HEMATOPOIESIS
Cell renewal, proliferation, differentiation, and maturation |
Hematopoietic inductive microenvironment (niche) in the bone marrow = regulate hematopoietic stem cell maintenance, self-renewal, and differentiation; where hematopoietic stem/progenitor cells (HSCs/HPCs) grow and develop |
Site of Hematopoiesis
Adults |
bone marrow |
Fetal development |
yolk sac > aorta-gonad mesonephros (AGM) region (mesoblastic phase) > fetal liver (hepatic phase) > bone marrow (medullary phase) |
ADULT HEMATOPOIETIC TISSUE
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Located in the bone marrow, lymph nodes, spleen, liver, and thymus |
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Lymphoid development occurs in primary and secondary lymphoid tissue. |
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Primary lymphoid tissue bone marrow and thymus = (T&B lymphocytes)
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Secondary lymphoid tissue (lymphoid cells that respond to foreign antigens) spleen, lymph nodes, and mucosa-associated lymphoid tissue
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Medullary (Myeloid) Phase
5th month of development = hematopoiesis begins in the Bone Marrow (Chief Site) |
“Medullary” = occurs in the medulla or inner part of the bone |
Myeloid-to-erythroid ratio = 3:1 |
Production of adult hemoglobins (HbA1 and HbA2) |
Bone Marrow
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Location = within the cavities of the cortical bones |
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Contains hematopoietic cells, stromal cells, and blood vessels |
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Red marrow = hematopoietically active; developing blood cells and their progenitors |
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Yellow marrow =hematopoietically inactive marrow; composed primarily of adipocytes (fat cells) |
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Retrogression = replacing the active marrow by adipocytes Infancy and early childhood = primarily red (active) marrow
5 and 7 years of age = adipocytes become more abundant
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Yellow marrow is capable of reverting back to active marrow in cases of increased demand on the bone marrow, such as in excessive blood loss or hemolysis
Stromal cells
Stromal cells play a critical role in the regulation of hematopoietic stem and progenitor cell survival and differentiation |
Types of Stromal Cells
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1. Endothelial cells form a single layer along inner surface of the arteries, veins, and vascular sinuses; regulate what enters or leaves the vascular sinuses
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2. Adipocytes large cells with a single fat vacuole; regulating volume of the marrow in which active hematopoiesis occur
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3. Macrophages phagocytosis; secrete various cytokines
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4. Osteoblasts bone-forming cells
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5. Osteoclasts bone-resorbing cells
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Originate from mesenchymal cells
Secrete a semifluid extracellular matrix to promote cell adhesion = matrix contains fibronectin, collagen, laminin, thrombospondin, tenascin, and proteoglycans
Spleen Pathophysiology
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Blood route entering the spleen: |
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1. Slow-transit pathway RBCs > cords > sinuses > RBC have hard time entering sinus thus, slow passage > but RBC metabolism is continuous > creates acidic, hypoglycemic, and hypoxic environment > environment stress in spleen > possible hemolysis
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2. Rapid-transit pathway RBC > sinuses > venous system > exit spleen
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Spleen
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Largest lymphoid organ in the body |
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Storage site for platelets (30% total plt are kept in spleen) |
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2 methods to remove senescent or abnormal RBCs from the circulation: 1. Culling = cells are phagocytized
2. Pitting = splenic macrophages remove inclusions or damaged surface membrane from the circulating RBCs.
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Blood enters the spleen through the central splenic artery |
senescence = loss of a cell's power of division and growth
Thymus
Densely populated with progenitor lymphoid cells that migrated from the bone marrow and will soon give rise to T cells. |
T cells from bone marrow > go to thymus > No surface markers yet (CD4 CD8) > go to corticomedullary junction > once influenced by chemokines, cytokines, and receptors > T cells go to cortex > express CD4 CD8 marker > go to medulla > T cell matures > leave thymus > go to T cell dependent areas (spleen, lymph nodes, and other lymphoid tissues) |
Medulla holds mature T cells until they are needed by the peripheral lymphoid tissues
Lymph Nodes
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Lymph fluid portion of blood escapes into the connective tissue
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Lymph > Enter in Afferent vessels > lymph nodes filter lymph > Exit in Efferent vessels |
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Three main functions: 1. Site of lymphocyte proliferation from the germinal centers
2. Initiation of the specific immune response to foreign antigens
3. Filter particulate matter, debris, and bacteria entering the lymph node
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Cytokines and Growth Factors
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Cytokines - group of specific glycoproteins -Such as interleukins (ILs), lymphokines, monokines, interferons, chemokines, and colonystimulating factors (CSFs) have an effect on other cells.
-Regulate the proliferation, differentiation, and maturation of hematopoietic precursor cells
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Cytokines promote growth and survival to hematopoietic progenitor cells |
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Cytokines prevent hematopoietic precursor cell death by inhibiting apoptosis |
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Apoptosis - programmed cell death; eliminates unwanted, abnormal, or harmful cells. |
Note: Cytokine and Growth Factor are often used synonymously
Cytokine Influence
Cytokines negative influence on hematopoiesis |
transforming growth factor-b, tumor necrosis factor-a, and the interferons |
Cytokines positive influence on hematopoiesis |
stimulate production and differentiation of precursor cell |
TGFβ - inhibit the growth of many types of cells; antagonize many immune responses
Early-Acting Multilineage GF
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KIT ligand (stem cell factor) - early-acting growth factor receptor-type tyrosine-protein kinase
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KIT ligand > bind to KIT receptor > signals from transduction pathways to the HSC nucleus > stimulate the cell to proliferate |
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FLT3 receptor-type tyrosine-protein kinase
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KIT ligand + FLT3 ligand Work synergistically with IL-3, GM-CSF, and other cytokines to promote early HSC proliferation and differentiation.
