Haematopoiesis - In level 6, thre is a MCQ test on this topic, and after using this note, 12 PDF

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Haematopoiesis Test Haematopoiesis= production of blood cells from pluripotent stem cells Stars from 3rd week by hemocytoblast stem cells Haematopoiesis in bone marrow= intramedullary haematopoiesis Haematopoiesis in liver, lymph nodes, spleen (outside of BM) in adults this only occur in disease = e...

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Haematopoiesis Test Haematopoiesis= production of blood cells from pluripotent stem cells Stars from 3rd week by hemocytoblast stem cells Haematopoiesis in bone marrow= intramedullary haematopoiesis Haematopoiesis in liver, lymph nodes, spleen (outside of BM) in adults this only occur in disease = extramedullary haematopoiesis

Site of hemopoiesis 0-2 months (yolk sac) 2-7 months (mostly liver and spleen) Infants 5-9 months only bone marrow (in all bones) At birth all bones contain BM (red marrow) Adults (bone marrow of ribs, sternum, vertebrae, cranium, femur, pelvis) At around 5-7 years of age, fat cells start to replace the red marrow in the longer bones of the arms and legs producing yellow marrow.

Life of blood cells RBC= 110-120days WBC= Neutrophil 7h- Eosinophil 6h- Basophil 3-11days- Monocytes70h Lymphocytes= 3d-20yrs (average 4-5yrs) Platelets=9-12days

Hematopoietic stem cells Pluripotent Hematopoietic stem cells (PHSCs) are rare type of stem cells that give rise to other blood cells they are multipotent and capable of self-renewal, differentiation and proliferation 1. Self-renewal= ensures that stem cell numbers are not used up so that marrow cellularity remains constant in a normal healthy steady state.(asymmetric division) 2. Proliferation= rise in number of progenitor cells by symmetric and asymmetric division 3. Differentiation= occur from the stem cell via committed haemopoietic progenitors which are restricted in their development potential (give rise to granulocyte, erythrocyte, monocytes and megakaryocytes and is termed CFU (colony forming unit-GEMM) 4. Maturation= immature (blast)-> mature(cytes) as the cell get more mature the ratio of nucleus to cytoplasm decreases and the cell get smaller therefore RNA and DNA synthesis decreases .as cells become more mature self-renewal capacity become lower. 5. Suppression of apoptosis = by G-CSF 6. Functional activation= activation of phagocytosis, killing, secretion, carrying O2,CO2 

Cells that undergo proliferation and differentiation are now committed and cannot return to a previous stage of development.

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Bone marrow is primary site of origin of lymphocytes. Spleen, lymph nodes and thymus are secondary sites of lymphocytes production. o Symmetric division is when both daughter cells are the same but different from parent cell o Asymmetric division is when one daughter cell is different from parent cell and the other is identical(self-renewal) Precursor cell(progenitor cell).  These cells have multipotency. Precursor cells are known as the intermediate cell before they become differentiated after being a stem cell.  Usually a progenitor cell is a stem cell which has the capacity to differentiate into only one cell type.  progenitor cells are capable of responding to haemopoietic growth factors with increases production of one or other cell line when the need arises.

Pluripotent stem cell(CD34)-> lymphoid/myeloid progenitor stem cell-> BFUe= burst forming unit-erythroid Bone marrow environment The bone marrow forms a suitable environment for stem cell survival, self-renewal and formation of differentiated progenitor cells. It is composed of stromal cells and a microvascular network. 1)haemopoietic tissues= contains of stem cells, immature but developing blood cells 2)Sinuses= the vascular spaces that are lined with endothelial cells to regulate the release of mature and immature cells 3)non haemopoietic cells that supports bone marrow and produce growth factor: the stromal cells include (connective tissue of bone) = mesenchymal stem cells, adipocytes, fibroblasts, osteoclasts, endothelial cells and macrophages and they secrete extracellular molecules such as collagen, glycoproteins (fibronectin and thrombospondin) and glycosaminoglycans (hyaluronic acid which provides a physical scaffold or support within the marrow to facilitate localization and retention of HSCs to the stem cell niche; and chondroitin derivatives) to form an extracellular matrix. In addition, stromal cells secrete several growth factors necessary for stem cell survival. Thrombospondin (THBS1) as a protein is an adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. Mesenchymal stem cells (MSCs are critical in stromal cell formation which means that MSCs are progenitors to stromal cells. Together with osteoblasts or endothelial cells they form niches and provide the GFs, adhesion molecules and cytokines which support stem cells e.g. the protein jagged on stromal cells binds to a receptor NOTCH1 on stem cells which then becomes a transcription factor involved in cell cycle.

As the stem cells in the bone marrow differentiate into different mature blood cells, they express different cell surface receptors i.e. cell adhesion molecules (CAMs) and cytokine/growth factor receptors. CD antigens= cluster of differentiation molecules are self-surface markers useful for the identification and characterization of leukocytes HLDA (human leukocytes differentiation antigens) pluripotent stem cell= CD34 myeloid stem cell CD34-CD33 CFU neutrophil CD15.

