Revising haematopoiesis - Geoffrey Brown

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Revising haematopoiesis - Geoffrey Brown

  1. 1. Geoffrey Brown College of Medical and Dental SciencesRevising textbook accounts of Haematopoiesis
  2. 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. 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. 4. Progressive Stages in Haematopoiesis STEM HAEMOPOIETIC MATURE CELLS PROGENITORS CELLSImmortal Lineage selection Functional Expansion Self renewal for Self renewal? lymphocytes
  5. 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. 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. 7. Two families of cells?
  8. 8. Colony forming assays reveal myeloid potentialsG-CFU M-CFU
  9. 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. 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. 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. 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. 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. 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. 15. There isn’t a strict myeloid/lymphoid dichotomy
  16. 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. 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. 18. Multiple routes to DCs, neutrophils and monocytes
  19. 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. 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. 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. 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. 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. 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. 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. 26. A pair-wise relationship model
  27. 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. 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. 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. 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. 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. 32. Versatility – Are leukaemia stem cells as versatile?
  33. 33. Is decision-making growth factor driven?A Pluripotent Unipotent stemcell progenitorB
  34. 34. What is the way forward? (i) High level cell indeterminacy Mature cells Outcome (ii) Boundary conditions & Growth factors, cell-cell contacts Performance
  35. 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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