Hematopioesis

About Hematopoiesis.Hematopoietic stem cell and its proginators.Cytokines and its role in Hematopoiesis

1. hematopoiesis

2. Contents Introduction Hematopoietic stem cell and its proginators Role of cytokines in hematopoiesis Conclusion Reference

3. Hematopoiesis Is the formation of  blood  cellular components. All cellular blood components are derived from  haematopoietic stem cells . 

4. STEM CELLS They can proliferate extremely well They are self-renewing They can differentiate into several (at least 2) different cell-types They can reconstitute tissues after injury DIFFERENT TYPES OF STEM CELLS: TOTIPOTENT STEM CELLS : Have the ability to generate an entire organism . Only embryonic stem cells are able to do this MULTIPOTENT STEM CELLS : Have the ability to differentiate into several different cell types , for ex, HSCs

5. Locations In developing embryos, blood formation occurs in aggregates of blood cells in the yolk sac, called blood islands . As development progresses, blood formation occurs in the spleen , liver and lymph nodes . When bone marrow develops, it eventually assumes the task of forming most of the blood cells for the entire organism.

6. Extra medullary In some cases, the liver, thymus, and spleen may resume their haematopoietic function, if necessary. This is called extramedullary haematopoiesis .

7. Maturation As a stem cell matures it undergoes changes in gene expression that limit the cell types that it can become and moves it closer to a specific cell type. These changes can often be tracked by monitoring the presence of proteins on the surface of the cell. Each successive change moves the cell closer to the final cell type.

8. Determination Cell determination appears to be dictated by the location of differentiation. , the thymus provides an ideal environment for thymocytes to differentiate into a variety of different functional T cells. For the stem cells and other undifferentiated blood cells in the bone marrow. the colony stimulating factors and other factors of the haematopoietic microenvironment determine the cells to follow a certain path of cell differentiation

9. SOURCES OF HSCs Bone marrow & mobilized peripheral blood Umbilical cord Embryonic stem cells

10. HALLMARKS OF HSCs SELF-RENEWAL: Ability to make copies with the same or very similar potential. DIFFERENTIATION: Differentiate into several different cellular components of blood. MIGRATION: Occurs at specific times during development(ie, seeding of fetal liver,spleen and eventually,bone marrow) and certain conditions(eg, cytokine-induced mobilization)later in life

11. HAEMATOPOIESIS

12. Hematopoietic Stem Cells and Progenitors All of the mature blood cells in the body are generated from a relatively small number of hematopoietic stem cells (HSCs) and progenitors. HSCs are able to generate every lineage found in the hematopoietic system including red blood cells, platelets, and a variety of lymphoid and myeloid cells. Each of these cell types can be generated from a single HSC, and each HSC has an enormous capacity to generate large numbers of these cells over many years.

13. HSCs are primarily found in the bone marrow. they are present in a variety of other tissues including peripheral blood and umbilical cord blood, and are found at low numbers in the liver, spleen, and perhaps many organs. HSCs are small cells with minimal cytoplasm, and they express high levels of the multidrug resistant (MDR) proteins and high levels of aldehyde dehydrogenase (ALDH). These cells tend not express surface markers seen on mature HSCs but can express low levels of the thy-1 surface protein and relatively high levels of the sca-1 surface marker. HSCs generate the multiple hematopoietic lineages through a successive series of intermediate progenators .

14. These include common lymphoid progenitors(CLPs),which can generate only B,T, and NK cells, and common myeloid progenitors (CMPs), which can generate only red cells, platelets, granulocytes, and monocytes . Downstream of the CLPs and CMPs are more mature progenitors that are further restricted in the number and type of lineages that they can generate. terminally differentiated cells are produced that cannot divide and undergo apoptosis after a period of time ranging from hours (for neutrophils ) to decades (for some lymphocytes).

15. MYLOID LINEAGE: Mononuclear Phagocytes The mononuclear phagocytic system consists of monocytes circulating in the blood and macrophages in the tissues . During hematopoiesis in the bone marrow, granulocyte- monocyte progenitor cells differentiate into promonocytes , which leave the bone marrow and enter the blood, where they further differentiate into mature monocytes . Monocytes circulate in the bloodstream for about 8 h, during which they enlarge; they then migrate into the tissues and differentiate into specific tissue macrophages or, into dendritic cells. : The cell enlarges five- to tenfold; its intracellular organelles increase in both number and complexity; and it acquires increased phagocytic ability, produces higher levels of hydrolytic enzymes, and begins to secrete a variety of soluble factors.

