Hematopoiesis.pptx

HEMATOPOIETIC Chapter 4 ORGANS ONTOGENY OF HEMATOPOIESIS Hematopoiesis begins as early as eighteenth day after fertilization  Occurs in an extraembryonic location  Yolk sac of human embryo  Cells produced  Erythrocytes  Transports critical oxygen to developing tissue early in g...

HEMATOPOIETIC Chapter 4 ORGANS ONTOGENY OF HEMATOPOIESIS Hematopoiesis begins as early as eighteenth day after fertilization  Occurs in an extraembryonic location  Yolk sac of human embryo  Cells produced  Erythrocytes  Transports critical oxygen to developing tissue early in gestation  Few macrophages Intraembryonic hematopoiesis  Begins in aorta-gonads-mesonephros (AGM) region  Along developing aorta  Cell production during this period  Primitive erythropoiesis  Hemoglobin produced during this period is different from later developing erythroblasts ONTOGENY OF HEMATOPOIESIS Third month of fetal development  Liver is the primary locale of blood cell production  Yolk sac and AGM cease their role in hematopoiesis  Liver produces a high percentage of erythroid cells  Myeloid and lymphoid cells begin to appear in greater numbers ONTOGENY OF HEMATOPOIESIS As fetal development progresses  Hematopoiesis seen in the  Spleen, kidney, thymus, lymph nodes  During late fetal and neonatal life  Gradual shifting from above sites to bone marrow  Erythroid, myeloid, early B lymphocyte cells  Sixth months of gestation  Bone marrow becomes primary site of hematopoiesis  Continues as primary source of blood production after birth and during adult life ONTOGENY OF HEMATOPOIESIS ONTOGENY OF HEMATOPOIESIS HEMATOPOIETIC ORGANS AND TISSUES Adult hematopoietic Bone marrow and thymus  Primary lymphoid tissues system includes  T and B cells develop from  Tissues and organs regulating the nonfunctional precursors proliferation, maturation, and  Become cells capable of responding destruction of blood cells to foreign antigens (immunocompetent cells) These organs and tissues include Spleen and lymph nodes  Secondary lymphoid tissues  Bone marrow  Possess immunocompetent T and B  Thymus cells  Spleen  Further differentiate and divide in  Lymph nodes response to antigens BONE MARROW Bone marrow  Blood-forming tissue found between the trabeculae of spongy bone  Composed of the vascular and hematopoietic compartment  Vascular compartment  Nutrient artery  Periosteal arteries  Central longitudinal vein  Arterioles  Sinuses BONE MARROW  Hematopoietic compartment  Location for formation and maturation of blood cells  Contains Stroma  Hematopoietic cells  Is a supporting bone marrow tissue  Stromal cells  Forms a meshwork that provides a three-dimensional scaffolding for hematopoietic cells  Stromal cells  Produce cytokines that regulate hematopoiesis Stroma composed of three major cell types  Macrophages  Reticular cells (fibroblasts)  Adipocytes BONE MARROW STROMAL CELLS Two major functions of macrophages in bone marrow  Phagocytose  Extruded nuclei of maturing erythrocytes  Abnormal cells such as B cells that have not differentiated properly  Differentiating cells that die during development  Secretion of hematopoietic cytokines Secondary functions of macrophages  Serve as the center for erythroblastic islands  Provides many colony-stimulating factors  For the development of myeloid lineage cells  BONE MARROW Histiocytes STROMAL CELLS (macrophages) BONE MARROW STROMAL CELLS Reticular cells Adipocytes  Located on the abluminal surface of  Cells whose cytoplasm is mostly the vascular sinuses replaced with a single fat vacuole  Send cytoplasmic processes into the  Mechanically control the volume of stroma BM in which active hematopoiesis  Produce reticular fibers occurs  Contribute to the three-dimensional  Provide steroids that influence supporting network  Hold the vascular sinuses and hematopoietic  Erythropoiesis sinuses  Maintain osseous bone integrity  Proportion of bone marrow composed of adipocytes changes with age of person BONE MARROW STROMAL CELLS Adipose Tissue Endothelial