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5. DEVELOPMENT OF BLOOD

5. DEVELOPMENT OF BLOOD. Blood cells. Mesonephric tubules. primitive hematopoiesis. ventral mesoderm. Fish gastrulation movie.

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5. DEVELOPMENT OF BLOOD

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  1. 5. DEVELOPMENT OF BLOOD

  2. Blood cells Mesonephric tubules

  3. primitive hematopoiesis ventral mesoderm Fish gastrulation movie

  4. scl, gata1/2, lmo2 - transcriptional factors that specify early hematopoietic tissue (gata2 expressed also in ectoderm)RBI – rostral blood islandsICM – inner cell mass gata1 promoter-driven GFP = early erythroid lineage dorsal aorta 5-somitestage embryo – hematopoiesis starts officially ICM 8h embryo 2d embryo circulation

  5. MYELOPOIESIS STARTS IN RBI @ 10-SOMITE STAGEspi1 – marker of myeloid lineage rostral spi1 detected by Fast Red riboprobe scl – early hematovascular cell fatefli1 – early vascular fatenkx2.5 – heart fate caudal

  6. 7.5 dpc mouse embryo (late gastrulation stage) 8.5 dpc – yolk sac encloses entire embryoblood islands merge to form vascular channels LacZ driven by b-globin promoter(X-gal staining – primitive erythroblasts) bl- blood islandsec - ectoplacental coneac - amniotic cavityte - trophectodermal - allantoiseem - extraembryonic mesoderm (blue)ve - visceral endoderme - embryonic ectoderm

  7. AORTA-GONAD MESONEPHROS (AGM) Development of intra-embryonic hemogenic site RUNX1 riboprobe lateral plate mesoderm hemogenic site fetal liver ICM A aorta HSC Rohon-Beard neurons A- aortaNO- notochordAV- axial veine - endothelial cell

  8. RUNX1 (CBFA2, AML1) is necessary for ‘definitive’ hematopoiesis to start at AGM Runx1+/- Runx1-/- E11.5: dark- hematopoietic cells only a few primitive erythrocytes left – likely a carry-over from the ‘primitive’ hematopoiesis

  9. EXTRAEMBRYONAL vs EMBRYONAL PRIMITIVE vs. DEFINITIVE

  10. BONE MARROW NICHE IS CRITICAL FOR HEMATOPOIESIS

  11. COLLAGEN TYPE-X DELETION Col X-/- wt wt Col X-/- thymus spleen wt Col X-/- aplasia normal hematopoiesis

  12. THE HUNT FOR HEMANGIOBLAST AND ITS HEM- ANGIO-DIFFERENTIATION

  13. HEMANGIOBLASTscattered among endothelial and HSC in heart field of the gastrula ventral marginal cells of the heart field, n- notochord

  14. Endothelial progenitor HEMANGIOBLAST or HAEMOGENIC EPITHELIA, or BOTH?

  15. blast colony-forming cell

  16. Hemangioblast culture tight adherent structure Angiopoietin 1 rec. Integrin alpha 2B

  17. Tie2hic-KIT+CD41_ can generate hematopoietic precursors endothelia in matrigel endothelial markers Tie2hic-KIT+CD41_ are present in vivo by FACS Tie2hic-KIT+CD41_ are present in vivo by IHC

  18. Runx1-/- Blast movies 3, 4Runx-/- movie

  19. TRANSCRIPTIONAL FACTORS IN BLOOD DEVELOPMENT

  20. GATA-1 - binds DNA via a zinc finger motif Dracula fish – loss-of-function mutation in GATA1 – impaired erythroid differentiation

  21. Spadetail/TBX16DNA binding domain derived from the prototype gene called transcription factor T impaired erythroid but not myelopoietic differentiation

  22. MoonshineTIM-family of transcriptional factors erythrocyte proerythroblast ‘primitive’ – survival of HSC ‘definitive’ – cardiomegaly and impaired red cell differentiation

  23. WHEN SOMETHING GOES WRONG WITH BLOOD

  24. ACUTE LYMPHOID LEUKEMIA

  25. CHRONIC MYELOID LEUKEMIA abl bcr-abl bcr mice transplanted with patient bone marrow

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