(1) Hematopoiesis

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BLOOD CELL FORMATION (HEMATOPOIESIS) dr. Mansyur Arif, Ph.D, SpPK Dept. of Clinical Pathology, Faculty of Medicine, Hasanuddin University, Makassar

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hematopoiesis

Transcript of (1) Hematopoiesis

  • BLOOD CELL FORMATION (HEMATOPOIESIS)dr. Mansyur Arif, Ph.D, SpPKDept. of Clinical Pathology, Faculty of Medicine,Hasanuddin University, Makassar

  • I. INTRODUCTION A. Definition Hematopoiesis is the proliferation of progenitor cells, which are maintained by the stem cells and their differentiation into all the cellular components of blood. B. Sites of hematopoiesis depend on the presence of disease and on the develop-mental state of the individual. 1. Normal conditions originate in the bone marrow

  • Some components (e.g., erythrocytes and platelets) complete their development at medullary (i.e., bone marrow) sites, whereas other components (e.g., T and B cells) complete their development at extramedullary.Foetus : 0 2 months yolk sac 0 7 months liver, spleen 5 9 months bone marrowInfants : Bone marrow (practically all bones)Adults : vertebrae, ribs, sternum, skull, sacrum, proximal ends of femur

  • 2. Disease In the presence of disease, extramedullary sites can serve as primary sites of blood cell development. II. BONE MARROW A. Stem cells CFU (Colony - Forming Unit) are found within the BM as the origin of all blood cells.

  • ~ Blood cells are formed by a process of differentiation from the least developed stem cells to highly specialized blood cells. (Table 1)~ Stem cells :1.pluripotential stem cells 3 main marrow cell lines :a). erythrocytes (red cells) b). granulocytes monocytes (white cells) c). thrombocytes (platelets) and probably lymphocytes (T & B lymp.,plasma cells).

  • 2. Multipotential stem cells myeloid multi-potential stem cells and lymphoid multipoten- tial stem cells. - Myeloid multipotential stem cells : * CFU-GEMM (CFU-S) CFU granulocytes, erythrocytes, monocytes and megakaryocy- tes; the earliest detectable myeloid precursor * CFU-C (CFU-GM) CFU - granulocytes and monocytes

  • * CFU-E and BFU-E - CFU-E CFU erythropoiesis - BFU-E Burst - Forming Unit - erythroid committed to erythropoiesis and precursor of the CFU-E - CFU-E and BFU-E are dependent on Epo * CFU-Meg - progenitor of megakaryocytes - derives from CFU-GEMM - controlled by thrombopoietinFigure 1. Schematically summarizes the role of the major progenitor cells of hematopoiesis

  • Pluripotent stem cell

    CFUGEMM Lymphoid stem cell

    BFUE CFUGMEo CFUbaso

    Erythroid CFUEo Progenitors CFUMeg CFUGM

    CFUE Thymus

    CFU-M CFU-G

    Red Cells Platelets Mono- Neutro-Eosino- Baso- Lymphocytes FIGURE 1. cytes philsphils phils

    BT

  • Tabel 1. Some hematopoietic progenitors cells

    TermRequired stimulusPostulated RoleCFU-LMMultiple GFPluripotent stem cellCFU-GEMM(CFU-S)GM-CSF, G-CSF, M-CSF, IL-3Pluripotent stem cell

    CFU-GM(CFU-C)GM-CSF, G-CSF, M-CSF, IL-3Committed progenitor of granulopoiesisBFU-EErythropoietin, helper T lymphocytes (IL-1, GM-CSF, IL-3, IL-4)Committed progenitor of erythropoiesis (early)CFU-EErythropoietinCommitted progenitor of erythropoiesis (late)CFU- MegIL-3, GM-CSF, G-CSF. thrombopoietinCommitted progenitor of thrombopoiesis

  • ~ Lymphoid multipotential stem cells leavethe bone marrow and complete diff. in lymph nodes (B cells) and thymus (T cells) B. Hematopoietic Growth Factors CSF (Colony- stimulating factor)Classification : a. Non-lineage-specific GF act on pluripo- tential and multipotential stem cells to initiate self-renewal and differentiation

  • ~ IL-3 (Multi-CSF) induces the formation of colonies granulocyte, monocytes, eosinophils, erythroid cells,megakaryocytes and mast cells production~ GM-CSF stimulates granulopoiesis and macrophage productionb. Lineage-specific GF act on the commit-ted progenitor cells and are involved in the diff. and maturation of blood cells in the later stages of hematopoiesis.