Adhesion molecules A large family of glycoprotein molecules termed adhesion molecules mediate the attachment of marrow precursors, leucocytes and platelets to various components of the extracellular matrix to endothelium, to other surfaces and to each other. The adhesion molecules on the surface of leucocytes are termed receptors and these interact with proteins termed ligands on the surface of target cells, e.g., endothelium. The adhesion molecules are important in the development and maintenance of inflammatory and immune response and in plated-vessel wall and leucocyte vessel wall interaction. the adhesion molecule may also determine whether or not cells circulate in the bloodstream or remain fixed in tissues. They may also partly determine whether or not tumour cells are subject to the bodys immune defences. CAMs anchor the developing cells in the bone marrow within a niche which again it is the environment containing GFs, nutrients, minerals etc., required for their proliferation and differentiation. Furthermore, CAMs help mature cells to leave the bone marrow and migrate to other regions of the body to carry out their functions.

Cytokines and growth factors GFs and cytokines regulate proliferation, differentiation and function of mature blood cells. Stromal cells are the major source of GFs except for erythropoietin (discussed below). Overall, these factors may cause the following:  Cell cycle signals for the cell to remain quiescent or enter cell cycle and undergo division  Signals to prevent or induce apoptosis  Signals which result in cells producing further growth factors which may act locally on other cells Cytokines can bind reversibly or irreversibly and they may be present continuously. But, a cell’s ability to respond to the cytokine will depend on the expression of the specific receptor. HGF may act locally where they are produced or circulate in blood plasma. Most are produced in the bone marrow environment by T-lymphocytes, monocytes/macrophages, endothelial cells and fibroblasts but not all An important aspect of haemopoietic growth factors is that they can act synergistically to stimulate a particular cell or one growth factor may instruct a cell to produce a different kind of GF.  Glycoproteins that act at very low concentration 

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Act hierarchically Act on transmembrane glycoprotein/receptors Usually produced by many cell types Usually affect more than one lineage(IL-3)

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Usually show synergistic or additive interaction with other growth factors (the combined action of two cytokines is greater than the additive affect) Often act on the neoplastic equivalent of a normal cell Multiple actions; proliferation, differentiation, maturation, functional activation, prevention of apoptosis of progenitor cells.

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Erythropoietin (EPO) (EPO) 90% produced by specialised cells within the kidney (peritubular interstitial cells of outer cortex of kidneys) and 10% by the liver and elsewhere. These cells detect a drop-in circulating blood oxygen levels (oxygen tension detected by kidney cells) and produce and secrete EPO. Hypoxia (low level of o2) induces ,hypoxia inducible factor (HIF 1α & β) which stimulate EPO production and also new vessel formation and transferrin receptor synthesis and reduces hepcidin synthesis increasing iron absorption. Erythropoietin stimulates erythropoiesis by increasing the number of progenitor cells committed to erythropoiesis. The transcription factor GATA-2 is involved in initiating erythroid differentiation from pluripotent stem cells. Subsequently, the TF GATA-1 with its cofactor FOG-1 are activated by erythropoietin receptor stimulation and are important in enhancing expression of erythroidspecific genes (e.g. globin, haem and cell membrane proteins) and also enhancing expression of anti-apoptic genes and of the transferrin receptor (CD71). Late BFU-E (burst forming units) and CFU-E (colony forming units which is the stage before haemoglobin synthesis) have EPO receptors, upon activation they produce haemoglobin. Thrombopoietin is a hormone made by the liver that stimulates the production of platelets by stimulating the production and differentiation of megakaryocytes. IL-1 and TNF act on stromal cells SCF, FLT3-L and VEGF act on pluripotential stem cells IL3, GM-CSF, IL6, G-CSF and thrombopoietin act on multipotential progenitor cells G-CSF,M-CSF,IL-5 (Eosinophil-CSF), Erythropoietin and thrombopoietin act on committed progenitor cells Erythrocytes RBC= GM-CSF, IL3,EPO Thrombocytes platelets =GM-CSF, IL-3, IL-7,IL-11, , IL-6 Granulocytes= IL-3,GM-CSF,G-CSF(neutrophil) /M-CSF(macrophage)/IL-5(eosiphil) Agranular leukocytes=IL-3, IL-4, IL-9 B AND T CELL= IL-1,3,2,7,6,4 Some examples of GFs and their effect: Erythropoietin (EPO)  Acts during the later stages of RBC production and haemoglobin development

Interleukin 1 (IL-1)  Produced by macrophages  Acts on early progenitors  Act on stromal cells

IL-3 and GM-CSF (granulocyte-macrophage colony stimulating factor)  Act on multipotential progenitor cells  Helps support the growth of Stem cells  Together supports growth of Granulocytes and Monocytes  G-CSF (Granulocyte colony stimulating factor)  Source is T cells, fibroblasts and endothelial cells  Supports the final stages of neutrophil differentiation...