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Blood and vessel formation therefore first occurs extraembryonally on the umbilical vesicle and in the chorionic villi

(extraembryonic phase of blood and vessel formation). Subsequently follows the intraembryonic phase, which is subdivided into hepatolienal and myeloid phases. First vessels and pluripotent stem cells arise within the embryo. These migrate from the dorsal aorta near the navel and mainly colonize the liver (hepatic phase). A small portion - primarily for erythropoiesis - appears after the 12th week in the spleen (lienal phase). In the myeloid phase daughter cells of these stem cells emigrate via the vessel system into the bone marrow and increasingly take over the formation of the blood. They are lifelong able to renew and differentiate themselves; they remain in the bone marrow and, according to need, can differentiate into every type of lymphoid and also myeloid cells. 1. Define Hematopoiesis - a continuous, regulated process of blood cell production that includes cell renewal, proliferation, differentiation, and maturation - results in the formation, development, and specialization of all functional blood cells 2. Phases of Hematopoiesis - Mesoblastic (yolk sac phase) - Hepatic phase - Medullary (myeloid) phase 3. Mesoblastic (Yolk Sac) Phase - begins around 19th day of development - mesodermal cells, which line the cavity of the yolk sac, give rise to primitive erythroblasts - these produce measurable amounts of Hgb - this phase occurs intravascularly Hemoglobins of Mesoblastic Phase - Portland - Gower-1 - Gower-2 Angioblasts - remaining cells surrounding the cavity of the yolk sac - will develop into the blood vessels Hepatic Phase begins at 4-5 gestational weeks - char. by clusters of developing eryhtorblasts, granulocytes, monocytes - occurs extravascularly, liver the major site --- reaches peak in liver at 3rd month - spleen (B), kidney (B), thymus (T) also contribute Hemoglobins of Hepatic Phase 4. Hepatic Phase - Hb F - Hb A - Hb A2 5. Medullary (Myeloid Phase) - begins in 5th month of development - occurs in medulla of bone marrow - mesenchymal cells migrate into bone and differentiate into skeletal and hematopoietic cells - myeloid:erythroid ratio reaches adult level of 3:1 Detectable levels of these substances are found in Medullary Phase: - EPO - G-CSF - GM-CSF - fetal Hgb - Hb A2 - adult Hb Primary vs Secondary 6. Lymphoid Tissue - tissues where lymphoid development occurs - primary: bone marrow, thymus and is where T & B cells are derived - secondary: spleen, lymph nodes, gut-assoc. lymphoid tissue and is where lymphoid cells become competent 7. Types of Marrow: - red: hematopoietically active --- found in sternum, skull, scapulae, vertebrae, ribs, pelvic bones, proximal ends of long bones - yellow: hematopoietically inactive, composed of adipocytes 8. Retrogression - process of replacing active red marrow with adipose yellow marrow - results in restriction of red marrow to particular bones 9. Nutrient and gas requirements of marrow are supplied by... - nutrient and periosteal arteries, which enter the bone foramina 10. Hematopoietic Microenvironment - supplies the semifluid matrix --- anchors developing h. cells

--- maintains differentiation/proliferation --- provides supporting tissue 11. Stromal Cells - found in semifluid matrix of h. microenvironment - include: endothelial cells, adipocytes, macrophages, osteoblasts, osteoclasts, reticular cells Liver - site of h. during hepatic phase - synthesizes transport proteins - stores minerals/vitamins for DNA/RNA synthesis - conjugates bilirubin from Hgb degradation - transports bilirubin to S.I. for excretion 12. Kupffer Cells - macrophages - remove debris from blood circulating thru liver - also, involved in protein synthesis 13. Porphyrias - blood-related disease - the liver exhibits enzymatic deficiencies that result in accumulation of porphyrins 14. Spleen - largest lymphoid organ - vital but not essential for life - contains about 350 mL of blood - 3 types of splenic tissue: red pulp, white pulp, marginal zone 15. Methods for removing senescent RBCs from circulation in the spleen - culling: cells are phagocytosed - pitting: splenic macrophages remove inclusions or damaged surface membrane from circulating RBCs 16. Lymph nodes - organs of lymphatic system that run parallel but are not part of the circulatory system - bean shaped structures 17. Functions of Lymph Nodes - help in formation of lymphocytes from germinal centers - involved in processing of immunoglobulins - filter particulates, debris, bacteria from lymph 18. Thymus - the "waiting zone" for progenitor lymphoid cells that have migrated from bone marrow - those cells give rise to T cells, which will disperse to other lymphoid tissues

- thymus is large at birth, biggest at puberty, begins shrinking to almost nothing at old age 19. Theories of Origin of h. Progenitor Cells - monophyletic theory: all blood cells derived from a single progenitor stem cell, pluripotential stem cell (most widely accepted theory) - polyphyletic theory: each of the blood cell lineages is derived from its own unique stem cell 20. Cytokines - glycoproteins that regulate proliferation, differentiation, and maturation of h. precursors - aka growth factors - include: interleukins, lymphokines, monokines, chemokines, interferons, CSFs 21. Why do h. precursors require cytokines? - growth factors inhibit apoptosis - stimulate division by decr transit time from G0 - G1 of cell cycle - regulate differentiation into various cell lineages BFU-E - blast forming unit erythroid - earliest ID colony, derived from CFU-GEMM - few EPO receptors (little influence by EPO)