Kuliah Patologi Klinik Rabu, 19 September 2012 Blok 234 FK UNSWAGATI Indriani Silvia Hematopoiesis sistem biologi sel stem yang meliputi interaksi seluler dalam perkembangannya dan homeostasis jaringan, siklus turunan sel stem, dan reaksi transkripsi (pengulangan siklus) dengan beragam fenotipe seluler yang spesifik (berdasarkan tahapannya). 1. Essential Hematology. AV Hoffbrand, JE Pettit, PAH Moss. 4th ed. 2. Denise M Harmening. Hematology and Hemostasis. . . proximal ends of femur • Developing cells situated outside of BM sinuses mature cells released into sinus spaces marrow microcirculation general circulation. practically all bones Adults Vertebrae. ribs. sacrum and pelvis. AGE SITE Fetus: 0-2 months Yolk sac 2-7 months Liver. sternum. . spleen 5-9 months Bone marrow Infants Bone marrow. . . . . . CD38- • Appearance ~ small/medium size lymphocyte • Cell differentiation occurs from the stem cell down the erythroid. granulocytic and other lineages via the committed hematopoietic progenitors cells restricted in their developmental potential.• Give rise to the separate cell lineage • Exact phenotype unkown immunological testing: CD34+. • Stem cell has the capability of self-renewal cellularity remains constant in a normal healthy steady state. . SC capable of responding to hematopoietic growth factors with increased production of one or other cell line when the need arises. . 1 SC capable of producing + 106 mature blood cells after 20 cell divisions. 4 PPSC . Fig. See Ross 5th Ed Table 10. Kierszenbaum. 6-16. one is transient amplifying cell) • Self-renewal .capacity of stem cell to regenerate itself • Transient amplifying cells .• Stem cell .asymmetric cell division yields cells with different fates (one is stem cell.symmetric cell division yields daughter cells with same fate (transient amplifying cells) • Differentiated cells .cells exit cell cycle and differentiate . g.g.. granulocyte-macrophage CFU) . erythroid CFU. limited self-renewal (e..undifferentiated cell capable of producing cells of one lineage. lymphoid SC) Committed progenitor . colony forming units (CFUs) (e. myeloid SC. capable of self-renewal Multipotent HSC Undifferentiated cell producing cells of multiple lineages.Pluripotent hematopoietic stem cell (HSC) Undifferentiated cell producing blood cells of all lineages. Early Intermediate Late Proerythroblast Polychromatophilic Reticulocyte erythroblast Basophilic Orthochromatic Erythrocyte erythroblast erythroblast (normoblast) . small cell size. biconcave shape. 7. matures in 1-2 days Erythrocyte mature. nucleus may be off-center nucleus extruded. 1-2% of cells in blood.6 µm diameter . enters peripheral Reticulocyte blood. active rRNA and ribosome synthesis (nucleoli visible) Proerythroblast active gene expression (euchromatin in nucleus) (pronormoblast) secretory pathway inactive (no cytoplasmic granules) rRNA synthesis largely complete (no nucleoli) Basophilic active protein synthesis in cytoplasm (basophilia) erythroblast gene expression in nucleus (some heterochromatin) Polychromatophilic protein synthesis mostly complete (less basophilia) erythroblast gene expression minimal (more heterochromatin) Orthochromatic protein synthesis complete (no or little basophilia) erythroblast gene expression silenced (condensed chromatin) (normoblast) no mitosis. Band Stage Kierszenbaum Fig. See Ross 5th Ed Table 10.4 . 6-20. Band Form Kierszenbaum. 6-21 .1. Fig. Promyelocyte 3. Myelocyte 4. Metamyelocyte 2. in lab) secretory pathway inactive (no cytoplasmic granules) active rRNA and ribosome synthesis (nucleoli present). some genes silenced (some heterochromatin). protein synthesis (some basophilia). enters blood . Promyelocyte active protein synthesis in cytoplasm (basophilia). secretory pathway active (1° granules synthesized). gene expression in nucleus (little heterochromatin) 1° and 2° granules (color of 2° = mature granulocyte). (do not identify active gene expression (euchromatin in nucleus). gene expression in nucleus (little heterochromatin) secretory pathway active (2° granules synthesized and Myelocyte Golgi visible). protein synthesis (some basophilia). active protein synthesis (basophilia). Myeloblast active rRNA and ribosome synthesis (nucleoli visible). non-mitotic 1° and 2° granules. some genes silenced (some heterochromatin). non-mitotic. Metamyelocyte Golgi visible. Band form nuclear segmentation continues. connective tissue See Ross 5th Ed Table 10. lymphatic tissue.bone marrow • Plasma cells .4 .present in marrow.Pluripotent stem cell • Lymphoid stem cell gives rise to T-lymphocyte and B-lymphocyte lineages • T-cell maturation .thymus • B-cell maturation . 6-14 • Bone marrow cavity . Fig. adipocytes.marrow proper and venous sinuses • Bone marrow cells .stromal cells. hematopoietic cells • Blood vessels .nutrient arteries supply marrow cavity • Stem cells and early precursor cells do not leave marrow .Kierszenbaum. macrophages. endothelial cells. . . • Reticulum thrombospondin) cella • Glycosaminoglycans • Endothelial (hyaluronic acid & . Stromal Extracellular cells: molecules: • adipocytes secrete • Collagen • Fibroblast • Glycoprotein (fibronectin. Suitable environment for SC growth & dev. Composed of stromal cells + microvascular network. • Glycoprotein hormones regulate proliferation & differentiation of hematopoietic pluripotent cell (HPC) & function of mature blood cells. • Act: – Locally at the site where they are produce by cell-cell contact. – Circulate in plasma . • Biological effects of HGF mediated through specific receptors on target cells. Major sources (except erythropoietin): T-lymphocytes Monocytes (& macrophages) Stromal cells Erythropoietin 90% synthesized in kidney Thrombopoietin largely made in liver . May bind to EC matrix form niches to which SC & PHC adhere. . differentiation. maturation.• Glycoprotein that act at very low concentration • Act hierarchically • Usually produced by many cell types • Usually affect more than 1 cell lineage • Usually active on stem/progenitor cells and on functional end cells • Usually show synergistic or additive interactions with other growth factors • Often act on the neoplastic equivalent of a normal cell • Multiple actions: proliferations. . prevention of apoptosis. functional activation. TNF Pluripotential stem cell Stem cell factor (SCF). GM-CSF. G-CSF. thrombopoietin Committed progenitor cell G-CSF*. Flt ligand (Flt-L) Multipotential progenitor cell IL-3. IL-6. M-CSF. IL-5 (eosinophil-CSF). Site of action HGF Stromal cell IL-1. thrombopoietin* . erythropoietin. . Evidence adults SC (in different organs) pluripotent. Bone marrow: Hematopoietic SC Mesenchymal SC clinical application th/mesenchymal disease . Embryonic SC totipotent generate all tissues. • Binding of GF to its receptor activates by JAKs then phosphorylate STATs which translocate to the nucleus and activate transcription of specific genes .Control hematopoiesis by growth factors: • Factors acts on cells expressing the corresponding receptors. . . . . . . . . . . selectins.• Glycoprotein • Mediate the attachment of marrow precursors. integrin . leukocytes and platelet to various components of the extracellular matrix to: – Endothelium – Other surfaces – Each other • On leukocyte receptors interact with ligand • 3 main families: Immunoglobulin.