Hemopoiesis 2.pdf

Hemopoiesis ❖ Mature blood cells have a relatively short life span and must be continuously replaced with new cells from precursors developing during hemopoiesis ❖ In the early embryo, these blood cells arise in the yolk sac mesoderm ❖ In the second trimester hemopoiesis (also c...

Hemopoiesis ❖ Mature blood cells have a relatively short life span and must be continuously replaced with new cells from precursors developing during hemopoiesis ❖ In the early embryo, these blood cells arise in the yolk sac mesoderm ❖ In the second trimester hemopoiesis (also called hematopoiesis) occurs primarily in the developing liver, with the spleen playing a minor role ❖ Skeletal elements begin to ossify and bone marrow develops in their medullary cavities, so in the third- trimester marrow of specific bones becomes the major hemopoietic organ ❖ Throughout childhood and adult life, erythrocytes granulocytes, monocytes and platelets continue to form from stem cells located in bone marrow ❖ The origin and maturation of these cells are termed, respectively: ❖ erythropoiesis, granulopoiesis, monocytopoiesis, and thrombocytopoiesis ❖ Lymphopoiesis or lymphocyte development occurs in the bone marrow and in the lymphoid organs to which precursor cells migrate from marrow ❖ Stem Cells, Growth Factors &Differentiation ❖ Stem cells are pluripotent cells ❖ Capable of symmetric division and self-renewal ❖ Some of their daughter cells form specific, irreversibly committed progenitor cells and other daughter cells remain as a small pool of slowly dividing stem cells ❖ Hemopoietic stem cells can be isolated by using fluorescence-labeled antibodies to mark specific cell surface antigens and passing the cell population through a fluorescence-activated cell-sorting (FACS) instrument ❖ Stem cells are studied using experimental techniques that permit analysis of hemopoiesis in vivo and in vitro ❖ Hemopoietic Stem Cells ❖ All blood cells arise from a single type of pluripotent hemopoietic stem cell in the bone marrow that can give rise to all the blood cell types ❖ These pluripotent stem cells are rare, proliferate slowly and give rise to two major lineages of progenitor cells with restricted potentials one for lymphoid cells (lymphocytes) and another for myeloid cells which develop in bone marrow ❖ Myeloid cells include granulocytes, monocytes, erythrocytes and megakaryocytes ❖ The lymphoid progenitor cells migrate from the bone marrow to the thymus or lymph nodes, spleen or other lymphoid tissue where they proliferate and differentiate ❖ Progenitor &Precursor Cells ❖ The progenitor cells for blood cells often called colony-forming units (CFUs) ❖ Because they give rise to colonies of only one cell type when cultured in vitro or injected into a spleen ❖ There are four major types of progenitor cells/CFUs 1.Erythroid lineage of erythrocytes 2. Thrombocytic lineage of megakaryocytes for platelet formation 3.Granulocyte-monocyte lineage of all three granulocytes and monocytes 4.Lymphoid lineage of B lymphocytes, T lymphocytes and natural killer cells ❖ Each progenitor cell lineage produces precursor cells (or blast) that gradually assume the morphologic characteristics of the mature, functional cell types they will become ❖ In contrast stem and progenitor cells can not be morphologically distinguished and simply resemble large lymphocytes ❖ While stem cells divide at a rate only sufficient to maintain their relatively small population, progenitor and precursor cells divide more rapidly producing large number of differentiated, mature cells ❖ Hemopoietic growth factors, often called colony-stimulating factors (CSF) or cytokines, are glycoproteins that stimulate proliferation of progenitor and precursor cells and promote cell differentiation and maturation within specific lineages ❖ Bone Marrow ❖ Under normal conditions, the production of blood cells by the bone marrow is adjusted to the body’s needs, increasing its activity several-fold in a very short time ❖ Bone marrow is found in the medullary canals of long bones and in the small cavities of cancellous bone https://bansalhospital.com/what-is-bone-marrow-and-its-types-and-what-does-it-do/ ❖ Two types of bone marrow according to their appearance at gross examination ❖ Blood forming red bone marrow whose color is produced by an abundance of blood and hemopoietic cells ❖ Yellow bone marrow which is filled with adipocytes that exclude most hemopoietic cells https://journals.sagepub.com/doi/full/10.1080/01926230600939856 ❖ In the newborn, all bone marrow is red and active in blood cell production ❖ As the child grows, most of the marrow changes gradually to the yellow variety ❖ Under certain conditions, such as severe bleeding or hypoxia, yellow marrow reverts to red https://hemepathreview.com/Heme-Review/Part15-1-BoneMarrowSpleenExamination.pdf ❖ Red bone marrow contains a reticular connective tissue stroma, hemopoietic cords or islands of cells and sinusoidal capillaries ❖ The stroma is a meshwork of specialized fibroblastic cells, called stromal cells (reticular or adventitial cells) and a delicate web of reticular fibers supporting the hemopoietic cells and macrophages ❖ Collagen type I, proteoglycans, fibronectin and https://veteriankey.com/bone-marrow-blood-cells-and-the-lymphatic- system/ laminin are also