LATEST-Hematopoiesis_Lec-8-13-24_240818_203559.pdf

HEMATOPOIESIS The Formation and Development of Blood Cells  Hematopoiesis  A continuous, regulated process of blood cell production that includes cell renewal, proliferation, differentiation, and maturation in the blood-forming organs. Hematopoietic Stem Cells (HSCs) ...

HEMATOPOIESIS The Formation and Development of Blood Cells  Hematopoiesis  A continuous, regulated process of blood cell production that includes cell renewal, proliferation, differentiation, and maturation in the blood-forming organs. Hematopoietic Stem Cells (HSCs)  They are the foundation of the adult hematopoietic system. The embryo produces the first adult repopulating HSCs.  They are also referred to as hemocytoblasts. TYPES OF HUMAN STEM CELLS (SC)  1. Totipotent SC- present the first few hours after fertilization. The most versatile type of SC because can develop into any human cell type, including dev't from embryo into fetus/.  2. Pluripotential SC- present several days after fertilization. Can develop into any cell type, except they cannot develop into fetus.  3.Multipotent SC- derived from pluripotential SC, found in adults,but they are limited to specific types of cells to form tissues. e.g.bone marrow SC  Human SC  can produce all types of blood cells, bone, cartilage, adipose/fat cells so are said to be MULTIPOTENTIAL  can differentiate along any cell line( erythrocytic, granulocytic, monocytic, megakaryocytic, lymphocytic)  the main factor that will influence what they will differentiate into is the NEED OF THE BODY. Early Dev't of Blood Cells  Blood cells originate from the mesenchymal tissue that arises from the embryonic germ layer, the mesoderm. The mesodermally derived STRUCTURES ARE:  1. paraaortic splannchnopleure  2. aorta-gonad-mesonephros region  In here production of multipotent progenitor cells and hematopoietic stem cells (HSCs) happens before their appearance in the yolk sac. 3 DIVISIONS OF HEMATOPOIETIC CELLS IN THE BONE MARROW  1. Primitive multipotential cells- stem cells, the most immature group capable of self-renewal and differentiation into all blood cell lines.  2. Intermediate cell or Progenitor cells- committed cell and are denoted by the prefix CFU /BFU. They are unipotential and are already committed to develop into a specific cell line.  3.Mature cells or Precursor cells- the developed group and are already with specific function/s.  STAGES OF HEMATOPOIESIS  Pre-natal Hematopoiesis  Post-natal Hematopoiesis  PRE-NATAL HEMATOPOIESIS I. MESOBLASTIC PERIOD  Starts on 14th day, peaks on the 1st month and persist up to 3rd month of gestation, start of ERYTHROPOIESIS.  Chief site – blood islands of yolk sac  3rd month fetal life = Primitive Erythroblast  Primitive Erythroblast  Formed intravascularly( or within developing blood cells), megaloblastic( bigger in size) , and retain their nuclei  Contains Embryonic Hemoglobin- Gower1, Gower 2, Portland  PRE-NATAL HEMATOPOIESIS II. HEPATIC PERIOD  Starts on the 5th to 7th week of gestation and persist up to birth( wanes- lowers in production)  Chief site – Liver, as well as spleen and lymph nodes, thymus (lesser extent)  Definitive Erythroblasts Formed extravascularly and extrude their nucleus, CONTAINS HbF Continuation of erythropoiesis, 3rd month- starts granulopoiesis & megakaryopoiesis  4th month- lymphopoiesis, 5th month- monocytopoiesis/ monopoiesis  PRE-NATAL HEMATOPOIESIS III. MEDULLARY or MYELOID PERIOD  Starts on the 5th month of fetal life up to adulthood  Bone Marrow is the chief site of hematopoiesis by the end of 24 weeks( 6 months). Measureble levels of Erythropoietin (EPO), Granulocyte- Colony Stimulating Factor, (G- CSF)Granulocyte-Monocyte/ Macrophage – colony stimulating factor( GM- CSF). HbA and HbF are detected.  