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Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
Revising haematopoiesis - Geoffrey Brown
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Revising haematopoiesis - Geoffrey Brown

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  • 1. Geoffrey Brown College of Medical and Dental SciencesRevising textbook accounts of Haematopoiesis
  • 2. Products of HaematopoiesisMARROW BLOOD TISSUESMegakaryoblast plateletErythroblast erythrocyteMast cell precursor mast cell mucosal and connective tissue mast cells basophilMyeloblast eosinophil in sites of inflammation neutrophilMonoblast monocyte tissue / lymphoid tissue macrophages; Kuppfer cell; osteoclastPrecursor? dendritic cell tissue dendritic cell / Langerhans’ cell; veiled cell; interdigitating cellPrecursor? natural killer cell lymphoid tissues; sites of inflammationPro-B cell type 1 and type 2 B cells in blood and secondary lymphoid tissues;(matures in marrow) plasma cells also in mucosal surfaces and bone marrowT cell precursor α / β and γ / δ T cells; CD4+ve and CD8+ve T cells; in blood,(matures in thymus) secondary lymphoid tissues and sites of inflammation
  • 3. Products of Haematopoiesis Granulocytes Monocyte Lymphoid cellsMegakaryocyte (i) Neutrophil (i) B lymphocyte (ii) T lymphocyte Macrophage (ii) Eosinophil Erythrocyte (iii) NK cell (iii) Basophil Dendritic Cell
  • 4. Progressive Stages in Haematopoiesis STEM HAEMOPOIETIC MATURE CELLS PROGENITORS CELLSImmortal Lineage selection Functional Expansion Self renewal for Self renewal? lymphocytes
  • 5. The ‘Conventional’ model of haematopoiesis - Weissman Hematopoietic Stem Cell Common Myeloid Common Lymphoid Progenitor ProgenitorM/E Progenitor G/M Progenitor B cell T cell NK cell Platelet Granulocyte Macrophage Erythrocyte Myeloid lineages Lymphoid lineages
  • 6. Haematopoiesis – Principles(i)Two families of cells – myeloid and lymphoid(ii)Preferred single route to each cell type(iii)Immortality confined to stem cells(iv)Growth factors permissive or instructive?
  • 7. Two families of cells?
  • 8. Colony forming assays reveal myeloid potentialsG-CFU M-CFU
  • 9. CONVENTIONAL MODEL OF HAEMATOPOIESIS Haematopoietic stem cell Myeloid progenitor (GEMM-CFU) Lymphoid progenitor BFU-E GM-CFC Eo-CFC Meg-CFC Mast-CFC Pro-B Pro-Terythrocyte neutrophil platelets B lymphocyte monocyte eosinophil mast cell T lymphocyte
  • 10. A lymphoid/myeloid dichotomy B and T lymphocytes More mundane are exceptional myeloid cells Dependent onDependent on receptor forunique antigen- growth factorspecific receptor Domain of Province of immunologists hematologists
  • 11. Haematopoiesis – Principles(i)Are there two families of cells – myeloid and lymphoid?(ii)Preferred single route to each cell type(iii)Immortality confined to stem cells(iv)Growth factors permissive?
  • 12. Evidence that precursor cells of monocytes and B lymphocytes are closely related Wong, Bunce, Lord, Salt & Brown – Exp. Hematol. 1989 3D gels of phosphoproteins IEFSDS HL60 cells restricted to Lines restricted to monocyte Pre-B cell lines neutrophil differentiation differentiation (U937, ML-1, (Nalm 6 & SMSB) (HL60Ast3) HL60M2 & 15-12)
  • 13. There are bi-potent B lymphocyte/monocyte cells Bi-potent 1982 – Macrophages from pre-B lymphoma progenitor cells (5-AZT & transduced CSF1 R (1990)) 1988/94 – HAFTL-1 and 702/3 cell lines 1992 – Foetal liver of mice (Cumano et al.) 1995 – Tumours in IL-7 transgenic mice (Fisher et al.) 2001 – Bone marrow of adult mice (Montecino-Rodriguez et al.)B cell Monocyte
  • 14. Progenitors with lymphoid potentials and an incomplete set ofmyeloid potentialsPax5 (B cell factor)-/- Lymphoid-primed MultiPotent Progenitors (Adolfsson et al., 2005) Pro-B cell LMPP Meg/Ery Gran/Mon potentials potentialsMyeloid NK cell T cellEarly Progenitors with Lymphoidand Myeloid develop. potential(Balciunaite et al., 2005) Lin-veSca-1+veKit+ve Lin-veSca-1+veKit+ve M-CSF IL-2 IL-7 IL-7 Flt3hiMpl+ve Flt3hiMpl-ve trans. Notch NotchMyeloid NK cell T cell B cell Lymphoid priming
  • 15. There isn’t a strict myeloid/lymphoid dichotomy
  • 16. Haematopoiesis – Principles(i)Two families of cells – myeloid and lymphoid(ii)Is there a preferred single route to each cell type?(iii)Immortality confined to stem cells(iv)Growth factors permissive?
