Hematopoiesis 2024 Dr. MERJEM PURELKU PDF

HEMATOPOESIS Ass. Professor Merjem PURELKU, MD, PhD BAU School of Medicine Histology and Embryology December 2024 Learning Outcomes Hematopoesis (T-1) 1- Explain prenatal and postnatal hematopoiesis 2- Classify the stages of hematopoiesis including erythropoiesis, gr...

HEMATOPOESIS Ass. Professor Merjem PURELKU, MD, PhD BAU School of Medicine Histology and Embryology December 2024 Learning Outcomes Hematopoesis (T-1) 1- Explain prenatal and postnatal hematopoiesis 2- Classify the stages of hematopoiesis including erythropoiesis, granulocytopoiesis, monocytopoiesis, platelet formation, lymphopoiesis and explain relevant clinical correlations. HEMATOPOESIS CELL TYPES Progenitor cells are the precursors to various blood cell lines, each with a specific suffix (“-blast”). ✓The granulocytes (neutrophils, eosinophils, basophils), monocytes, lymphocytes, erythrocytes, and megakaryocytes are the primary blood cell types produced in the bone marrow. Mesenchymal stem cells in the bone marrow stroma give rise to non-hematopoietic cell types, including bone, cartilage, muscle, and fat cells. Haematopoiesis is crucial for: ✓Maintaining metabolism through the production of RBCs, that carry oxygen. ✓Sustaining the immune system through the production of leukocytes (white blood cells) in a process known as leukogenesis.  HEMATOPOESIS ❑ During the first trimester of fetal development, blood cell production, or hematopoiesis, begins in specialized areas of the yolk sac called hematopoietic islands. This stage is known as the yolk-sac stage. ❖ The yolk sac is the first place where blood cells are made during early development.  HEMATOPOESIS Second Trimester (Hepatic Stage): The liver becomes the main site of blood cell production, known as hemopoietic centers. A small amount of blood cell production also takes place in the spleen. 7th Month of Pregnancy (Bone Marrow Stage): the bone marrow becomes the primary organ for hematopoiesis (blood cell production) and continues to be the main site for blood formation throughout adulthood. This phase is known as the Bone Marrow (BM) Stage of hematopoiesis. HEMATOPOESIS BONE MARROW Under normal conditions, blood cells are produced by the bone marrow. Bone marrow is found in the medullary cavities of long bones and the small spaces of flat bones. ❖ Red bone marrow: rich in blood cells and hematopoietic cells, which gives it its red color. ❖ Yellow bone marrow: filled with adipocytes (fat cells) and contains very few hematopoietic cells.  In newborns, all bone marrow is red and actively participates in blood cell production. As a person grows, most of the bone marrow turns into yellow bone marrow. In situations like severe bleeding or hypoxia (low oxygen levels), yellow marrow can revert back to red bone marrow to increase blood cell production. Red Bone Marrow; Contains reticular connective tissue, also known as the stroma, hematopoietic cords or islands, as well as sinusoidal capillaries in the bone marrow. It is mainly found in flat bones (like the sternum, ribs, and pelvis) and the ends of long bones (like the femur and humerus).  ❑1. Stromal Section of Bone Marrow: ❑2. Hematopoietic Cell Section: Bone marrow, two main parts: 1). Stromal Section of Bone Marrow: Found scattered within the trabecular bone and consists of several components: Fat cells (Adipocytes); Fibroblasts; Stromal cells; Endothelial cells of blood vessels; Macrophages (Apoptosis); Network of blood vessels; Bone Marrow STROMA: Stromal cells (also known as reticular or adventitial cells) are specialized fibroblastic cells in the bone marrow. Reticular fibers form the ‘supportive framework’, or "roof," that helps support the hematopoietic cells (blood-forming cells) and macrophages within the marrow. In the bone marrow, old and damaged cells are phagocytosed) by macrophages, ensuring the removal of defective or worn-out cells from the system. 2) Hematopoietic Cell Section: This section is well-vascularized, - essential for supporting the production of blood cells. Key Components: Nutrient arteries: supply the necessary nutrients to support hematopoiesis. Capillary network: A system of tiny blood vessels that facilitate nutrient and gas exchange. Specialized sinusoids: large, leaky blood vessels that allow blood cells to pass through more easily than regular capillaries. Hematopoietic cells: the blood-forming cells, including stem cells, progenitor cells, and the developing blood cells. Cell Migration: Mature blood cells (such as RBCs, some WBCs and PLTs) migrate through the endothelial layer (the lining of blood vessels) - into the sinusoids by a process called transendothelial migration. This allows them to enter the bloodstream. Immature blood cells (such as stem cells and progenitor cells) cannot migrate through the endothelial barrier because they lack the necessary migration capabilities.  These cells play a crucial role in regulating blood cell production Endothelial Cells, by synthesizing Bone Marrow Hematopoietic Fibroblasts, Growth Factors and Stromal Cells; and Cytokines.  