Hemopoiesis Lecture Notes PDF

JABIR IBN HAYYAN MEDICAL Lecture By : Hussein bahaa UNIVERSITY COLLEGE OF MEDICINE Lec : 6 DEPARTMENT OF HUMAN ANATOMY Section of Histology Hemopoiesis...

JABIR IBN HAYYAN MEDICAL Lecture By : Hussein bahaa UNIVERSITY COLLEGE OF MEDICINE Lec : 6 DEPARTMENT OF HUMAN ANATOMY Section of Histology Hemopoiesis Mature blood cells have a relatively short life span and must be continuously replaced with new cells from precursors developing during hemopoiesis (Gr. haima, blood + poiesis, a making). 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 more minor role. Skeletal elements begin to ossify and bone marrow develops in their medullary cavities, so that 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. Hemopoietic Stem Cells Stem cells are pluripotent cells capable of asymmetric division and self-renewal. Some of their daughter cells form specific, irreversibly differentiated cell types, and other daughter cells remain as a small pool of slowly dividing stem cells. All blood cells arise from a single major type of pluripotent stem cell in the bone marrow that can give rise to all the blood cell types. These pluripotent stem cells are potentials (committed to produce specific blood cells): one for lymphoid cells(lymphocytes)and another for myeloid cells(Gr. myelos, marrow) that develop in bone marrow. Myeloid cells include granulocytes,monocytes, erythrocytes, and megakaryocytes. The lymphoid progenitorcells migrate from the bone marrow to the thymus or the lymph nodes, spleen, and other lymphoid structures, wherethey proliferate and differentiate. Progenitor & Precursor Cells The progenitor cells for blood cells are commonly called colony-forming units (CFUs), because they give rise to colonies of only one cell type when cultured or injected into a spleen. There are four major types of progenitor cells/CFUs: Erythroid lineage of CFU-erythrocytes (CFU-E). Thrombocytic lineage of CFU-megakaryocytes (CFU-Meg). Granulocyte-monocyte lineage of CFU-granulocytesmonocytes (CFU-GM), and Lymphoid lineage of CFU-lymphocytes of all types (CFU-L). Each progenitor cell/CFU lineage produces precursor cells (or blasts) that gradually assume the morphologic characteristics of the mature, functional cell types they will become. In contrast, stem and progenitor cells cannot 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 numbers of differentiated, mature cells. Hemopoiesis depends on a microenvironment, with specific endocrine, paracrine, and juxtacrine factors. These requirements are provided largely by the local cells and extracellular matrix (ECM) of the hemopoietic organs, which together create the microenvironment in which stem cells are maintained and progenitor cells develop. 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, with two types based on their appearance at gross examination: 1-Red bone marrow, the blood-forming whose coloris produced by an abundance of blood and hemopoietic cells. 2-Yellow bone marrow, which is filled with adipocytes that exclude most hemopoietic cells. In the newborn all bone marrow is red and active in blood cell production, but 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. Red bone marrow contains: 1-Reticular connective tissue stroma (Gr. stroma, bed), The stroma is a meshwork of specialized fibroblastic cells called stromal cells(also called reticular or adventitial cells) and a delicate web of reticular fibers supporting the hemopoietic cells and macrophages. 2-Hemopoietic cords or islands of cells. 3-Sinusoidal capillaries between the hematopoietic cords run the sinusoids, which have discontinuous endothelium, through which newly differentiated blood cells and platelets enter the circulation. Red marrow is also a site where older, defective erythrocytes undergo phagocytosis by macrophages, which then reprocess homebound iron for delivery to the differentiating erythrocytes. Maturation of Erythrocytes A mature cell is one that has differentiated to the stage at which it can carry out its specific functions. Erythrocyte maturation is an example of terminal cell differentiation involving hemoglobin synthesis and formation of a small, non- nucleated, biconcave corpuscle. Several major changes take place during erythropoiesis. Cell and nuclear volumes decrease, while the nucleoli diminish in size and disappear. Chromatin density increases until the nucleus presents a pyknotic appearance and is finally extruded from the cell. There is a gradual decrease in the number of polyribosomes (basophilia), with a simultaneous increase in the amount of hemoglobin (a highly eosinophilic protein). Mitochondria and other organelles gradually disappear. There are three to five intervening cell divisions between the proerythroblast and the mature erythrocyte. The development of an erythrocyte from its first recognizable progenitor cell to the release of reticulocytes into the blood takes approximately 1 week. The glycoprotein erythropoietin, a growth factor produced by cells in the kidneys, stimulates production