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 / and / 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 isnt 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.