found ❖ Maturation of Erythrocytes ❖ Erythrocyte maturation is an example of terminal cell differentiation involving hemoglobin synthesis and formation of a small, enucleated, biconcave corpuscle ❖ Several major changes take place during erythropoiesis 1. Cell and nuclear volume decrease 2. Chromatin density increases until the nucleus presents a pyknotic appearance and finally extruded from the cell 3. There is a gradual decrease in the number of polyribosomes (basophilia) with a simultaneous increase in the amount of hemoglobin (a highly acidophilic protein) https://study.com/academy/lesson/do-red-blood-cells-have-a-nucleus.html  3. Mitochondria and other organelles gradually disappear ❖ Erythropoiesis requires approximately a week and involves three to five cell divisions between progenitor cell stage and the release of functional cells into the circulation ❖ The erythropoietin (glycoprotein) is a growth factor produced by cells in the kidneys and it stimulates production of mRNA for protein components of hemoglobin and is essential for https://medcell.org/systems_cell_biology/haematopoiesis_lab.php erythrocyte production ❖ The distinct erythroid progenitor cell is the proerythroblast. It is a large cell and contains loose, lacy chromatin, nuclei and basophilic cytoplasm ❖ In the next stage, proerythroblast replaces by the basophilic erythroblast. This cell is slightly smaller, its cytoplasm is basophilic and nucleus is more condensed. The basophilia is caused by the large number of free polysomes synthetizing hemoglobin https://slideplayer.com/slide/10725800 / ❖ During the next stage 1. cell volume is reduced 2. polysomes decrease 3. some cytoplasmic areas begin to be filled with hemoglobin (acidophilic and basophilic) ❖ Now, newly formed cell is polychromatophilic erythroblast ❖ Cell and nuclear volumes continue to condense and basophilia is gradually lost, producing cells with uniformly acidophilic cytoplasm, orthochromatophilic erythroblasts (normoblasts) https://quizlet.com/69578669/cytokinetics-stem-cells-and- erythropoiesis-pp-11-15-28-30-flash-cards/ ❖ Late in this stage, the nucleus is extruded and phagocytosed by macrophages ❖ The cell still retains a few polyribosomes and named as reticulocyte ❖ These cells enter the circulation (where they may constitute 1% of red blood cells) quickly loose all polyribosomes and transforms into erythrocytes https://www.quora.com/What-are-the-stages-of-synthesis-of- RBCs https://www.medical-labs.net/normoblastic-erythropoiesis-3381/ ❖ Maturation of Granulocytes ❖ Granulopoiesis involves cytoplasmic changes controlled by synthesis of proteins for 1.Azurophilic granules 2.Specific granules ❖ These protein are produced in the rough ER and Golgi apparatus in two successive stages ❖ The first formed granules are the azurophilic granules which contain lysosomal hydrolases, stain with basic dyes and are generally similar in all three of granulocytes ❖ Then, Golgi activity changes to package proteins for the specific granulocytes and donate each type with different properties which are specific for each type http://hematologyoutlines.com/atlas_topics/130.html ❖ In section of bone marrow, cords of granulopoietic cells can be distinguished from erythropoietic cords by their granule-filled cytoplasm ❖ The myeloblast is the most immature recognizable cell in the myeloid series ❖ Typically these have finally dispersed chromatin and faint nucleoli ❖ In the next stage, the promyelocyte is characterized by basophilic cytoplasm and azurophilic granules containing lysosomal enzymes and myeloperoxidase ❖ Different promyelocytes activate different sets of genes, resulting in lineages for the three types of granulocytes ❖ The first visible sign of this differentiation appears in the myelocyte stage ❖ In the myelocyte stage specific granules gradually increase in number and eventually occupy most of the cytoplasm at the metamyelocyte stage ❖ These neutrophilic, basophilic and eosinophilic metamyelocytes mature with further condensation of their nuclei ❖ Before its complete maturation the neutrophilic granulocyte passes through an intermediate stage, the band cell, in which the nucleus is elongated but not yet polymorphic https://www.lecturio.com/concepts/white-myeloid-cells/ ❖ The majority of granulocytes are neutrophils and the total time required for a myeloblast to produce mature, circulating neutrophils ranges from 10 to 14 days ❖ Five mitotic divisions normally occur during the myeloblast, promyelocyte and neutrophilic myelocyte stages ❖ Developing and mature neutrophils exist in four functionally and anatomically defined compartments: 1. The granulopoiteic compartment in active marrow 2. Storage as mature cells in marrow until release 3. The circulating population 4. A population undergoing margination, a process in which neutrophils adhere loosely and accumulate transiently along the endothelial surface in venules and small veins ❖ Margination of neutrophils in some organs can persist for several hours and is not always followed by the cell’s emigration from the microvasculature https://en.m.wikipedia.org/wiki/File:Marg ination_of_neutrophils.jpg ❖ At sites of injury or infection, neutrophils and other granulocytes enter the connective tissue by migrating through intercellular junctions between endothelial