of mRNA for globins, the protein components of hemoglobin, and is essential for the production of erythrocytes. The distinct progenitor cell of the erythroid series is the proerythroblast, a large cell with loose,lacy chromatin, nucleoli, and basophilic cytoplasm. The next stage is represented by the basophilic erythroblast, with more strongly basophilic cytoplasm and a condensed nucleus with no visible nucleolus. The basophilia of these two cell types is caused by the large number of polysomes synthesizing hemoglobin. During the next stage cell volume is reduced, polysomes decrease, and some cytoplasmic areas begin to be filled with hemoglobin, producing regions of both basophilia and acidophilia in the cell, now called a polychromatophilic erythroblast. In the next stage, the cell and nuclear volumes continue to condense and no basophilia is evident, resulting in a uniformly acidophilic cytoplasm—theorthochromatophilic erythroblast(also called a normoblast). Late in this stage, this cell ejects its nucleus which is then phagocytosed by macrophages. The cell still has a small number of polyribosomes that form a faintly stained (reticulum) and the cell called the reticulocyte. Reticulocytes pass to the circulation (where they may constitute 1% of the red blood cells), quickly lose the polyribosomes, and mature as erythrocytes. Maturation of Granulocytes Granulopoiesis involves cytoplasmic changes dominated by synthesis of proteins for the azurophilic granules and specific granules. These proteins are produced in the rough ER and the prominent Golgi apparatus in two successive stages. Made initially are the azurophilic granules, which contain lysosomal hydrolases, stain with basic dyes, and are basically similar in all three types of granulocytes. Golgi activity then changes to produce proteins for the specific granules, whose contents differ in each of the three types of granulocytes and endow each type with certain different properties. In sections 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 finely 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 which 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 condensations of the nuclei. Before its complete maturation, the neutrophilic granulocyte passes through an intermediate stage, the band cell (or stab cell), in which the nucleus is elongated but not yet polymorphic. The vast 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 divisionsnormally occur during the myeloblast, promyelocyte, and neutrophilic myelocyte stages. Maturation of Agranulocytes 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 in smear preparations are discriminated mainly on the basis of size and nuclear shape. Monocytes The monoblastis a committed progenitor cell that is virtually identical to the myeloblast morphologically. Further differentiation leads to the promonocyte, a large cell (up to18 μm in diameter) 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 All lymphocyte progenitor cells originate inthe bone marrow. Some of these lymphocytes migrate to thethymus, 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 peripheral lymphoid organs, where they inhabitand 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. As lymphocytes develop, their nuclei become smaller, nucleoli become less visible, and the cells decrease in size overall. In the bone marrow and in the thymus, these cells synthesize 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. Origin of Platelets The membrane-enclosed cell fragments called platelets or thrombocytes originate in the red bone marrow by dissociating from mature megakaryocytes(Gr. megas, big +karyon, nucleus, + kytos), which in turn differentiate from megakaryoblasts in a process driven by thrombopoietin. The megakaryoblast has a large ovoid or kidney-shaped nucleus, often with several small nucleoli. 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 (ie, 64N or >30 times more DNA than ina normal diploid cell). The cytoplasm of this cell is homogeneous and highly basophilic. Megakaryocytes are giant cells, with large, irregularly lobulated polyploid nuclei, coarse chromatin, and no visible nucleoli. Their cytoplasm contains numerous mitochondria, a well-developed RER, and an extensive Golgi apparatus from which arise the conspicuous specific granules of platelets. They are widely scattered in marrow, typically near sinusoidal capillaries. To form platelets, megakaryocytes extend several long branching processes called proplatelets. These cellular extensions penetrate the sinusoidal endothelium and are exposed in the circulating blood of the sinusoids. Internally proplatelets have a framework of actin filaments and loosely bundled, mixed polarity microtubules along which membrane vesicles and specific granules are transported. A loop of microtubules forms a teardrop-shaped enlargement at the distal end of the proplatelet, and cytoplasm within these loops is pinched off to form platelets with their characteristic marginal bundles of microtubules, vesicles, and granules.