  • 17. Is there just a single route to each cell type? Dendritic cell sub-sets are phenotypically and transcriptionally identical (Ishikawa et al. 2007) Mon B NK Neu CLP T CMP Eos Bas Ery MegThere are at least two alternative routes to dendritic cells
  • 18. Multiple routes to DCs, neutrophils and monocytes
  • 19. A. Platelet/Erythroid Granulocyte/Monocyte CMP Granulocyte/Monocyte Platelet/Erythroid NK cell HSC T cell B cell C. HSC CLP B. CMPErythroid Myeloid MEP ? ? MEP Erythroid ? pro TPlatelet T cell Platelet HSC B cell Myeloid B cell (NK?) T cell Myeloid Myeloid
  • 20. More versatility - thymus progenitors have clandestine myeloid potentials DC NKB cell Myeloid Thymus-Settling Early Thymocyte Double Negative-2 DN-3 Progenitors Progenitors (DN1) (DN2) Loss of CD117 & CD44 CCR9+ve, CD135+ve, Loss of CCR9 & CD135 Gain of CD25 Gain of cytoplasmic CD3 CD117high, CD44+ve, CD25-ve X X B cell NK DC Myeloid
  • 21. Haematopoiesis – Principles(i)Two families of cells – myeloid and lymphoid(ii)Preferred single route to each cell type(iii)Is immortality confined to stem cells?(iv)Growth factors permissive?
  • 22. Immortality extends to lineage-biased cells STEM HAEMOPOIETIC MATURE CELLS PROGENITORS CELLSMyeloid- biasedLymphoid -biased Immortal Lineage selection Functional Expansion Self renewal for Self renewal? lymphocytes
  • 23. Haematopoiesis – Revised Principles(i)A single family of cells(ii)Immortality extends to lineage-biasedcells(iii)More than one route to some cell types(iv)Progenitors have clandestine options(v)HSC and progenitors are more versatilethan previously thought
  • 24. The Sequential Determination Model (1985) Mast Cell/ Basophil Neutrophil B lymphocyte Platelet Eosinophil Monocyte T lymphocyte ErythrocyteHSC CLP Neutrophil Monocyte Meg Ery Bas Eos Neu Mon B T Megsensitivity to Ery macrophages from DMSO pre-B lymphoma lines Bas Eos NeuG GM M MonAst4 Ast3 HL60 M2 Ast25 Ast1 B ? Sp1 M4 17-6 T 15-12
  • 25. Mast Cell/ Basophil Neutrophil B lymphocyte Platelet Eosinophil Monocyte T lymphocyte ErythrocyteHSC CLP (i)A single family of cells (ii)Immortality extends to lineage-biased cells (iii)More than one route to some cell types (iv)Progenitors have clandestine options (v)HSC and progenitors are more versatile than previously thought
  • 26. A pair-wise relationship model
  • 27. TRANSCRIPTION FACTORS AND PAIR-WISE RELATIONSHIPSKnock-out mice Gene expressionGATA-2 megakaryocytec-myb GATA-1 erythrocyte EKLF & decreasing mast cell NF-E2 levelsPU.1 basophil eosinophil neutrophil C/EBPβ monocyteikarus B lymphocyte } EBF T lymphocyte } GATA-3
  • 28. C/EBPα PU.1 EDAGMybhigh Meg Ery Bas Eos Neu Mon DC B NK T NotchEKLF /CSL Pax5 GATA-1 E proteins MLLT3 FOG-1
  • 29. IL-7 IL-5 IL-4 IL-21 IL-15IL-9 IL-3 IL-33 GM-CSF IL-10 Meg Ery Bas Eos Neu Mon DC B NK T Tpo Epo G-CSF M-CSF
  • 30. Haematopoiesis – Revised Principles(i)A single family of cells(ii)Immortality extends to lineage-biasedcells(iii)More than one route to some cell types(iv)Progenitors have clandestine options(v)HSC and progenitors are more versatilethan previously thought
  • 31. Lineage – where to draw the lines? Lymphocytes Archetypes? B cell T cell NK cell CD8 T cell IFNγ, IL-2, Ltα CD4 T cell ? (IL-10) IL-4, IL-5 IL-13, IL-10 IL-25 IL-17a, IL-17f IL-4?T helper 1 IL-21, IL-22 TGFβ, IL-35 IL-21 Accessorised? IL-10 IL-10 T helper 2 T helper 17 T reg T follicular helper
  • 32. Versatility – Are leukaemia stem cells as versatile?
  • 33. Is decision-making growth factor driven?A Pluripotent Unipotent stemcell progenitorB
  • 34. What is the way forward? (i) High level cell indeterminacy Mature cells Outcome (ii) Boundary conditions & Growth factors, cell-cell contacts Performance
  • 35. Dr G Brown and Prof A Rot - University ofBirmingham;Prof R Ceredig - National University of Ireland,Galway;Prof A Rolink - University of Basel;Prof E Marcinkowska - University of Wroclaw;Prof. G Studzinski - University of Medicine andDentistry, New Jersey;Drs A Zelent and K Petrie - The Institute of CancerResearch, London;Prof A Kutner - The Pharmaceutical ResearchInstitute, Warsaw;Dr S Elliman - Orbsen Therapeutics Ltd., Galway;Prof N Barnes - Celentyx Ltd., Birmingham.Martin Smith - High-Point Rendel Ltd, LondonProf Michael Danilenko, Ben Gurion University ofthe Negev, IsrealDr Eustace Johnson, University of AstonProf Daniela Finke, University of Basel

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