Cells BONE MARROW Osteoblasts  Form calcified bone STROMAL  Provide a niche for resting hematopoietic CELLS stem cells  Commonly seen in children and Don’t confuse with these: metabolic bone diseases BONE MARROW STROMAL CELLS Osteoclasts  Related to macrophages  Involved in resorption and remodeling of calcified bone  Are multinucleated  Granular cytoplasm that can be acidophilic or basophilic BONE MARROW STROMAL CELLS Osteoblast Osteoclast BONE MARROW STROMAL CELLS Mast Cells  Connective tissue cell of mesenchymal origin  Major effector cells of allergic reactions BONE MARROW HEMATOPOIETIC CELLS Hematopoietic cells  Arranged in niches within marrow cavity  Erythroblasts compose 25-30% of the marrow cells and are produced near the sinuses  Develop in erythroblastic islands  Composed of a single macrophage  Surrounded by erythroblasts in different states of maturation  Macrophage cytoplasm extends out to contact surrounding erythroblasts  Macrophages  Regulate erythropoiesis by secreting various cytokines during this association BONE MARROW HEMATOPOIETI C CELLS  Granulocytes produced in nests  Close to the trabeculae and arterioles  Relatively distant from the venous sinuses BONE MARROW HEMATOPOIETIC CELLS  Megakaryocytes  Large, polyploid cells  Produce platelets from their cytoplasm  Located near vascular sinus  Cytoplasmic processes of the megakaryocyte form long proplatelet processes Scanning electron micrograph of the luminal face of the myeloid sinus wall with an intraluminal segment of a proplatelet process (PP) showing periodic constriction along its length. Pl: platelet displaying tear-drop shape. (Reprinted, with permission, from DeBruyn PPH: Structural substrates of bone marrow function. Semin. Hematol. 1981;18:179.) BONE MARROW HEMATOPOIETIC CELLS  Lymphocytes  Produced in lymphoid aggregates near arterioles  Lymphoid progenitor cells  Depart the bone marrow, travel to the thymus  Mature into T lymphocytes  Some of these cells remain in the bone marrow  Mature into B lymphocytes  Some activated B cells return to bone marrow  Transform into plasma cells  Reside in bone marrow, produce antibody CHANGES TO MARROW CELLULARITY Bone marrow hyperplasia Bone marrow hypoplasia  An excessive development of normal  Hematopoietic tissue becomes cells inactive  Occurs with all conditions of  Fat cells increase increased or ineffective  Offers a cushion for the marrow hematopoiesis  Causes  Degree of hyperplasia related to  Environmental factors  Severity and duration of the pathological state  Chemicals  Conditions that cause BM hyperplasia  Toxins  Acute blood loss  Genetically determined  Chronic anemia  Leukemia Normocellular Bone Marrow Hypocellular Bone Marrow Hypercellular Bone Marrow THYMUS Primary Hematopoietic Organ Serves as a compartment for  Located in upper part of anterior maturation of T lymphocytes mediastinum  Supplies immunocompetent T  Bilobular organ with an outer cortex lymphocytes to T-dependent areas of and central medulla the  Cortex densely packed with  Lymph nodes, spleen, other peripheral lymphoid tissue  Small lymphocytes (thymocytes)  Well-developed at birth  Cortical epithelial cells  Continues to increase until puberty when it  Few macrophages begins to atrophy  Medulla (less cellular)  Atrophy of thymus continues through old age  More mature thymocytes  Still capable of producing new T cells if  Medullary epithelial cells and dendritic cells peripheral pool becomes depleted  Macrophages SPLEEN Located in upper left quadrant of the abdomen  Beneath the diaphragm and to the left of the stomach  Enclosed by a capsule of connective tissue  Contains largest group of lymphocytes and macrophages in the body  These cells with a reticular meshwork are concentrated in different areas of the spleen  Contribute to the formation of three zones of tissue  White pulp  Red pulp  Marginal zone SPLEEN Important Functions of Spleen Spleen – red pulp  Filtrates foreign substances  Contains  Filtrates old RBCs from circulation  