  • These factors include : ~ Epo stimulates erythropoiesis, mediates its feed-back control ~ G-CSF inducing formation of granulocyte and stimulates proliferation of some leuke- mic cells~ M-CSF influencing macrophage prod. ~ Thrombopoietin influencing CFU-mega (Table 2)

  • Table 2. Myeloid Hematopoietic Growth Factor

    FactorMajor Biological Activities in VivoErythropoietin(Epo)Stimulates erythropoiesis. Mediates its feedback controlGM-CSFStimulates granulopoiesis and macrophage productionG-CSFStimulates granulopoiesis and proliferation of some leukemic cellsM-CSFStimulates macrophage productionIL-3 (Multi-CSF)Stimulates granulocyte, monocyte, eosinophils, erythroid cells, megakaryocyte and mast cells productionThrombopoietinInfluencing CFU-mega

  • Lymphokines and monokines - released by lymphocytes and monocytes (macrophages) have wide-ranging h.poietic effects through extensive network of interaction involving immune responses to infection and tumor invasion.

  • - IL (Interleukin) : secreted by lymphocytes,affect the function of other leukocytes (com-munication links between leukocytes) -engage in complex interactions with other IL, HGF and many other protein such a TNF and lymphotoxins (Table 3)

  • Table 3. Lymphoid Hematopoietic Growth Factors

    NameSourceFunctionIL - 1Macrophages, T and B cells, fibroblastsStimulates growth of T and B cells, mediates inflammation, inhibits growth of some cancer cells.IL - 2 (T cells GF)T cellsBinds to receptors on cytotoxic T cells, promote their growth, stimulates growth of helper T cells.IL - 4 T cells, NK cells, mast cellsStimulates & regulates growth and diff. of T and B cells, eosinophils and basophils.IL 5(EoGF)T cellsRegulates production of eosinophils. Activates mature eosinophils. IL - 6Lymphocytes, fibroblastsPromotes macrophage formation. Stimulates IgG production by B cells.IL-7Stromal CellsSupports long-term survival of B and T cells in vitro.IL - 8Fibroblasts, vasc. endot.Enhancement of neutrophil function

  • Common General Features of Hematopoietic Growth Factors1.All are glycoproteins2.Regulators of blood cell development and maturation and enhancers of mature cell functions, which are active at very low concentration3.Active both in vitro and in vivo4.Produced by cells of many types

  • 5.Usually have both unique and overlapping specificities6.Active on both stem (progenitor) cells and end cells 7.Biologic affects are mediated after binding to a small number of specific high - affinity receptors on the surfaces of target cells

  • 8.Also bind to receptors on some nonhema - topoietic cells. The significance of this is unknown9.Display synergy or additive effects with other growth factor10.Also act on neoplastic counterparts of normal cell type

  • III. SPLEENThe chief organ of RES, which also includes BM, lymph nodes, liver, circulating monocytes and fixed tissue macrophages. Its chief role in hematopoiesis occurs in utero ; its postnatal participation is limited.Extramedullary hematopoieis in the spleen occurs in several circumstances

  • Functions :Participates in immunologic and phagocytic activitiesProduces stem cells capable of differentiating along hematopoietic, histiocytic and fibroblastic cell linesPlay roles in the autoantibody response anddetermining blood volume.

  • IV. EVALUATION OF THE BONE MARROW1. Indication for a bone marrow aspirate :Evaluation of decreased numbers of cells from a single lineageEv. of patients with decreased blood cell counts (bicytopenia or pancytopenia) and leukemias (stem cell defects & disorder)Ev. of iron stores and abnormal iron in erythroid precursor

  • Diagnosis of tumor involvementTo demonstrate possible infection by intracellular organismTo investigate an immunologic disorderDiagnosis of nonhematopoietic diseases2. Indications for a BM biopsyFailure to obtain an adequate marrow aspirate

  • Evaluation of pancytopenia or bicytopeniaLeukoerythroblastic findings in the peripheral blood smearEvaluation of hematologic malignancies and tumor stagingTo defined endpoint of aplasia

  • Erythropoiesis is the segment of hemato-poiesis concerned with the production of erythrocytes (red cells). In essence, it is a system for the production and packaging of Hb molecules.Maturation stages begin with the pronormo-blast, which derives from a pool of more primitive stem cells ERYTHROPOIESIS

  • STEM CELLSPRONORMOBLAST BASOPHILIC NORMOBLAST POLYCHROMATOPHILIC NORMOBLAST ORTHOCHROMATOPHILIC NORMOBLAST RETICULOCYTE MATURE RED CELL

    MATURATION STAGES

  • Pool of nucleated erythroid precursor in marrow ~2% pronormoblast~18% basophilic normoblast~54% polychromatophilic normoblasts~26% orthochromatophilic normoblastsNucleated red cells (normoblasts) appear in the blood if erythropoiesis is occurring outsides the marrow (e.medullary e.poiesis) and also with some marrow diseases.

