Hematology 1: General Principles of Hematopoiesis PDF

Hematology 1 General Principles of Hematopoiesis Hematopoiesis (or Hemopoiesis) is the process of blood cell production, including renewal, proliferation, differentiation, and maturation. It is a continuous and regulated process tha...

Hematology 1 General Principles of Hematopoiesis Hematopoiesis (or Hemopoiesis) is the process of blood cell production, including renewal, proliferation, differentiation, and maturation. It is a continuous and regulated process that results in the formation, development, and specialization of all functional blood cells that are released from the bone marrow. These mature blood cells develop from a common hematopoietic stem cell. This stem cell is capable of both self-renewal and directed differentiation into the different cell lineages – ie. the hematopoietic stem cell can proliferate and can give rise to any of the functional blood cell lineages. Hematopoiesis in humans is characterized by selective distribution of embryonic stem cells in specific sites that are rapidly changing during the course of development. In healthy adults, hematopoiesis is primarily confined to the bone marrow. During fetal development, blood cell development begins in the (1) yolk sac, that later progresses to the Aorta- Gonad-Mesonephros (AGM) region (mesoblastic phase); (2) transfers to the fetal liver (hepatic phase); and (3) terminally, resides in the bone marrow (medullary phase). Mesoblastic Phase: - Starts at the 19th day after fertilization - Progenitor cells of mesenchymal origin relocate to the yolk sac; give rise to Hematopoietic Stem Cells (HSCs) - Erythroblasts (immature red blood cells) come from mesodermal cells lining the yolk sac; remaining cells surrounding the cavity develop into angioblasts and later on form the blood vessels - Yolk sac differs from other phases of hematopoiesis in that yolk sac hematopoiesis occurs intravascularly (within the blood vessels) - Primitive erythroblasts are differentiated from later erythroblasts in that primitive erythroblasts never lose their nucleus. These erythroblasts are found in ‘blood islands’ surrounding a macrophage called Nurse cell.  Hematology 1 - Primitive erythroblasts start to produce the following hemoglobins: Portland hemoglobin, Gower 1 hemoglobin, and Gower 2 hemoglobin - Some cells of mesodermal origin also transfer to the AGM region to develop into HSCs for definitive hematopoiesis. Hepatic Phase - Begins at around 4-5 weeks after fertilization; Peaks at third month of development - The liver becomes the primary site of hematopoiesis - Characterized by recognizable clusters of myeloid cells. - Lymphoid cells begin to appear - Megakaryopoiesis (development of platelet precursors, the megakaryocytes) begins - Sites of secondary hematopoiesis: Thymus begins to produce T cells; Spleen and kidneys produce B cells - With detectable levels of HbF (fetal hemoglobin), HbA / HbA1 (major adult hemoglobin), and HbA2 (minor adult hemoglobin - Activity remains until 1-2 weeks after birth Medullary Phase - Starts at the 5th month of development; cells of various stages of maturation in all lineages are seen - Mesenchymal cells transfer to the skeletal tissues and develop into HSCs - Myeloid to erythroid (M:E) ratio reaches 3:1 (adult M:E ratio) at the 21st week - Bone marrow becomes the major site of hematopoiesis. Shortly after birth, the BM remains as the only tissue capable of blood cell production. When the BM is in distress or is not functioning properly, secondary hematopoietic organs such as the liver and spleen revert to their hematopoietic function (extramedullary hematopoiesis) - Erythropoietin, G-CSF, and GM-CSF (Growth Factors) reach detectable levels - Hemoglobins produced are HbA / HbA1, HbF, and HbA2 (minor adult hemoglobin)  Hematology 1 Sites of Hematopoiesis in the developing individual ©M. Komorniczak Illustration by: Michał Komorniczak. This file has been released into the Creative Commons 3.0. Attribution-ShareAlike (CC BY-SA 3.0)  Hematology 1 Organs involved in hematopoiesis: 1. Bone Marrow – primary site of hematopoiesis in an adult 2. Liver – major site of hematopoiesis during the hepatic period 3. Spleen – secondary site of hematopoiesis during the hepatic period 4. Thymus – secondary lymphoid organ; involved in the maturation of T cells 5. Lymph Nodes – secondary lymphoid organ; involved in production of lymphocytes, filtration and removal of old and damaged cells 6. Bursa equivalent organ – in humans, the Bursa-equivalent organ is the bone marrow. In the Fabricius bird, the bursa is the site of maturation of B cells. 7. Mononuclear Phagocyte System 8. Kidneys – produce erythropoietin 9. Stomach – produces intrinsic factor 10. Yolk sac – site of primitive erythropoiesis Adult Hematopoietic Tissue: - Bone Marrow is the major site of hematopoiesis - Lymphoid development occurs in primary and secondary lymphoid organs: o Primary Lymphoid Organs: sites of maturation of lymphocytes - Bone Marrow and Thymus o Secondary lymphoid Organs: sites of activation of lymphocytes - Spleen, Lymph Nodes, Mucosa-associated lymphoid tissue (MALT), Gut-associated lymphoid tissue (GALT)  Hematology 1 Bone Marrow - composed of red marrow and yellow marrow; red marrow is the hematopoietic tissue and the yellow marrow is composed of adipose - In adults, red marrow is located in the sternum, skull, vertebrae, scapulae, ribs, pelvic bones, and proximal ends of long bones - Ratio of red marrow to yellow marrow in the developing individual: Before birth: 100% Red Marrow At birth: 90:10 At 19-20 y/o: 60:40 In adulthood: 50:50 At 65 y/o: 40:60 - Yellow marrow can revert to red marrow when there is increased demand for hematopoiesis, such as in acute blood loss and hemolysis - The bone marrow is the site of production and maturation of myeloid cells – erythrocytes, megakaryocytes, neutrophils, eosinophils, basophils, and monocytes - The bone marrow produces the lymphocytes. The B cells mature in the bone marrow. The T cells, however, mature in the Thymus. The lymphocytes are activated in secondary lymphoid organs.  