Sinuses  Stores platelets  Dilated vascular spaces for venous blood  Assists in immune defense  Red color comes from presence of erythtocytes in the sinuses Can live without, but impairs  Cords immune syststem  Masses of reticular tissue and macrophages  Lie between the sinuses  Provides zones for  Platelet storage  Destruction of damaged blood cells SPLEEN  Generously supplied with blood by heart Slow transit pathway  Blood enters the spleen through splenic  Blood moves slowly through a artery circuitous route of macrophage-lined  Branches into many vessels in the cords trabeculae  Gains access to the sinuses  Vessel branches can end in the  White pulp, red pulp, or marginal zone  Plasma moves freely  Blood entering the spleen can follow two  RBCs meet resistance in the sinus pathways: wall  Rapid transit pathway (closed circulation)  Squeeze through tiny openings  Slow transit pathway (open circulation)  Sluggish blood flow and continued erythrocyte  Culling metabolic activity in cords  Pitting  Immune Defense  Results in an environment that is  Storage  Hypoxic, acidic, hypoglycemic SPLEEN Culling Defends body from blood-borne  Discriminatory filtering and infections destruction of senescent or damaged  Rich in lymphocytes and phagocytic red cells cells  Slow movement through white pulp Pitting and marginal zones due to transit  Refers to spleen’s ability to “pluck circulation out” articles from intact RBCs without  Allows for close contact between antigens and destroying them cells  Pinched off membrane can reseal itself  Spleen’s immunologic protection  Cannot produce new lipids or proteins more important for children  Results in reduced surface-to-volume ratio  Less-developed immune system  Spherocytes Storage  Red pulp cords store about one-third of peripheral platelet mass, acting as a reservoir for platelets SPLEEN Splenectomy (removal of the spleen)  Can relieve the effects of hyersplenism Hypersplenism  Appears to be most beneficial in patients with hereditary or acquired conditions  Infiltration of spleen with additional  Blood cells remain abnormal after splenectomy cells or metabolic byproducts  The major site of their destruction is removed  Allows the cells to have a more normal life span Splenomegaly  Lifespan of healthy RBCs remains the same after splenectomy  Enlargment of spleen  Liver assumes the culling function  Not as effective a filter as the spleen  Blood flow through the liver is slowed by Causes a decrease in circulating RBC, passage through sinusoids PLTS, and WBCs.  Kupffer cells  Special macrophages that line the sinusoids  Perform similar filtering functions as the phagocytes in the splenic cords and marginal zones LYMPH NODES  Act as filters removing foreign particles from lymph by dendritic cells and macrophages  Dendritic cells stimulate T and B cells  Stimulated B cells move from the Lymphatic system consists of germinal centers to the medulla  Lymph nodes and lymphatic vessels  Reside as plasma cells and secrete antibody  Lymph nodes provide immune defense  Drain into the left and right lymphatic ducts against pathogens in virtually all tissues  Vessels carry lymph toward the ducts near the neck where lymph enters the blood Lymphadenopathy  Lymph is formed from blood fluid that  Enlargement of the lymph nodes by escapes into connective tissues expansion of the tissue within the node  Lymph nodes  Causes of lymphadenopathy include  Bean-shaped and occur in groups or chains  Inflammation of the lymph node along the larger lymphatic vessels  Prolonged immune response to infectious agents  Lymph nodes contain an outer area called the  Malignant transformation of lymphocytes or cortex and an inner area called the medulla macrophages  Metastatic tumors that originate in extranodal sites MUCOSAL ASSOCIATED LYMPHOID TISSUE (MALT) Collection of loosely organized lymphocytes  Located throughout the body in association with mucosal surfaces  Peyer’s patches in intestine (lymphoid aggregates)  Tonsils and appendix  Basic