Bone Marrow Contains 3 MAIN TYPES OF CELL POPULATIONS: 1. Hematopoietic Stem Cells (HSCs): ✓ undifferentiated cells; ✓ unique ability to self-renew and give rise to all the blood cell types. 2. Progenitor (Precursor) Cells: ✓ differentiated cells that still have the ability to develop into various types of blood cells. Hematopoietic ✓ Progenitor cells are more specialized than stem cells but have not yet reached the final stage of differentiation. Cell Populations ✓ They give rise to specific blood cell lines: 1. Myeloid progenitors: Will differentiate into red blood cells, platelets, and granulocytes (neutrophils, eosinophils, basophils). 2. Lymphoid progenitors: Will differentiate into lymphocytes (T- cells, B-cells). 3. Mature Cells: ✓ fully differentiated blood cells that are ready to be released into the bloodstream to perform their specific functions. ✓ These include: 1. Erythrocytes; 2. Leukocytes; 3. Platelets (thrombocytes). Pluripotent stem cells are capable of self-renewal and can differentiate into two main types of precursor cells: Myeloid Stem Cells (CMP); Give rise to various blood cell types through further differentiation. Lymphoid Stem Cells (CLP); Differentiate into lymphoid blood cells. Myeloid Cells (CMP): Myeloid stem cells differentiate into 5 types of colony-forming units (CFUs), each giving rise to different blood cells: Erythrocyte CFU – Produces red blood cells (erythrocytes) that carry oxygen. Megakaryocyte CFU – Produces platelets (thrombocytes) that are involved in blood clotting. Basophil CFU – Produces basophils, a type of white blood cell involved in allergic reactions and inflammation. Eosinophil CFU – Produces eosinophils, which play a role in fighting parasitic infections and modulating allergic responses. Granulocyte and Macrophage CFU – Produces granulocytes (like neutrophils) and macrophages (like monocytes), which are essential for immune defense. Lymphoid Cells (CLP): Lymphoid progenitor cells give rise to lymphocytes (T-cells, B-cells), which are key players in the immune system.  The Erythroid Series refers to the development & maturation process of RBCs (erythrocytes) in the bone marrow. ✓series of stages Erythropoiesis: Erythroid The maturation of RBCs - forming a small, anucleate, & Series biconcave blood cell. The regulator of erythropoiesis is erythropoietin (EPO), a hormone primarily produced by the kidneys in response to low oxygen levels (hypoxia). Erythropoietin stimulates the bone marrow to increase red blood cell production. Other cytokines involved include IL-3, IL-4, IL-9, GM- CSF, and insulin-like growth factor. The Maturation Process of Erythrocytes Stages of Erythropoiesis: Proerythroblast Basophilic erythroblast Polychromatophilic erythroblast Orthochromatic erythroblast Reticulocyte Erythrocyte  The Maturation Process of Erythrocytes  The Maturation Process of Erythrocytes A large cell with loose, lacy chromatin, a prominent nucleus, and a basophilic Proerythroblast: cytoplasm. The nucleus becomes condensed, and the cytoplasm remains strongly basophilic Basophilic Erythroblast: (blue-stained due to ribosomes and RNA). Polychromatophilic Cytoplasmic areas begin to fill with hemoglobin. The cell shows both acidophilic (pink) and basophilic (blue) areas due to the presence of both hemoglobin and Erythroblast: residual RNA. The cell and nucleus condense (dense chromatin). There is no longer significant Orthochromatic basophilia, and the cell shows a uniform, homogeneous acidophilic cytoplasm (due to high hemoglobin content). Erythroblast: This is a post-mitotic stage, where the cell is near its final form. The nucleus is ejected, and the cell enters circulation as a reticulocyte. Reticulocyte: It quickly loses its polyribosomes and matures into a fully functional erythrocyte. Granulocytic Series LEUKOPOIESIS (GRANULOPOIESIS): The process involving the differentiation of cells from the granulocyte and agranulocyte series. It involves cytoplasmic changes that are dominated by protein synthesis for azurophilic granules and specific granules. GRANULOCYTES: Granulocyte-macrophage CFU (Colony-Forming Unit): This is the precursor that gives rise to neutrophils and macrophages. Granulocytic Series Myeloblast Promiyelocyte Mitosis + Myelocyte Metamyelocyte (Band form cell) Mature form Myeloblast: ✓ The most easily recognizable cell in the myeloid series. ✓ It is an undifferentiated cell lacking cytoplasmic granules! ✓ The nucleus has fine, diffuse chromatin and a pale nucleolus. Basic Histology Junqueire LC Promyelocyte; ✓ Basophilic cytoplasm. ✓ Synthesis of azurophilic granules, which contain lysosomal enzymes and myeloperoxidase (MPO). ✓ Different gene activations in various promyelocytes. Basic Histology Junqueire LC Myelocyte; ✓ The first stage where differentiation becomes evident. ✓ The synthesis of specific or "specialized granules" begins at this stage for the first time. Metamyelocyte; ✓ The cytoplasm is largely filled with granules (both azurophilic + & specific granules +++). Basic Histology Junqueire LC Band form (or stab cell): ✓ Seen during neutrophil maturation. ✓ It is the stage after the metamyelocyte. ✓ The nucleus has elongated and taken on a "U" shape, but it is not yet polymorphic (not fully segmented).  