cells of postcapillary venules in diapedesis ❖ Inflamed connective tissues thus form a fifth terminal compartment for neutrophils, where the cells reside for a few days and then die by apoptosis , regardless of whether they have performed their major function of bacterial phagocytosis https://quizlet.com/399943154/unique-characteristics-of-leukocytes-diagram/ ❖ Changes in the number of neutrophils in the blood must be evaluated by taking all their compartments into consideration ❖ Neutrophilia an increase in number of circulating neutrophils, does not necessarily imply an increase in granulopoiesis. Intense muscular activity of the administration of epinephrine can cause neutrophils in marginating compartment to move into the circulating compartment, producing neutrophilia even though granulopoiesis has not increase. However, glucocorticoids (such a cortisone) increase the mitotic activity of neutrophil precursors and this also increases the blood count of neutrophils ❖ Maturation of Agranulocytosis ❖ The precursor cells of monocytes and lymphocytes do not show specific cytoplasmic granules or nuclear lobulation, both of which facilitate the distinction of cells in the granulopoietic series ❖ Monocytes and lymphocytes are discriminated mainly on the basis of size and nuclear shape ❖ Monocytes ❖ The monoblast is a committed progenitor cell that is virtually identical to the myeloblast morphologically ❖ Further differentiation leads to the promonocyte , a large cell with basophilic cytoplasm and a large, slightly indented nucleus ❖ The chromatin is lacy and nucleoli are evident ❖ Promonocytes divide twice as they develop into monocytes ❖ Differentiating monocytes contain extensive RER and large Golgi complexes forming lysosomes, which are observed as fine azurophilic granules at maturity ❖ Monocytes circulate in blood for several hours and enter tissues where they mature as macrophages (or other phagocytic cells) and function for up to several months ❖ Lymphocytes ❖ Circulating lymphocytes originate mainly in the thymus and in the peripheral lymphoid organs (spleen, lymph nodes and tonsils) ❖ However, lymphocyte progenitor cells originate in the bone marrow ❖ Some of these cells migrate to the thymus, where they acquire the properties of T lymphocytes ❖ Subsequently, T lymphocytes populate specific regions of peripheral lymphoid organs ❖ Other bone marrow lymphocytes differentiate into B lymphocytes in the bone marrow and then migrate to the peripheral lymphoid organs, where they inhabit and multiply within their own niches ❖ The first identifiable progenitor of lymphoid cells is the lymphoblast, a large cell capable of dividing two or three times to form lymphocytes https://www.youtube.com/watch?app=desktop&v=EOeKlUERe RU ❖ As lymphocytes develop, their nuclei become smaller, nucleoli disappear and cell size decreases ❖ In the bone marrow and in the thymus, these cells synthetize the specific cell surface proteins that characterize B or T lymphocytes, respectively ❖ Mature and functionally active B and T cells are generally larger than newly formed lymphocytes ❖ Subsets of lymphocytes acquire distinctive cell surface and other proteins during differentiation which can be detected by immunocytochemical techniques and used to sort the specific lymphocyte types ❖ Origin of Platelets ❖ The small, membrane-enclosed formed elements called platelets or thrombocytes originate by fragmentation from mature megakaryocytes which in turn differentiate from megakaryoblasts in a process driven by thrombopoietin ❖ The megakaryoblast has basophilic cytoplasm and a large, ovoid or kidney shaped nucleus often with several nucleoli https://en.wikipedia.org/wiki/Platelet ❖ Before differentiating these cells undergo endomitosis, with repeated rounds of DNA replication not separated by cell divisions, resulting in a nucleus that is highly polyploid https://www.mdpi.com/2073-4409/8/2/134 ❖ Megakaryocytes are giant cells and the polyploid nuclei are large and irregularly lobulated with coarse chromatin ❖ Their cytoplasm contains numerous mitochondria, a well-developed RER and an extensive Golgi apparatus from which arise the conspicuous specific granules of platelets ❖ Best seen in bone marrow megakaryocytes also occur in the interstitial tissue of the spleen and lungs, most often associated with vascular sinusoids or capillaries ❖ For platelet formations megakaryocytes rapidly extend several long, wide branching processes, called proplatelets, which penetrate adjacent microvascular endothelium are exposed in the circulating blood ❖ Internally proplatelets have a framework of actin filaments and loosely bundled, mixed polarity microtubules along which membrane vesicles and https://www.science.org/doi/10.1126/science.1148946 specific granules are transported ❖ During platelet growth, microtubules polymerize in both directions ❖ Proplatelet elongation depends on both this polymerization an dynein-based sliding of microtubules past one another ❖ Mature megakaryocytes also have numerous invaginations of plasma membrane ramifying throughout the cytoplasm, called demarcation membranes ❖ This membrane were formerly considered “facture lines” for the release of platelets but are now thought to represent a membrane reservoir facilitating continuous elongation Thank You