  • Erythropoietin (Epo)- Regulate erythropoietic activity - Also shorten the total time taken for a pro-normoblast to mature into marrow reticu-locytes & for the later to be released into the circulationThe life span averages aprox. 120 days.

  • Marrow requires many precursor to synthesize the new cells & large amount of Hb. The substances are : 1. Metals : iron, manganese, cobalt 2. Vitamins : vit. B12, folate, vit.C, vit.E, vit.B6, thiamine, riboflavin & pantothenic acid 3. Amino acid 4. Hormones : SCF, IL-3, GM-CSF, Epo, androgen and thyroxine

  • GRANULOPOIESISLeucocyte or white cell refer to any of the nucleated cells normally present in blood, whose major function is defense against foreign invadersTypes of leucocytes :- Type of defense function : phagocytes (i.e., granu-locytes and monocytes) and immunocytes (i.e., lymphocytes and plasma cells)

  • - Shaped of the nucleus polymorpho-nuclear or mononuclear)- Site of origin myeloid or lymphoid- Presence of absence of specific- staining granules granulocytes or non-granu-locytes

  • Maturation stages MYELOBLAST PROMYELOCYTE MYELOCYTE METAMYELOCYTEBAND FORMMATURE PMN GRANULOCYTE

  • 1. NEUTROPHILS Functions : ~ Chemotaxis ~ Cytotoxic activities : phagocytosis and granule toxicity Life span and circulation : ~ Transit time in blood for mature neutrophils : 1 day or less. ~ Probably survive 1-2 days in tissue. ~ N peripheral blood levels : 4.0 10 x 103/ul

  • 2. EOSINOPHILS Functions : ~ a first line defense against parasites~ modulate hypersensitivity reactions~ migrate to inflammatory sites Life span and circulation :~ Usually exist in concentr. of 100-400/ul in PB~ BM maturation time : 2-6 days , circ. half life : 6 - 12 hours

  • 3. Basophils and Mast cells Functions :~ involved in immediately hypersensitivity~ trigger anaphylactic degranulation~ active arachidonic acid metabolites (e.g..leukotrienes, prostaglandin)Life span and circulation :~ Basophils : about 1-2 days~ Mast cells : present in blood only in pathologic conditions. Murine studies : mast cells survive several weeks to several month in tissue

  • 4. MONOCYTES Functions : Morphology : ~ Activating stimuli Monoblast~ Chemotaxis~ Phagocytosis Promonocytes Monocytes Life span :4.5 10 hours (mean 8.5 h)

  • LYMPHOCYTOPOIESISThere are three major functional classes of lymphocy-tes : B lymphocytes (B cell), T lymphocytes (T cell) and Natural Killer (NK cell)Differentiation :~ B - lymphocyte diff. in BM : Early pre-B cell pre B-cell immature B cell mature B cell

  • ~ T-lymphocyte diff. in the thymus :Pre-T cell (thymic lymphoblast)Early thymocyte (large cortical thymocyte)Intermediate thymocyte (small c. thymocyte)Late thymocyte (medullary thymocyte)Mature T cell

  • Function :~ B cell function : humoral immunity (i.e.,anti body/immunoglobulins production)~ T cell function : cell-mediated immunity including delayed hypersensitivity, graft rejection, contact allergic reactionLife span : years

  • THROMBOPOIESISBlood platelets play an essential role in hemostasis, thrombosis and coagulation of bloodThe platelet count ranging from 140,000-450,000/ulLife span : 8 to 12 daysFunctions : Platelets participate in the formati-ons of a platelet plug and a stable fibrin clot (adhesion and aggregation)

  • Maturation stagesPluripotential stem cell CFU-Meg Megakaryoblast Proliferation

    CSF-Mega

    Megakaryocyte maturation Platelet shading

    Thrombopoietin (TP)

  • THANK YOU

    CFU-Granulocytes, Erthtrocytes, Monocytes, Megakaryocytes (CFU-GEMM)CFU-Granulocytes, Monocytes (CFU-GM)CFU-Erthropoiesis (CFU-E)

    Burst FU-erthroid (precursor of CFU-E)CFU-Meg (megakaryocytes)

    **Stem pro baso polychroma orthochroma reticulocyte mature RC*Myeloblast promyelocyte myelocyte metamyelocyte band form mature granulocyte*