16. Monocytes They are normally refered to as the mononuclear phagocytic cells .Found as free circulating cells in the blood stream. They constitute approximately 4-10% of the nucleated cells in the blood. The monocyte has a diameter of 12-17mM with a characteristic Horseshoe-shaped nucleus and cytoplasmic granules. The monocytes are the precurssors of the tissue-bound macrophages. They migrate to the tissues and becomes macrophages .

17. Macrophages After the monocytes become macrophages most importently the phagocytic property of the cell increased. It contains azurophilic lysosomal granules that contains myeloperoxidase , lysozyme , acid hydrolases such as beta glucuronidase , phosphate etc. The activated macrophages express high level of MHC class II molecules, the ones that are required to present the antigen to the T helper cells, which is prerequisites for immune response. Due to this activity the macrophages are refferd to as “antigen presenting cells” Macrophages express certain characteristic molecules on their cell surface, which can be identified by specific monoclonal antibodies. A systematic nomeclature has been attributed to those molecules, in which CD stands for cluster of differentiation. They are assigned with different numbers according to the monoclonal antibodies to which they respond. The different CD markers of the macrophages are CD64, CD32 and CD64 which acts as Fc receptor of the antibody

18. Alveolar macrophages in the lung Histiocytes in connective tissues Kupffer cells in the liver Mesangial cells in the kidney Microglial cells in the brain Osteoclasts in bone

19. Granulocytic Cells Neutrophils from the major part of the white blood carpusles (40-75%) they are motile short lived cells with multilobed nucleus, the cytoplasm contains granules which do not take up acidic or basic stains strongly and hence named neutrophils . The major function of the neutrophils is phagocytosis which is similar to macrophages. Neutrophils can attack and destroy bacteria and viruses even in the circulating blood, when a tissue is damaged or inflamed, the neutrophils reach that area along with macrophages destroy the unwanted tissues by phagocytosis

20. These are acidophilic leucocytes and are called eosinophils because, eosin, an acidic dye stains the granules of the cytoplasm of these cells intensely. The granules are rich in hydrolytic enzymes. The nucleus is usually bilobed or ellipsoid. They are about 2-5% of the leucocytes in healthy individuals. Increase in number of eosinophils ( eosinophilia ) is observed in allergic reaction especially during infection with intestinal parasites. At the time of parasitic infection, degranulation of eosinophils occurs and hydrolytic components of the granules are released, which kill the parasites. Eosinophils

21. These cells are named so, because of their cytoplasm containing granules that stains with basic dye. Basophils constituets about 0.4% of white cells. The basophils granules are belived to contain heparin, histamine, serotonin, platelet activating factor and other vasoactive amines that may be released at the site of inflammation or regions of immediate hypersensitivity reaction. Basophils

22. Platelets Platelets , also called  thrombocytes  ( thromb -  +  - cyte , "blood clot cell), are a component of blood whose function (along with the  coagulation factors ) is to stop bleeding by clumping and clotting blood vessel injuries .  Platelets have no cell nucleus : they are fragments of  cytoplasm  that are derived from the megakaryocytes of the  bone marrow , and then enter the circulation. These unactivated platelets are biconvex discoid (lens-shaped) structures, 2–3 µm in greatest diameter .

23. Erythropoiesis This occurs entirely in the red bone marrow. Red marrow can be found in vertebrae, ribs, skull, sternum, scapula, and proximal ends of the limb bones (known as the  trabecular area).  Red marrow is also known as myeloid tissue. It is not generally found in other areas of the long limb bones; which are instead filled with fatty yellow marrow During childhood, red marrow is far more extensive.

24. The  haemocytoblast , in the presence of Multi-CSF, will develop into a Progenitor cell. These cells will go on to form all types of blood cell, except Lymphocytes. In the presence of EPO, the progenitor cell will become a  proerythroblast . In the presence of EPO, this will develop into a basophilic erythroblast In the presence of more EPO, this will develop into a  polychromatophilic erythroblast, then a  normoblast , which will then eject its nucleus, and become a  reticulocyte , before finally becoming a fully formed RBC.

25. LYMPHOID LINAGE: Lymphocytes constitute 20%–40% of the body’s white blood cells and 99% of the cells in the lymph. These lymphocytes continually circulate in the blood and lymph and are capable of migrating into the tissue spaces and lymphoid organs, Two morphological distinct lymphocytes can be observed in the blood the first type is the small agranular lyphocyte having high nuclear-to-cytoplasm ratio.these lymphocytes are further divided into two types they are T and B lymphocytes The second type is a large cell, which is granulated, and posses low nuclear-to-cytoplasmic ratio. They are called as large granulated lymphocytes. Lymphocytes normally possess specific receptors for antigens and thus mediate specific immunity.