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IL-3 control granulocytes and macrophages production, differentiation, and function to regulate blood cell production
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Activation of the KIT receptor by KIT ligand is essential in the early stages of hematopoiesis. |
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GM-CSF stimulate HSC differentiation to common myeloid progenitor |
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Hematopoietic Stem Cells
Hematopoietic stem cells (HSCs) are capable of self-renewal |
They are pluripotent and can differentiate into all the different types of blood cells. |
Mesoblastic Phase
Begins during nineteenth day of embryonic development |
1. Cells from the mesoderm migrate to the yolk sac> form primitive erythroblasts> produce hemoglobin (Gower-1, Gower-2, and Portland) for delivery of oxygen |
2. Cells from the mesoderm migrate to the AGM>give rise to HSC |
Hepatic Phase
5 to 7 gestational weeks |
Liver = remaining the major site of hematopoiesis during the second trimester of fetal development |
Liver Hematopoiesis = peak by the third month, declines after the sixth month |
Thymus = site of T cell production |
Kidney and spleen = site of B cell production |
Production of megakaryocytes begins |
Lymphoid cells begin to appear |
Fetal hemoglobin (Hb F) is the predominant hemoglobin |
Spleen, kidney, thymus, and lymph nodes contribute to the hematopoietic process during this phase. |
Occurs extravascularly
Thymus - the first fully developed organ in the fetus
Red Marrow
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Composed of extramedullary cords that contain all developing cells (stem and progenitor cells, adventitial cells, and macrophages) |
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Bone foramina where nutrient and periosteal arteries enters to provide nutrient and oxygen to the marrow; also where the blood exits from BM
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Liver
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Second trimester of fetal development Major site of hematopoiesis
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Hepatocytes functions: Protein synthesis and degradation, coagulation factor synthesis, carbohydrate and lipid metabolism, drug and toxin clearance, iron recycling and storage, and hemoglobin degradation (bilirubin is conjugated and transported to the small intestine for excretion)
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Kupffer cells (macrophages) Remove senescent cells and foreign debris from the blood in the liver; secrete mediators that regulate protein synthesis in the hepatocytes
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Liver Pathophysiology
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Porphyrias Defects in the enzymes involved in heme biosynthesis = accumulation of intermediary porphyrins = damage hepatocytes, erythrocyte precursors, and other tissues
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Severe hemolytic anemia Liver > increases the conjugation of bilirubin and storage of iron
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Liver removes membrane-damaged RBCs from circulation |
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If BM is damaged (myelofibrosis) Liver can extramedullary hematopoiesis - keep hematopoietic stem&progenitor cells to produce various blood cells
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Spleen Pathophysiology
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Splenomegaly Spleen becomes enlarged and is palpable
Caused by: chronic leukemias, inherited membrane or enzyme defects in RBCs, hemoglobinopathies, Hodgkin disease, thalassemia, malaria, and the myeloproliferative disorders
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Splenectomy Excessive destruction of RBCs due to autoimmune hemolytic anemia (corticosteroids does not effectively suppress hemolysis) or severe hereditary spherocytosis
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After splenectomy = platelet and leukocyte counts increase |
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Autosplenectomy Sickle cell anemia = sickled RBCs trapped in the small-vessel circulation of the spleen = tissue damage/necrosis
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Hypersplenism Enlargement of the spleen (pancytopenia)
Most common causes 1. congestive splenomegaly 2. cirrhosis of the liver 3. portal hypertension
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Lymph Node Pathophysiology
Antigenic stimulation > cortical region develop cluster of activated B cell called germinal centers |
Paracortex region = contains T cells and macrophage
Medullary cord region = contains plasma cells and B cells |
Too much microorganism enter lymph node > macrophage are overwhelmed > result to adenitis (infection of the lymph node) |
Worst case: malignant cells from tumors enter lymph node > spread to nearby lymph nodes |
Follicles with germinal centers are called secondary follicles, while those without are called primary follicles
Germinal centers = Site of lymphocyte proliferation
Stem Cell Theory
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Monophyletic theory Suggests that all blood cells are derived from a single progenitor stem cell called a pluripotent hematopoietic stem cell; widely accepted theory
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Polyphyletic theory Suggests that each of the blood cell lineages is derived from its own unique stem cell
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Common lymphoid progenitor T, B, and natural killer lymphocyte and dendritic lineages
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Common myeloid progenitor granulocytic, erythrocytic, monocytic, and megakaryocytic lineages
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SC Phenotypic & Functional Characterization
Origin of HSCs can be determined by immunophenotypic analysis using flow cytometry |
General characteristics of maturation include decrease in nuclear and cell diameter, loss of nucleoli, condensation of nuclear chromatin, and decreased basophilia in cytoplasm. |
Colony-Stimulating Factors
Interleukins
Proteins/group of cytokines that regulates autoimmune, inflammatory reactions, and hematopoiesis |
Synergize with other cytokines |
Effective at very low concentrations |
LINEAGE: Erythropoiesis
The CFU-GEMM gives rise to the earliest identifiable colony of RBCs, called the burst-forming unit–erythroid (BFU-E) |
BFU-Es under the influence of IL-3, GM-CSF, TPO, and KIT ligand develop into colony-forming unit–erythroid (CFU-E) colonies |
CFU-E has many EPO receptors and has an absolute requirement for EPO |
Small amount of EPO is produced by the liver |
Oxygen availability in the kidney is the stimulus that activates production and secretion of EPO |
LINEAGE: Megakaryopoiesis
The liver is the main site of production of TPO |
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