Hematology 1 Liver - Plays a significant role in hematopoiesis during fetal life (hepatic phase) - Responsible for synthesis of most proteins and vitamins that play a role in regulating hemostasis - Responsible for conjugating bilirubin from hemoglobin breakdown - Responsible for detoxification of blood - Site of protein synthesis and degradation - Kupffer cells lining the canaliculi remove senescent and damaged red blood cells from circulation as they pass through the liver Spleen - Largest lymphoid organ in the body; secondary site of hematopoiesis during hepatic phase Functions of the spleen: 1. Culling: removal of senescent (old) red blood cells from blood circulation by phagocytosis 2. Pitting: removal of inclusion bodies from the surface of red blood cells (ex. Pappenheimer bodies – accumulated iron; Howell-Jolly bodies – DNA remnants; Heinz bodies – globin remnants) 3. Immune defense – it is a secondary lymphoid organ, serving as a site of activation of lymphocytes (B and T cells) 4. Storage of platelets – the spleen sequesters 1/3 of platelets produced to serve as reservoir Thymus – primary lymphoid organ; secondary site of hematopoiesis during hepatic phase - Site of maturation of T cells Lymph Nodes – Secondary lymphoid organ - Site of activation of lymphocytes - Filters debris, particulate matter, and bacteria from the lymph - Serves as site of proliferation of lymphocytes  Hematology 1 Mononuclear phagocyte system – composed of the monocytes and macrophages Functions: 1. Phagocytosis – removal of debris, particulate matter, and foreign cells from the blood (monocytes) and tissues (macrophages) 2. Antigen Presentation – Antigens from digested foreign cells (bacteria) are presented to T cells for activation of the adaptive immune system 3. Mitogen (substances that promote mitosis) secretion 4. Secretion of hematopoietic growth factors (substances that influence the maturation and differentiation of blood cells) Kidneys – responsible for production of erythropoietin (growth factor that drives maturation of RBC precursors) in response to hypoxia. Erythropoietin acts on erythroblasts in the bone marrow to stimulate proliferation and maturation, for eventual release into the circulation Stomach – produces intrinsic factor. Intrinsic Factor is necessary for absorption of Vit. B12 in the intestines. Deficiency of IF leads to deficiency in Vit. B12 and would lead to pernicious anemia (a type of Megaloblastic anemia) Stem Cell Theory: Stem cells are characterized by its ability for/to: 1. self-renewal; 2. give rise to differentiated progeny (ie. a hematopoietic stem cell can differentiate into a common myeloid stem cell or common lymphoid stem cell to later on give rise to mature and functional blood cells); 3. reconstitute the hematopoietic system in a lethally irradiated individual  Hematology 1 Normal cell development depends the interaction of: 1. Pluripotent stem cell 2. Microenvironment 3. Hematopoietic Growth Factors A pluripotent hematopoietic stem cell can be stimulated to undergo one of three possible fates: self-renewal, differentiation, or apoptosis. When the stem cell divides, it gives rise to two identical daughter cells. The daughter cells may likewise be stimulated to undergo any of the three outcomes. A stem cell can also be stimulated for differentiation - eg. An HSC can differentiate into a common myeloid stem cell (common myeloid progenitor) or a common lymphoid stem cell (common lymphoid progenitor). The common myeloid stem cell may differentiate into committed (lineage-specific) precursor cells such as a Proerythroblast to eventually give rise to mature erythrocytes or Megakaryoblast to give rise to platelets. Differentiation of stem cells and maturation of precursor cells occurs under the influence of hematopoietic growth factors and under optimal conditions of the microenvironment. Cytokines and Growth Factors: a group of glycoproteins that regulate the proliferation, differentiation, and maturation of hematopoietic precursor cells. Cytokines can either promote or inhibit proliferation, differentiation, and maturation of blood cells. Cytokines may also inhibit apoptosis (programmed cell death), allowing cells to proliferate. Cytokines may be Colony Stimulating Factors (CSF), early-acting multilineage growth factors or interleukins.  Hematology 1 The diagram above shows the derivation of hematopoietic stem cells and the sites of action of cytokines. From Rodak’s Hematology: Clinical Principles and Applications (Keohane, EM, Smith, LJ, & Walenga, JM) ©2016.  Hematology 1 General changes undergone by hematopoietic cells as they mature: 1. As the cells mature, they decrease in size. 2. As the cells mature, cytoplasmic staining becomes less basophilic. 3. As the cells mature, Nucleus-to-Cytoplasm (N:C) ratio decreases. 4. As the cells mature, nuclear chromatin becomes denser. 5. As the cells mature, nucleoli start to disappear. *These are general changes. Some lineages might have some exceptions to these rules.  Hematology 1 References: Aceron, Z. B. (unpublished). Lecture notes Bermido, C. M., Cabanban, I. D., & Lim, N. S. (2013). Lecture Notes in Hematology 1. Manila, Philippines: Centro Escolar University Dinglasan, R. J. A. R. (unpublished). Review notes Keohane, E. M., Smith, L. J., & Walenga, J. M. (2016). Rodak’s Hematology: Clinical Principles and Applications (5e). SG: Elsevier Pte. Ltd. Turgeon, M. L. (2012). Clinical Hematology: Theory and Procedures (5e). Philadelphia, PA: Lippincott Williams & Wilkins