《Shenzhen-tal终稿》.ppt

The “feedback” mechanism of megakaryocytopoiesis via platelet molecules: a hypothesis Mo YANG PhD Department of Paediatrics, The Chinese University of Hong Kong. Contents Background and hypothesis: Platelet molecules may regulate megakaryocytopoiesis via direct effect on MK progenitors Part 1. PDGF and megakaryocytopoiesis I. PDGF on in vitro megakaryocytopoiesis II. PDGF receptors and signal pathway in MK cells III. To apply PDGF on ex vivo expansion of MK and in vivo megakaryocytopoiesis Part 2. 5-HT and megakaryocytopoiesis Part 3. TSP1 and megakaryocytopoiesis General conclusions Background The role of cytokines in megakaryocytopoiesis. Kaushansky. N Eng J Med 1998, 10; 746-754. Background Expression of IL-1 receptors on MK lineage. Yang Li et al, Br J Haematol 2000,111:371-380 Background IL-1b enhances megakaryocytopoiesis and NF-E2 expression. Yang Li et al, Br J Haematol 2000,111:371-380 Background TPO is a major growth factor for MK and platelets The existence of a humoral regulator for MK and platelet production, termed thrombopoietin (TPO) Kelemen et al. Acta Haematol 1958, 20;350) TPO was isolated and cloned. Bartley et al. Cell 1994, 77; 1117-1124. de Sauvage et al. Nature 1994, 369;533-538. Lok et al. Nature 1994, 369; 565-568. Kuter et al. PNAS 1994,91;11104-11108. Kato et al. J Biochem 1995, 118; 229-236. Background The structure of TPO gene. Background Cytokines in megakaryocytopoiesis Major Growth Factor: TPO Others: IL-1b, IL-3, IL-6, IL-11 SCF, FL G-CSF, EPO Background Transcriptional Regulation of Megakaryocytopoiesis: NF-E2 GATA-1 FOG-1 CBFA2 Shivdasani. Stem Cells 2001, 19: 397-407. Background TPO regulation by platelets. Kaushansky. N Eng J Med 1998, 10; 746-754. Hypothesis Alternatively, platelet molecules may regulate megakaryocytopoiesis by a direct effect on MK progenitors. Yang et al. Blood 1999, 94; 41a. Objective Effect of PDGF, 5-HT and TSP1 on megakaryocytopoie