Cells at various stages of maturation can be seen in all blood cell lineages/ lines. POST-NATAL HEMATOPOIESIS I. MEDULLARY/ MYELOID Bone Marrow – is the only site of erythropoiesis, myelopoiesis and thrombopoiesis IN POST-NATAL LIFE. A. Red Bone Marrow – Hematopoietically active marrow- PRODUCE BLOOD CELLS B. Yellow Bone Marrow – composed primarily of adipocytes (fats) Bone Marrow at Birth 1.5 % of total body weight Bone Marrow (Adult) 4.5% of total body weight Red Bone Marrow Site of Blood Cell Yellow Bone Marrow Formation Red Bone Marrow POST-NATAL HEMATOPOIESIS II. EXTRAMEDULLARY  Blood cell production in hematopoietic tissue other than bone marrow. This is resorted to when the converted yellow marrow to red marrow is insufficient to meet the body’s demands A. Lymph nodes-T & B cells dendritic cells(DC)( antigen-presenting cells), macrophages, plasma cells B. Spleen –T and B cells, plasma cells, macrophages C. Liver-can be hematopoietic when needed  2 characteristics of stem cells 1. Uncommitted 2. Mutipotential and can differentiate along any cell line( depending on the body’s need) Theories of Blood Cell Production A. Monophyletic All blood cells are derived from uncommitted stem cells which are capable of giving rise to several types of cells- the accepted theory B. Polyphyletic The first recognizable and most primitive blood cells are already committed to develop into a specific cell line- not accepted theory  3 compartments of cells in Bone Marrow( BM) 1. Hematopoietic Stem Cells (HSCs)  most immature, can do self-renewal & differ- entiation into any of the cell lineages  Divide by mitosis to give rise to multipotent progenitors  Have the morphology of medium- sized lymphocytes  CD34+ but lacks MHC Class II antigen  Can give rise to CFU-L and CFU- GEMM(myeloid) 3 compartments of cells in the BM 2. Progenitors  Starts to commit, as they mature, acquire more cluster of differentiation (CD), remain CD34+ for identification. CD34 is marker for immaturity  Cells with prefix- BFU or CFU  They are unipotential- committed to differentiate along a single cell line  Cells in the BM 3. Precursor cells  Recognized due to additional expression of antigens (CD38) CD71+ – erythroid CD10+ – B cells CD33+ – myeloid CD7+ – T cells CD5+ - T cells Cells in the BM  The formation & dev't of mature blood cells from the multipotent Stem Cells is controlled by growth factors & inhibitors, and the microenvironment. The microenvironment or locale influences behavior & controls the proliferation of multipotential stem cells.  The bone provides the microenvironment most appropriate for proliferation & maturation of cells.  The BM is encased by endosteum Progenitor Cells  The hematopoietic progenitor cells (HPCs) can be mobilized from the BM to the blood by a wide variety of stimuli, including the hematopoietic growth factors & chemokines.  Individual hematopoietic cytokines can be lineage- specific or can regulate cells in multiple lineages, and for some cell types, e.g. stem cells, the simultaneous action of multiple cytokines is required for proliferative responses. HSC  The HSCs in the BM exist in a highly organized microenvironment composed of stromal cells & an extracellular matrix rich in fibronectin, collagen, & various proteoglycans.  HSCs can be found in umbilical cord blood (UCB) also. UCB hematopoietic cells is used as therapeutic source of autologous & allogeneic transplants for more than 20 yrs. Cryopreservation prolongs the storage time of UCB.  Aside from UCB, BM and peripheral blood are sources of stem cells for therapeutic purposes. Hematopoietic Processes  1. Erythropoiesis- process of red blood cell (RBC) formation. Occurs in erythroblastic islands, which are specialized niches in which erythroid precursors proliferate, differentiate, & enucleate( extrude their nucleus). Each island consists of a macrophage(mother cell surrounded by a cluster of developing normoblasts. Within erythroid niches, cell-cell & cell-extracellular matrix adhesion, positive & negative regulatory feedback. Erythroid cells account for 5%- 38% of nucleated cells in BM. Maturation of Blood Cells  A. Principles of Synchronistic Maturation- when nucleus & cytoplasm mature at the same time resulting in normal/ typical cells. While the following cytoplasmic occur, the nuclear changes also occur:  1. Cytoplasmic Changes  a. Loss of basophilia- Generally, the younger the cell, the higher is the RNA content