hematopoiesis

• Hematopoiesis


  The continuous, regulated process of renewal, proliferation, differentiation, and maturation of all blood cell lines
• Hematopoietic stem cell (HSC)


  Capable of self-renewal (i.e., replenishment) and directed differentiation into all required cell lineages
• Mesoblastic Phase


  1. Cells from the mesoderm migrate to the yolk sac

  2. Some cells form primitive erythroblasts in the central cavity of the yolk sac

  3. Others (angioblasts) surround the cavity of the yolk sac and eventually form blood vessels
• Yolk sac hematopoiesis


  • Occurs intravascularly (or within developing blood vessels)
  • Differs from hematopoiesis that occurs later in the fetus and adult
• Hepatic Phase


  1. Begins at 5 to 7 gestational weeks

  2. Characterized by recognizable clusters of developing erythroblasts, granulocytes, and monocytes colonizing the fetal liver, thymus, spleen, placenta, and ultimately the bone marrow space

  3. Hematopoiesis occurs extravascularly

  4. Fetal liver remains the major site of hematopoiesis during the second trimester of fetal life

  5. Hematopoiesis in the fetal liver reaches its peak by the third month of fetal development, then gradually declines after the sixth month
• Medullary (Myeloid) Phase


  1. Hematopoiesis in the bone marrow begins between the fourth and fifth month of fetal development

  2. HSCs and mesenchymal cells migrate into the core of the bone

  3. Mesenchymal cells differentiate into structural elements that support developing hematopoietic elements

  4. Myeloid activity is apparent during this stage of development

  5. By the end of 24 weeks' gestation, the bone marrow becomes the primary site of hematopoiesis
• Adult hematopoietic tissue


  • Bone marrow
  • Lymph nodes
  • Spleen
  • Liver
  • Thymus
• Bone marrow


  • Contains developing erythroid, myeloid, megakaryocytic, and lymphoid cells
  • Composed of red marrow (hematopoietically active) and yellow marrow (hematopoietically inactive)
• Red marrow


  • Composed of hematopoietic cells arranged in extravascular cords
  • Cords are located in spaces between vascular sinuses and are supported by trabeculae of spongy bone
  • Hematopoietic cells develop in specific niches within the cords
• Yellow marrow is capable of reverting back to active marrow in cases of increased demand on the bone marrow, such as in excessive blood loss or hemolysis
• Stromal cells play a critical role in the regulation of hematopoietic stem and progenitor cell survival and differentiation
• Endothelial cells regulate the flow of particles entering and leaving hematopoietic spaces in the vascular sinuses
• Fixed and Stained Bone Marrow Biopsy Specimen

  • Extravascular tissue consists of blood cell precursors and various tissue cells with scattered fat tissue
  • Normal adult bone marrow displays 50% hematopoietic cells and 50% fat
• Hematopoietic cells


  Blood cell precursors
• Stromal cells


  Cells that originate from mesenchymal cells and migrate into the central cavity of the bone, including endothelial cells, adipocytes, macrophages, lymphocytes, osteoblasts, osteoclasts, and reticular adventitial cells
• Endothelial cells


  • Broad, flat cells that form a single continuous layer along the inner surface of the arteries, veins, and vascular sinuses
  • Regulate the flow of particles entering and leaving hematopoietic spaces in the vascular sinuses
• Adipocytes


  • Large cells with a single fat vacuole
  • Play a role in regulating the volume of the marrow in which active hematopoiesis occurs
  • Secrete cytokines or growth factors that positively stimulate HSC numbers and bone homeostasis
• Macrophages and lymphocytes


  • Function in phagocytosis and secrete various cytokines that regulate hematopoiesis
• Osteoblasts


  • Bone-forming cells
• Osteoclasts


  • Bone-resorbing cells
• Reticular adventitial cells


  • Form an incomplete layer of cells on the abluminal surface of the vascular sinuses
  • Extend long, reticular fibers into the perivascular space that form a supporting lattice for the developing hematopoietic cells
• Megakaryocytes


  • Located adjacent to the walls of the vascular sinuses, which facilitates the release of platelets into the lumen of the sinus
• Maturation of myeloid (granulocytic) cells

  1. Immature cells through the metamyelocyte stage are located deep within the cords

  2. As these maturing granulocytes proceed along differentiation, they move closer to the vascular sinuses
• Release of mature blood cells into peripheral circulation

  1. Highly complex interaction between the maturing blood cells and the vascular sinus wall

  2. Blood cells pass between layers of adventitial cells that form a discontinuous layer along the abluminal side of the sinus

  3. Adventitial cells are capable of contracting, which allows mature blood cells to pass through the basement membrane and interact with the endothelial layer

  4. Cells bind to the endothelial cell surface through a receptor-mediated process, pass through pores in the endothelial cytoplasm, and are released into the vascular sinus
• Nutrient and periosteal arteries

  • Enter the bone via the bone foramina
  • Nutrient artery supplies blood only to the marrow
  • Arteriole branches that enter the inner lining of the cortical bone (endosteum) form sinusoids (endosteal beds), which connect to periosteal capillaries that extend from the periosteal artery
• Central longitudinal vein


  • Passes along the bone canal and blood exits the marrow via this vein
• Hematopoietic inductive microenvironment or niche


  Plays an important role in nurturing and protecting HSCs and regulating their quiescence, self-renewal, and differentiation
• Key stromal cells in the bone marrow niche

  • Osteoblasts, endothelial cells, mesenchymal stem cells, CXCL12-abundant reticular cells, perivascular stromal cells, glial cells, and macrophages
• HSCs are predominantly quiescent, maintained in a nondividing state by intimate interactions with thrombopoietin-producing osteoblasts
• Vascular cells are critical to HSC maintenance through CXCL12, which regulates migration of HSCs to the vascular niche
• Niches may overlap, providing multiple signals simultaneously and thus ensuring tight regulation of HSCs
• Liver


  Major site of blood cell production during the second trimester of fetal development
• Hepatocytes


  • Arranged in radiating plates emanating from a central vein
  • Adjacent to the longitudinal plates of hepatocytes are vascular sinusoids lined with endothelial cells
  • A small noncellular space separates the endothelial cells of the sinusoids from the plates of hepatocytes
• Kupffer cells


  • Macrophages that remove senescent cells and foreign debris from the blood that circulates through the liver, and secrete mediators that regulate protein synthesis in the hepatocytes
• Spleen


  Largest lymphoid organ in the body, vital but not essential for life, functions as an indiscriminate filter of the circulating blood
• Splenic tissue


  • White pulp, red pulp, and marginal zone
• White pulp


  • Consists of scattered follicles with germinal centers containing lymphocytes, macrophages, and dendritic cells
• Marginal zone


  • Surrounds the white pulp and forms a reticular meshwork containing blood vessels, macrophages, memory B cells, and CD4+ T cells
• Red pulp


  • Composed primarily of vascular sinuses separated by cords of reticular cell meshwork (cords of Billroth) containing loosely connected specialized macrophages
• Functions of the spleen

  • Removes senescent or abnormal RBCs from the circulation through culling and pitting
  • Serves as a storage site for platelets