26. T lymphocytes The T lymphocytes are found in the bone marrow as pre T lymphocytes. Then they enter the thymus to become matured T lymphocytes. Most of the circulating lymphocytes are T lymphocytes and contribute to about 80% of the lymphocyte population. The T cells play two important function- effector and regulatory. The effector function includes cytolysis of cell infected with microbes and tumour cells and lymphokine production. The regulatory functions are either to increse or to supress other lymphocytes and accessory cells. T cells are two types: T helper cells T cytotoxic cells

27. T helper lymphocytes that help B lymphocytes to produce antibiodies and help phagocytes to destroy ingested microbes. T cytotoxic lymphocytes that kill cells harbouring intracellular microbes. These two types of T cells shows differences in their surface markers. The T helper cells express CD4 marker on their cell surface, whereas the T cytotoxic cells express CD8 marker on their cell surface. Thus T h cells will be referred to as CD4 cells and Tc cells as CD8 cell.

28. B lymphocytes Bone marrow is its major site of maturation A single B cell has an identical binding site for antigen. Among the other molecules expressed on the membrane of mature B cells are the following: B220 (a form of CD45) is frequently used as a marker for B cells and their precursors. They are very important in antibody-mediated immunity as they secrete specific immunoglobulins in response to antigenic stimulus. The B cells are of two subunits. T-cell-independent cell: which do not require the help of T h cells for the production of immunoglobulins . T-cell-dependent cell: which require the help of T h cells for the production of immunoglobulins .

29. The dendritic cell (DC) acquired its name because it is covered with long membrane extensions that resemble the dendrites of nerve cells. the same major function, the presentation of antigen to TH cells The dendritic cell decend from the myeloid cell lineage. They circulate in blood as immature cells and mature as complete dendritic cell in the tissue. The dendritic cell express high level of both class I and class II MHC molecules. They are potent antigen-presenting cells. Most dendritic cells process the antigen and present it to T h cells. There are different types of dendritic cells Langerhans ’ cells Interdigitating dendritic cells Interstitial dendritic cells Veiled cells DENDRITIC CELLS

30. Natural killer cells NK cells were subsequently shown to play an important role in host defense both against tumor cells and against cells infected with some, though not all, viruses. These cells, which constitute 5%–10% of lymphocytes in human peripheral blood, they can recognize potential target cells in two different ways. NK cells express CD16, a membrane receptor for the carboxyl-terminal end of the IgG molecule, called the Fc region, they can attach to these antibodies and subsequently destroy the targeted cells

31. HAEMATOPOIETIC GROWTH FACTORS The discovery of growth factors has been a major advance in this area. It is now known that a number of cytokines play a role in the differentiation of blood cells. Many cytokines that influence the development of the various hematologic cells have been identified. It is the balance of these cytokines within the microenvironment surrounding the pluripotent stem cell and its subsequent lineage that determines the pathway of differentiation. Growth factors play a role in hematopoiesis not only by causing differentiation of stem cells toward a particular cell type, but also by inducing the proliferation of cells.

32. Role of cytokines in hematopiosis Early work in Australia and Israel demonstrated that soluble factors could support the growth and differentiation of red and white blood cells. The first of these soluble factors to be characterized, erythropoietin, was isolated from the urine of anemic patients and shown to support the development of red blood cells. Many cytokines have been shown to play essential roles in hematopoiesis During hematopoiesis , cytokines act as developmental signals that direct commitment of progenitor cells into and through particular lineages A myeloid progenitor in the presence erythropoietin would proceed down a pathway that leads to the production of erythrocytes. Suitable concentrations of a group of cytokines including IL-3, GM-CSF, IL-1, and IL-6 will cause it to enter differentiation pathways that lead to the generation of monocytes , neutrophils , and other leukocytes of the myeloid group.

33. Summary In our body each and every process will takes place through blood only, blood cells plays an important role in the body i.e immune function, oxygen supply etc…. Hence the synthesis of blood cells is essential way to control our immune system. All blood cells arise from a single type of a cell i.e HSC which is totipotent in nature having self-renewing capacity. Hsc gives rise to two lineage 1.lymphoid and myloid lineage. then these leads to the synthesis of different immune cells like monocytes , macrophages, neutrophils , eosinophils , basophils , platlets involved in immune function and these immune cell production depends on the secretion of cytokines from the cell when all are independent in nature.

34. Reference Kuby,’Immunology ’-sixth edition www.news-medical.net http://en.m.wikipedia.org I Kannan , immunology .

35. Vikas CJ By: THANK YOU