Hematopoiesis is the generation of all the cells of the blood - white blood cells, red blood cells, and platelets.
Cytokines and other hematopoietic growth factors are involved in specific steps of hematopoiesis.
These are generally glycoproteins acting in low concentrations, and are produced by stromal cells, monocytes, and lymphocytes.
Growth factors often act specifically, but they can also affect more than one lineage in similar or different ways. They can act synergistically or additively.
stem cell factor
infants: bone marrow of almost all bones
adults: vertebrae, ribs, sternum, skull, sacrum, pelvis, and end of femurs. There is progressive fatty replacement of marrow in other areas.
Fatty marrow is capable of reverting to hematopoiesis if necessary. The liver and spleen can also resume extramedullary hematopoiesis in some situations.
Erythropoiesis is controlled primarily by erythropoietin, but also GM-CSF, IL3, and IL11. Erythropoietin is released from kidney peritubular interstitial cells in response to oxygen levels.
EPO production increases in states of decreased tissue oxygen delivery. These included decreased Hb oxygenation (high altitudes, pulmonary dysfunction), hemoglobin levels (anemia), or hemoglobin affinity for oxygen (shift in oxygen dissociation curve). EPO expression increases logarithmically once levels fall below 120 g/L.
EPO levels are decreased by inflammatory cytokines such as TNF-a and TGFb. Drugs such as chemotherapy, cyclosporin A, and theophylline decrease EPO production.
EPO travels to the marrow, where it binds to EPO receptors on committed RBC precursors. Within hours, there is a noticable increase in DNA synthesis, followed by proliferation and differentiation. The full marrow response takes several days, with a detectable increase in hematocrit taking a week or more.
Cell cytoplasm changes from a deep basophilic RNA-rich substance to a substance
3-4 x 109 EBC/kg are made each day.
RBCs survive an average of 120 days.
Erythropoiesis takes place in erythroid islands containing macrophages, which contain the iron the RBCs need and also eat the nuclei.
Reticulocytes leave the marrow and mature into RBCs.
Platelets live for 10 days, and 2-3 x109 platelets per kg are formed daily.
Thrombopoietin, the key mediator of platelet production, is produced in liver. GM-CSF, IL3, IL6, EPO are also involved.
As megakaryocytes grow, they become large and multinucleated. Nuclear division happens without cell division.
Platelet maturation follows various steps:
Neutrophils mature over 5-7 days in the bone marrow and circulate for 7-10 hours before migrating into tissues. There they die within 48 hours.
Key regulatory factors: G-CSF, GM-CSF, IL-3
As granulocytes mature, nuclei segmentate, and cells acquire primary, then secondary granules.
1-2 x109 granulocytes per kg are formed daily.
the left shift, which is an expansion of circulating neutophil precursors, is most commonly caused by infection. TNF and IL-1 stimulate production of G-CSF, GM-CSF, and M-CSF, leading to release of neutrophil precursors into the blood.
B cells mature within the bone marrow. Key factors include: IL3, IL7, IL2, IL4, and others.
T cells mature into thymocytes in the bone marrow, then migrate to the thymus where they fully mature. Key factors include: IL3, IL7, IL2, IL4, and others.
Stages of maturation are defined by surface antigen:
B cells: Cd19, CD20, surface Ig
T cells: CD3, CD2, CD5, CD7, CD4, CD8, TCR
NK cells: CD56, CD16, CD2
During maturation, VDJ recombination occurs, allowing for tremendous variability but also predisposing for malignancy.
Burkitt's lymphoma: IgH/c-myc translocation - t(8;14)
follicular lymphoma: Bcl-2/IgH translocation - t(14;18)
M-CSF is the key factor in the development of monocytes.