organization similar to lymph nodes  B- and T-cell rich areas not as clearly demarcated as in lymph nodes  Functions of MALT  Trap antigens crossing mucosal surfaces  Rapidly initiate immune responses OTHER SECONDARY LYMPHOID TISSUE Gut-associated lymphoid tissue (GALT) Thoracic duct Bronchus-associated lymphoid tissue (BALT) Skin-associated lymphoid tissue Blood HEMATOPOIESIS Chapter 4 HEMATOPOIESIS Tissue homeostasis Hematopoiesis  Maintenance of an adequate  The process responsible for the replacement of circulating cells number of cells  Depends on  Careful balance between  The proliferation of precursor cells that  Cellular proliferation still retain mitotic capability  Cellular differentiation  Governed by multiple cytokines  Cell death (apoptosis)  Takes place in a specialized microenvironment HEMATOPOIESIS Circulating cells are Hematopoietic precursors cells  Mature  Located primarily in the bone marrow in adults  Incapable of mitosis  Consist of a hierarchy of cells  Exception: lymphocytes  Enormous proliferation potential  Described as terminally  Daily production of differentiated  ~ 2 x 1011 RBCs  Must be replaced by less differentiated,  ~ 1 x 1011 WBCs mitotically active precursor cells  ~ 1 x 1011 Platelets  Can increase production of cells rapidly and efficiently HEMATOPOIETIC PRECURSOR CELLS Stem Cells ↓ Progenitor Cells ↓ Maturing Cells STEM CELLS Undifferentiated cells  Give rise to all of the bone marrow cells by the process of proliferation and differentiation Multipotential precursors  High self-renewal capacity  Give rise to daughter cells that are exact replicas of the parent cell  Nondifferentiating cell division Stem cell population is sustained throughout the individual’s lifespan STEM CELLS Believed to reside in unique “stem cell niches” in the bone marrow Humans contain ~ 2 x 104 HSCs Not morphologically distinguishable  Look like lymphocytes  Measured by functional (clonal) assays Quiescent cell population (reside in G0) of cell cycle Hemangioblasts  Precursor cells that during embryonic development give rise to  Hematopoietic stem cells  Vascular endothelium FIG URE 3-1 DERIVATIO N AN D FATES OF HE MATOPO IETIC STE M C ELLS (HSC). H EMAN GIOB L ASTS ARE PREC URSOR C E LLS GIVIN G RISE TO BOTH H SC A N D VASC U L AR E ND OTHE LIU M DU RING E MB RYO NIC DEVELOPMENT. LT (LON G -TE RM) HSC AN D ST (S HO RT-TERM) H SC REFE R TO TH E LEN GTH OF TIME TH ESE S UB POPUL ATIO NS OF H SC TA KE TO REPOPUL ATE DEPLETED HE MATOPO IETIC TISS UE WITH LT C ELLS B EING DEVE LOPME NTA LLY MO RE PRIMITIVE THA N ST C ELLS. H SCS HAVE TH RE E POSSIB LE FATES: SE LF- RE NEWA L, COMMITME NT TO D IFF ERE NTIATION (B ECOMING CO MMON LYMPHO ID PRO GE NITO RS [C LP ] O R CO MMO N MYE LO ID PRO GE NITO RS (C MP ]), OR A POPTOSIS. THIS CE LL-FATE DEC ISION IS HIGHLY RE GU L ATE D AN D INVO LVES SPECIF IC TR AN SCRIPTION FACTO RS. (A DAPTED FROM Z HU J , EME RSON SG. H EMATOPOIETIC CY TO KINES , TRA NSC RIPTION FACTORS AN D LIN EAG E CO MMITMENT. ONCOG EN E. 2002;21:3295–3313.) PROGENITOR CELLS Some stem cells will ultimately Daughter cell of the HSC undergo differentiation  Initially retains the potential to generate cells of all hematopoietic Occurs through lineages  Down regulation of HSC-associated  Multipotential progenitor cells (MPP) genes  Gradually become restricted in  Up-regulation and activation of differential potential to one cell line lineage-specific genes  Unilineage or committed progenitor cell Upon commitment the HSC Progenitor cell compartment enters the next compartment  Contains all precursor cells between  Progenitor cell (PC)  HSCs and morphologically recognized precursor cells PROGENITOR CELLS ~3% of total nucleated Able to produce colonies of cells hematopoietic cells in semisolid media in vitro  Transit population without true self-  Colony-forming units (CFU) renewal  CFU-GEMM – progenitor cell giving rise to  Population can be amplified by  Granulocytes, erythroid cells, monocytes, proliferation megakaryocytes  CFU-GM – progenitor cell giving rise to  Not morphologically identifiable  Granulocytes, monocytes Growth-regulatory glycoproteins  CFU-Mk – progenitor cell giving rise to  Megakaryocytes  Influence survival and differentiation of precursor cells MATURING CELLS >95% of total hematopoietic precursor cells  Committed (unipotential) transit population  Population can be numerically amplified by proliferation  Proliferative sequence complete before full maturity  Morphologically recognizable  First recognizable cell – “Blast”  Measured by morphologic analysis  Cell counting differentials COMPARISON OF HEMATOPOIETIC PRECURSOR CELLS PHENOTYPE OF HEMATOPOIETIC PRECURSOR CELLS CYTOKINES Chapter 4 GROWTH FACTORS (CYTOKINES) Produced by many cells  Monocytes, macrophages, activated T lymphocytes, fibroblasts, endothelial cells, osteoblasts, adipocyte (bone marrow stromal cells) Most are produced by stromal cells in the hematopoietic microenvironment  Exception is erythropoietin  Produced mainly in the kidney Most are not lineage specific  Each has multiple functions (pleiotrophy) CHARACTERISTICS OF HEMATOPOIETIC GROWTH FACTORS HEMATOPOIETIC GROWTH FACTORS (GFS) LINEAGE-SPECIFIC REGULATION Erythropoiesis Granulocytopoiesis and  Progenitor cells give rise to Monopoiesis  BFU-E  Derived from CFU-GM  Regulated by IL-3, GM-CSF  Growth factors  CFU-E  GM-CSF and IL-3  Depends primarily on EPO  M-CSF  Gives rise to the first recognizable  Supports monocyte differentiation erythrocyte precursor  G-CSF  Pronomoblast  Supports neutrophil differentiation  Eosinophils and basophils come from GFU-GEMM  Eosinophils – IL-5  Basophils – IL-3/IL-4 LINEAGE-SPECIFIC REGULATION Megakaryocytopoiesis/ Lymphopoiesis Thromobopoiesis  Occurs in multiple anatomic locations  Platelets are derived from  Bone marrow, thymus, lymph nodes, spleen megakaryocytes  Multiple GFs play a role in  Come from CFU-EMk lymphopoiesis  CFU-Mk  Growth factors that influence the proliferation and differentiation of megakaryocytes the most  IL-11 and TPO NEGATIVE REGULATORS Negative regulators of hematopoiesis  Limit the production of hematopoietic precursor cells  Hematopoiesis may be inhibited by  Decreasing production of stimulating factors  Increasing factors that inhibit cell growth CYTOKINE PATHWAYS Cytokines  Must bind to surface membrane receptors to express their activity  Signaling pathways  The cytokine (external stimuli) binds to its specific receptor causing an intracellular signal  The intracellular signaling molecules translocate to the nucleus  Recruit transcription factors which either  Activate or silence genes FIGURE 3-5 A MODEL FOR THE TRANSFER OF SIGNALS FROM EXTRACELLUL AR STIMULI (CY TOKINES) INTO APPROPRIATE INTRACELLUL AR RESPONSES. THE BINDING OF A CY TOKINE OR LIGAND (L) TO ITS COGNATE RECEPTOR GENERALLY INDUCES RECEPTOR DIMERIZATION, THE ACTIVATION OF A CASCADE OF DOWNSTREAM SIGNALING MOLECULES (A, B, C-SIGNAL TRANSDUCTION PATHWAYS), CONVERGING ON THE NUCLEUS TO INDUCE OR REPRESS CY TOKINE- SPECIFIC GENES. THE RESULT IS AN ALTERATION OF TRANSCRIPTION, RNA PROCESSING, TRANSLATION, OR THE CELLUL AR METABOLIC MACHINERY. FIGURE 3-6 CY TOKINE RECE PTOR- JAK-STAT MODEL OF SIGNAL TRAN SDUCTION. CY TOKINE (E.G., EPO) INTER ACTION WITH ITS SPECIFIC RECEPTOR LEAD S TO RECE PTOR DIMERIZ ATION AND ACTIVATION OF JAK KINAS ES ASSOCIATED WITH THE ACTIVATED RECEPTOR. ACTIVATED JAK KINAS ES MEDIATE AUTOPHOSPHOSPHORYL ATION AS WELL AS PHOSPHORYL ATIO N OF THE RECEPTOR , WHICH THEN SERVES AS A DOCKIN G S ITE FOR STATS (SIGNAL TRANSDUCE RS AN D ACTIVATO RS O F TRANSCRIPTION). THESE STATS ARE PHOSPHORYL ATED, DISSOCIATE FROM TH E RECEPTO R, DIMERIZE , AN D TRAN SLOCATE TO THE NUC LEUS WHERE TH EY ACTIVATE GENE TRANSCRIPTIO N. CLINICAL USE OF HEMATOPOIETIC GROWTH FACTORS Cloning and characterization of genes enable production of cytokines Can be produced in large quantity Used in therapeutic regimens for hematopoietic disorders CLINICAL APPLICATIONS OF HEMATOPOIETIC GROWTH FACTORS Insert Table 3-7