    • Enormous proliferative capacity
    • One stem cell: 10 6 mature blood cells after 20 divisions
    • Rare: One stem cell per 20 million nucleated cells
  • STROMAL MICROENVIRONMENT
    • Stem cells require a suitable environment to grow and divide
    • Stromal Matrix
      • Stromal cells
        • Adipocytes, fibroblasts, endothelial cells, macrophages
      • Microvascular network
        • Collagen, glycoproteins, glycosamines
    • Stromal cells also secrete growth factors necessary for stem cell survival
    • Mesenchymal cells, critical for stromal cell formation
      • osteoblasts, chondrocytes , adipocytes
  • BONE MARROW HUMAN STEM CELL
  • EMBRYONIC HAEMOPOIESIS
    • Earliest recognizable at 2 weeks
      • Large nucleated red cell precursors
    • Haemoglobin Gower 1 ( ζ 2 ε 2 )
    • Leucopoiesis/Thrombopoiesis @6 wks gestation
    • Lymphocytes in lymph sacs@7 wks gestation
    • Primary source foetal cells until @30 wks Liver
      • Ceases @ 40wks
      • Haemoglobin F ( α 2 γ 2 )
  • BONE MARROW
    • Foetal spleen produces blood cells @10 wks
      • Continues through second trimester
    • Bone cavities from @20 wks gestation
    • Humans Bone marrow sole source of blood cells by 40 wks
    • Gradual replacement of Hb F with Hb A ( α 2 β 2 )
    • Birth, haemopoietically active marrow fills every available space
  • THALASSAEMIA PATIENT WITH FACIAL DEFORMITIES Orthodon.Craniafacial Res. 10 2007 36-44
  • HAEMOPOEISIS TO ADULTHOOD
    • Childhood marrow vol.increases parallel to increased marrow space made available by growth
    • Average 3 year old, 1500ml active marrow
    • Entirely active & sufficient for needs of adult
    • As child grows, further expanding marrow space filled with inactive marrow
    • Adult ¾ active marrow pelvis, vertebrae, sternum
    • Adult, six fold reserve capacity
    • Extramedullary haemopoiesis
  • CELL CYCLE
    • Cell division cycle
    • M. Phase, mitotic phase: division of cell
    • Interphase: duplication of chromosomes
      • G 1 : cell begins to commit to replication
      • S phase: DNA content doubles, chr. replicate
      • G 2 : organelles copied, cytoplasmic vol. Increased
    • G 0 State: resting stage
    • Controlled by two checkpoints
  • CELL CYCLE
    • Co-ordinate division end of G 1 & G 2
    • Controlled by
      • Cyclin dependent protein kinases (CDK)
      • Cyclins
    • Majority of HSC’s in quiescent G 0 stage
    • Cell cycle dependent drugs, 5’Fluorouracil
    • S phase specific agents
      • Cytosine arabinoside
      • Hydroxyurea
  • P53
    • Quiescent state maintained by Transforming growth factor β (TGF β ) mediated by p53
    • Tumour suppressor gene
    • Normally, short lived protein present at low levels in unstressed mammalian cells
    • Under stress, p53 accumulates in the nucleus & binds to specific DNA sequences
  • P53
    • Induces or inhibits expression > 150 genes
      • p21,GADD45,MDM2 ,IGFBP3 ,BAX4
    • DNA damage, p53 signalling network activated, induces cell cycle arrest, DNA repair and apoptosis
    • p53 targets enzyme p21, a cyclin dependent kinase inhibitor
    • p21 regulates activity of cyclin-CDK complexes
    • Inhibitors of c-CDK’s prevent phosphorylation of retinoblastoma proteins
  • CELL CYCLE
    • Retinoblastoma proteins remain bound to transcription factor of E2F family
    • Therefore genes required for progression of cell cycle not transcribed
    • Cells remain in quiescence
  • MAINTENANCE OF STEM CELL QUIESCENCE Post graduate Haematology 5th Ed.2005
  • CONTROL OF HAEMOPOIESIS
    • Intrinsic, extrinsic or both?
    • Extrinsic
      • Cell-cell interaction in microenvironment
      • Cytokines
        • Stem Cell Factor / receptor c-kit
        • Flt3 ligand/ receptor Flt3
    • Intrinsic
      • SCL, Stem cell leukaemia haemopoietic transcription factor
      • GATA-2
      • Both required for haemopoiesis in the yolk sac
  • E2F Retinoblastoma