The precursors of different hematopoietic cell lineages develop in close proximity to each other within the bone marrow.  A large portion of granulocytes are neutrophils. The total time.. from the myeloblast to the mature neutrophil entering circulation is between 10 to 14 days. MONOCYTES Differentiates from the Granulocyte-Macrophage Progenitor CFU (GM-CFU). ✓GM-CFU directs the precursor cells toward the monoblast lineage, which gives rise to monocytes. ✓The M-CSF receptor is specific to the monocyte series. The precursor cells of monocytes and lymphocytes do not exhibit specific cytoplasmic granules or nuclear segmentation. The monoblast is structurally similar to the myeloblast. The nucleus is large and basophilic.  LYMPHOCYTES/ LYMPHOPOESIS All lymphocyte precursor cells originate from the bone marrow. Some of these lymphocytes migrate to the thymus, where they acquire the characteristics of T lymphocytes before migrating to peripheral lymphoid tissues as effector cells. B lymphocytes, on the other hand, mature in the bone marrow. The first identifiable precursor lymphoid cells are lymphoblasts, which divide two or three times to form mature lymphocytes.  ❑Thrombopoiesis is the production of platelets, they play a key role in: ✓primary hemostasis, ✓coagulation & Platelets ✓inflammation. (Thrombocytes) Thrombopoiesis The main regulator of thrombopoiesis is thrombopoietin (Tpo), synthesized primarily in the liver. Tpo is produced at a constant rate. When platelet mass is low, more Tpo is free in plasma, stimulating thrombopoiesis. endomitosis). Regulation of Hematopoiesis Complex Control: Hematopoiesis is highly regulated, involving multiple redundancies, feedback mechanisms, and pathways that overlap with other physiological and pathological processes. The hematopoietic system is under both local and systemic control, responding rapidly to stimuli. Blood cell production and turnover are balanced to maintain normal cell numbers (steady-state kinetics). Cytokine Influence: Cytokines play a key role in regulating hematopoiesis, affecting cells of different lineages and various stages of differentiation. Hematopoietic Cell Lifespan and Regulation Lifespan of Mature Cells: Different mature blood cells have varying lifespans: Neutrophils: Hours Platelets: Days Erythrocytes: Months Lymphocytes: Years Bone Marrow Release: Normally, the bone marrow releases only mature cell types or very nearly mature cells into the bloodstream. Under certain physiological or pathological conditions, the bone marrow may release immature cells earlier in their development. Bone Marrow Bone Marrow Responses to Injury: Overview Bone marrow can respond to injury with various changes, affecting hematopoietic function. ❖These responses may lead to altered blood cell concentrations and include: Hyperplasia: Increased cell number (e.g., erythroid or granulocytic hyperplasia in response to hypoxia/inflammation). Reactive thrombocytosis is a form of megakaryocytic hyperplasia. Hypertrophy: Increase in cell size; typically not used for hematopoietic cells, but large cells may indicate dysplasia (altered cell formation due to infections, toxins, or imbalance). Myelophthisis: Replacement of hematopoietic tissue by abnormal cells (fibrous or malignant). Hypoplasia & Aplasia: Decreased or absent hematopoietic tissue, affecting specific or all lineages (e.g., aplastic pancytopenia). Myelofibrosis: Bone marrow fibrosis, often linked to sepsis, malignancy, or immune diseases like nonregenerative IMHA. Bone Marrow Inflammation: Can include granulomatous inflammation or immune-mediated cytopenias with hyperplasia, fibrosis, and necrosis. Additionally, myeloid metaplasia can lead to blood cell production outside the marrow (e.g., spleen/liver). Table : Histological Characteristics of Bone Marrow Cells Cell Type Histological Characteristics Function Hematopoietic Stem - Size: Small, round - Multipotent progenitors: Differentiate into all Cells - Nucleus: High nuclear-to-cytoplasm ratio blood cell types - Appearance: Prominent nucleolus Progenitor Cells - Size: Larger than stem cells, less - Develop into specific blood cell lineages nucleocytoplasmic ratio (erythroid, myeloid, etc. - Appearance: Distinct nucleus and cytoplasm Erythroblasts - Shape: Round with large, dark nucleus - Precursor to erythrocytes: Start hemoglobin - Cytoplasm: Blue due to ribosomal RNA production and mature into red blood cells Myeloblasts - Shape: Large, round with large nucleus - Precursor to granulocytes (neutrophils, - Cytoplasm: Blue with no granules eosinophils, basophils Megakaryocytes - Size: Very large (up to 100 micrometers) - Platelet production via cytoplasmic - Nucleus: Multilobed, often 8-16 nuclei fragmentation Macrophages - Shape: Large, irregular shape - Phagocytosis of cellular debris, pathogens - Cytoplasm: Abundant and pale, large vacuoles - Immune response