Megakaryocyte

A megakaryocyte (mega- + karyo- + -cyte, 'large-nucleus cell') is a large bone marrow cell with a lobated nucleus responsible for the production of blood thrombocytes (platelets), which are necessary for normal blood clotting. Megakaryocytes usually account for 1 out of 10,000 bone marrow cells in normal people, but can increase in number nearly 10-fold during the course of certain diseases. Owing to variations in combining forms and spelling, synonyms include megalokaryocyte and megacaryocyte. A megakaryocyte (mega- + karyo- + -cyte, 'large-nucleus cell') is a large bone marrow cell with a lobated nucleus responsible for the production of blood thrombocytes (platelets), which are necessary for normal blood clotting. Megakaryocytes usually account for 1 out of 10,000 bone marrow cells in normal people, but can increase in number nearly 10-fold during the course of certain diseases. Owing to variations in combining forms and spelling, synonyms include megalokaryocyte and megacaryocyte. In general, megakaryocytes are 10 to 15 times larger than a typical red blood cell, averaging 50–100 μm in diameter. During its maturation, the megakaryocyte grows in size and replicates its DNA without cytokinesis in a process called endomitosis. As a result, the nucleus of the megakaryocyte can become very large and lobulated, which, under a light microscope, can give the false impression that there are several nuclei. In some cases, the nucleus may contain up to 64N DNA, or 32 copies of the normal complement of DNA in a human cell. The cytoplasm, just as the platelets that bud off from it, contains α-granula and dense bodies. Megakaryocytes are derived from hematopoietic stem cell precursor cells in the bone marrow. They are produced primarily by the liver, kidney, spleen, and bone marrow. These multipotent stem cells live in the marrow sinusoids and are capable of producing all types of blood cells depending on the signals they receive. The primary signal for megakaryocyte production is thrombopoietin or TPO. TPO is sufficient but not absolutely necessary for inducing differentiation of progenitor cells in the bone marrow towards a final megakaryocyte phenotype. Other molecular signals for megakaryocyte differentiation include GM-CSF, IL-3, IL-6, IL-11, chemokines (SDF-1, FGF-4). and erythropoietin. The megakaryocyte develops through the following lineage: CFU-Me (pluripotential hemopoietic stem cell or hemocytoblast) → megakaryoblast → promegakaryocyte → megakaryocyte. The cell eventually reaches megakaryocyte stage and loses its ability to divide. However, it is still able to replicate its DNA and continue development, becoming polyploid. The cytoplasm continues to expand and the DNA complement can increase up to 64N in human and 256N in mouse. Many of the morphological features of megakaryocyte differentiation can be recapitulated in non-hematopoietic cells by the expression of Class VI β-tubulin (β6) and they provide a mechanistic basis for understanding these changes. Once the cell has completed differentiation and become a mature megakaryocyte, it begins the process of producing platelets. The maturation process occurs via endomitotic synchronous replication whereby the cytoplasmic volume enlarges as the number of chromosomes multiplies without cellular division. The cell ceases its growth at 4N, 8N or 16N, becomes granular, and begins to produce platelets. Thrombopoietin plays a role in inducing the megakaryocyte to form small proto-platelet processes. Platelets are held within these internal membranes within the cytoplasm of megakaryocytes. There are two proposed mechanisms for platelet release. In one scenario, these proto-platelet processes break up explosively to become platelets. Alternatively, the cell may form platelet ribbons into blood vessels. The ribbons are formed via pseudopodia and they are able to continuously emit platelets into circulation. In either scenario, each of these proto-platelet processes can give rise to 2000–5000 new platelets upon breakup. Overall, 2/3 of these newly produced platelets will remain in circulation while 1/3 will be sequestered by the spleen. Thrombopoietin (TPO) is a 353-amino acid protein encoded on chromosome 3p27. TPO is primarily synthesized in the liver but can be made by kidneys, testes, brain, and even bone marrow stromal cells. It has high homology with erythropoietin. It is essential for the formation of an adequate quantity of platelets. After budding off platelets, what remains is mainly the cell nucleus. This crosses the bone marrow barrier to the blood and is consumed in the lung by alveolar macrophages.