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HSC CMP Common Lymphoid Progenitor proB preB B CD4- CD8- CD4+ GMPMEP CD8+ Thymus Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage.

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Presentation on theme: "HSC CMP Common Lymphoid Progenitor proB preB B CD4- CD8- CD4+ GMPMEP CD8+ Thymus Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage."— Presentation transcript:

1 HSC CMP Common Lymphoid Progenitor proB preB B CD4- CD8- CD4+ GMPMEP CD8+ Thymus Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte CD4+ CD8+ immature Hematopoiesis IgM IgD CLP

2 Thymopoiesis Thymus TN3 HSC 44+25- 4+8+ 44-25- 44+25+ 44-25+ 4+ 8+ TN4 TN2 TN1 Myeloid Erythroid CMP Common Myeloid Progenitor CD3-CD4-CD8- (TN, 3-5%) CD4+CD8+ CD4+ CD8+ Common Lymphoid Progenitor CLP

3 HSC CMP Common Lymphoid Progenitor proB preB B CD4- CD8- CD4+ GMPMEP CD8+ Thymus Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte CD4+ CD8+ immature Hematopoiesis IgM IgD CLP

4 PROPERTIES OF PLURIPOTENTIAL HEMATOPOIETIC STEM CELLS Self-Renewal Differentiation

5 Dick, J. 2003. Nature 423:231-232 HSC Self-Renewal and Differentiation

6 Weissman, I.L. 2000. Science 287:1442-1446 Phenotypic Characteristics of HSC

7 FACS Profile of HSC

8 Dorshkind, K. 1990. Annu. Rev. Immunol. 8:111-137.

9

10 HSC CMP Common Lymphoid Progenitor proB preB B CD4- CD8- CD4+ GMPMEP CD8+ Thymus Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte CD4+ CD8+ immature Hematopoiesis IgM IgD CLP

11 Specification versus Commitment

12 Akashi et al. 2000. Nature. 404:193-197. Expression of Transcription Factors During Hematopoiesis

13 Busslinger, M. 2000. Curr. Opinion Immunol. 12:151-158. Expression of Pax5 is Required for B Lymphopoiesis

14 Where Should Branchpoints Be Drawn?

15 HSC CMP Common Lymphoid Precursor proB preB B CD4- CD8- CD4+ GMPMEP CD8+ Thymus Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte CD4+ CD8+ immature Hematopoiesis IgM IgD CLP

16 FACS Resolution of CMP and GMP

17 HSC CLP CMP Multipotentl Lymphoid Precursor proB GMPMEP Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte Common Lymphoid Progenitor CD45R CD43 IgM immaturemature IgD Myelopoiesis preB ETP CD4+ CD8+ Thymus Granulocyte Macrophage Progenitor Megakaryocyte Erythrocyte Progenitor

18 Adolfsson et al. Cell 121:295, 2005 Lin- Sca-1+ c-kit+ Flt3+ cells Have B, Granulocyte, and Macrophage Developmental Potential

19 HSC CMP Common Lymphoid Progenitor proB preB B CD4- CD8- CD4+ GMPMEP CD8+ Thymus Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte CD4+ CD8+ immature Hematopoiesis IgM IgD CLP

20 Adolfsson et al. Cell 121:295, 2005 Lin- Sca-1+ c-kit+ Flt3+ cells Have B, Granulocyte, and Macrophage Developmental Potential

21 Adolfsson et al. Cell 121:295, 2005 Lin- Sca-1+ c-kit+ Flt3+ cells Lack Erythroid andMegakaryocyte Developmental Potential

22 Adolfsson J. et al. Cell 121:295, 2005 Alternative Models of Hematopoiesis

23 HSC CMP Common Lymphoid Progenitor proB preB B CD4- CD8- CD4+ GMPMEP CD8+ Thymus Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte CD4+ CD8+ immature Hematopoiesis IgM IgD CLP

24 Identification of bone marrow CLP

25 Kondo et al. Cell 1999. 91:661-672.

26 Notch and T Cell Development MacDonald H.R. 2001. Trends in Immunol. 22:155-160.

27 Radtke, F. et al. 1999. Immunity 10:547-558.

28 Thymopoiesis Thymus TN3 HSC 44+25- 4+8+ 44-25- 44+25+ 44-25+ 4+ 8+ TN4 TN2 TN1 Myeloid Erythroid CMP Common Myeloid Progenitor CD3-CD4-CD8- (TN, 3-5%) CD4+CD8+ CD4+ CD8+ Common Lymphoid Progenitor CLP