of its cytplasm. The RNA is the cytoplasmic component which give it basophilia( love for basic dyes) Synchronistic Maturation  b. Production of cytoplasmic granules- this is a special feature of the granulocytes (neutrophil, eosinophil, basophil). In the promyelocyte, the non-specific/ primary granules develop. In the next stage, the early myelocytic stage, secondary granules appear. On the late myelocytic stage,tertiary granules appear. Both secondary & tertiary granules are specific granules At the myelocytic stage then, the 3 types of granulocytes are distinguishible from each other because of the color of their cytoplasmic granules. Synchronistic Maturation  c. Elaboration of Hemoglobin (Hb)- a special feature of the erythrocytic cells. Hb formation starts in the pronormoblasts(1st stage of devt) and seen first in the polychromatophilic normoblast stage, continues in the orthochromic stage, up until the reticulocytic stage. At the reticulocytic stage, only 35% of Hb are formed and is thne one used by the erythrocyte for its function of oxygen delivery to the tissues for its entire life span in the blood of 120 days.  Synchronistic Maturation 2. Nuclear Changes  a. Lobulation of nucleus- a special feature of the granulocytic cells. The granulocytes, increase in in nuclear lobes on matutaion. At maturation, the neutrophil has 2-5 nuclear lobes with an average of 3. The eosinophil, has 2-3 lobes, and mostly are bi- lobed. The basophil does not increase its lobe on maturation, but retains its stab-shaped nucleus.  Synchronistic Maturation b. Changes in the structure and cytochemistry of chromatin material - At an early stage, the nuclear chromatin are fine and linear because of the DNA’s double-helical structure. This is referred to as euchromatin. In maturing stages, the chromatin becomes coarse & clumped and are called the heterochromatin. In stages where, heterochromatin is observed, there are non-staining areas seen and are called the parachromatin. Synchronistic Maturation  c. Extrusion of nucleus- a special feature of the erythrocytic cells. In immature stages, from pronormoblast- orthochromic normoblast, these cells are nucleated. Enucleation/ Nucleolysis, the process of removal of the nucleus happens just before the orthochromic normoblast becomes a reticulocyte, the 5th stage. After 2-3 days as retics in the BM, the cell migrates to the blood a & remains in the blood for 1 day until it becomes an erythrocyte.  Synchronistic Maturation  3. Reduction in size of cells- As cells mature, they undergo mitosis, and the daughter cells become smaller, except the megakaryocytic cells. The megakaryocytic cells become bigger as they mature. This cell line undergo endomitosis/ endoreduplication where these do not occur: late telophase & cytokinesis, hence, one megakaryoblast matures into ultimately one mature megakaryocyte or metamegakaryocyte which is the mother cell of platelets. This cell line results in polyploid cells.  Asynchronistic Maturation Pathologic hematopoiesis results in abnormal nuclear maturation, abnormal cytoplasmic differentiation & abnormal size. Their development is asynchronistic. 1. Abnormal cytoplasmic differentiation- In RBC, this is characterized by persistent cytoplasmic basophilia & late hemoglobinization. Abnormal cytoplasmic inclusion bodies may be found in the cytoplasm of borh erythrocytes and leukocytes, especially in the granulocyes. Asynchronistic Maturation  2. Abnormal nuclear maturation- in leukemia & other severe disturbances, 2 nuclei may be present; one may be diploid & the other polyploid. The nucleus may be hypersegemnted or hyposegemented. In megaloblastic anemia, the megalocytes' nucleus takes longer to mature than its cytoplasm. This is so because the mitotic & intermitotic phases in megalocytes are prolonged when compared to the normal red cells. Asynchronistic maturation  3. Abnormal size - abnormally large cells are frequently seen in benign or malignant proliferation. In the erythrocytic series, the megaloblasts are larger than normal mature erythrocytes. Likewise, abnormally small cells may be found.