29 Based on Allman et al., Nat. Immunol. 4:168, 2003 Isolation of ETP by FACS

30 Models of Early Thymopoiesis Bhandoola et al. J. Immunol 171:5653, 2003

31 HSC CMP Common Lymphoid Progenitor proB preB B CD4- CD8- CD4+ GMPMEP CD8+ Thymus Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte CD4+ CD8+ immature Hematopoiesis IgM IgD CLP

32 FETAL HEMATOPOIESIS

33 HSC CMP Common Lymphoid Precursor proB preB B CD4- CD8- CD4+ GMPMEP CD8+ Thymus Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte CD4+ CD8+ immature Adult Hematopoiesis IgM IgD CLP

34 HSC CMP GMP MEP Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte Fetal Hematopoiesis B IgM Pro-B Pre-B Macrophage B/f

35 Fetal Hematopoiesis Godin and Cumano Nat. Rev. Immunol. 2: 593, 2002

36 Quail Chick

37 Fetal Hematopoiesis Godin and Cumano Nat. Rev. Immunol. 2: 593, 2002

38 Dzierzak E. et al. 1998. Immunol. Today 19:228-236.

39 Gekas et al. Developmental Cell 8:365, 2005. Identification of Hematopoietic Stem Cells in the Placenta

40 Fetal Adult Fetal RBC Myeloid Cells gd T cells B-1 B Cells Adult RBC Myeloid Cells B2 B Cells Fetal Hematopoiesis

41 B1 B2 B1 and B2 B Cells IgM IgM high CD5+/- CD11b CD45R IgD low IgD high Serous Cavities (peritoneum); self- renewing; function in innate immunity Spleen and Lymph Nodes; Produced throughout life; function in adaptive immunity

42 Fetal Liver B-1 B Cells B2 B Cells Adult Bone Marrow

43 Adapted from Rothstein TL. J. Immunol. 168:4257, 2002 Models of B1 B Cell Development LineageSelection B1 Progenitor B1 Precursor B2 Progenitor B2 Precursor B1 B2 ? B2 Progenitor B2 Precursor BCR signals

44 I. B Cell Development: Recent History

45 Carvalho TL et al. J.Exp. Med. 194:1141, 2001 B Cell Development In IL-7 -/- Mice

46 Carvalho TL et al. J.Exp. Med. 194:1141, 2001 B-1 B Cells Are Present In IL-7 -/- Mice

47 AGM Placenta Melchers, F. Nature 277:219, 1979 d9-11 Paige et al.,J. Exp. Med. 150:548, 1979 d8 Owen, Cooper, & Raff. Nature 249:361, 1974 d12 Solvason et al. Int. Immunol. 3:543, 1991 d13 Velardi, A. and M. Cooper. J. Immunol. 133:672, 1984. d14 Appearance of B Lineage Cells During Embryogenesis Godin, I. et al. PNAS. 92:773, 1995 d8

48 AGM Placenta Solvason et al. Int. Immunol. 3:543, 1991 d13 Appearance of B Lineage Cells During Embryogenesis

49 Milne CD et al. Immunol. Rev. 197:75, 2004 Regulation of B Lymphopoiesis By IL-7 and TSLP IL-7 TSLP

50 Giliani, S. et al. Immunol. Rev. 203:110, 2005 The IL-7 and TSLP Receptors IL-7R TSLPR aga

51 Vosshenrich et al. PNAS 101:11070, 2004 B1 B Cell Numbers Are Reduced In Mice That Fail to Express IL-7Ra

52 HSC CMP GMP MEP Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte Fetal Hematopoiesis B IgM Pro-B Pre-B Macrophage B/f

53 Effects of Aging on Hematopoiesis

54 Embryogenesis Senescence

55 CD4 + CD8 + T cells B CELLS Memory B cells Activation Germinal center reaction MZ B cells Skewed V H repertoire T CELLS Memory T cells Activation Oligoclonal dominance Cytokine production Effector generation Thymus Bone Marrow IgM + B cells Aging Spleen Primary and secondary follicle with germinal center Periarteriolar lymphoid sheath MZ B Cells Exit of IgM+ cells T cell production Antibody-forming cells Aging


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