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Megakaryocyte
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<h2 id="structure">Structure</h2> <p>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 <a href="/facts/DNA/nB89Iauz">DNA</a> without <a href="/facts/Cytokinesis/hhrnmTwY">cytokinesis</a> in a process called <a href="/facts/Mitosis/ExxrSUs8">endomitosis</a>. 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. </p><p>The <a href="/facts/Cytoplasm/Wa0sE6xf">cytoplasm</a>, just as the platelets that <a href="/facts/Budding/TEB3zXxB">bud off</a> from it, contains <a href="/facts/Alpha_granule/XBXqAfkd">α-granules</a> and <a href="/facts/Platelet/I0xrDVGa">dense bodies</a>. </p> <h2 id="development">Development</h2> <p>The megakaryocyte develops through the following lineage: </p> <a href="/facts/CFU-Meg/SA15rCHG">CFU-Meg</a> (<a href="/facts/Hematopoietic_stem_cell/RQNE9IRu">hematopoietic stem cell</a>/hemocytoblast) → <a href="/facts/Megakaryoblast/Up7LSYUb">megakaryoblast</a> → <a href="/facts/Promegakaryocyte/sKEm10v5">promegakaryocyte</a> → megakaryocyte <p>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 <a href="/facts/Multipotent/81323LbR">multipotent</a> 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 <a href="/facts/Thrombopoietin/0Whum9R8">thrombopoietin</a> (TPO). TPO is sufficient but not absolutely necessary<a class="footnote-ref" id="fnref:2" href="#fn:2"><sup>2</sup></a> for inducing differentiation of progenitor cells in the bone marrow towards a final megakaryocyte <a href="/facts/Phenotype/vxWXKGLj">phenotype</a>. Other molecular signals for megakaryocyte differentiation include <a href="/facts/GM-CSF/U15M21QE">GM-CSF</a>, <a href="/facts/Interleukin_3/mXKTzRve">IL-3</a>, <a href="/facts/Interleukin_6/FVQeAWkt">IL-6</a>, <a href="/facts/Interleukin_11/fQ5UJws2">IL-11</a>, <a href="/facts/Chemokine/YrySj9eD">chemokines</a> (<a href="/facts/Stromal_cell-derived_factor-1/K1IrAmDP">SDF-1</a>, <a href="/facts/FGF-4/DFg3nVtj">FGF-4</a>),<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> and <a href="/facts/Erythropoietin/jgYFo1R6">erythropoietin</a>.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> </p><p>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 <a href="/facts/Polyploid/L7xyKHdK">polyploid</a>.<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> The cytoplasm continues to expand and the DNA amount can increase up to 64n in humans and 256n in mice. 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.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> </p> <h2 id="function">Function</h2> <h3>Platelet release</h3> <p>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.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> <a href="/facts/Thrombopoietin/0Whum9R8">Thrombopoietin</a> 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.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> It is possible to visualize the spontaneous release of platelets using holotomographic <a href="/facts/Live-cell_imaging/sXGo63QX">live-cell imaging</a>. Alternatively, the cell may form platelet ribbons into blood vessels. The ribbons are formed via <a href="/facts/Pseudopodia/EHHnuk4f">pseudopodia</a> 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.[<i>medical citation needed</i>] </p> <p>Thrombopoietin (TPO) is a 353-amino acid protein encoded on <a href="/facts/Chromosome_3/2lHrRbHd">chromosome 3p</a>27. TPO is primarily synthesized in the liver<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> but can be made by kidneys, testes, brain, and even bone marrow stromal cells. It has high homology with <a href="/facts/Erythropoietin/jgYFo1R6">erythropoietin</a>. It is essential for the formation of an adequate quantity of platelets. </p><p>After budding off platelets, what remains is mainly the cell nucleus. This crosses the <a href="/facts/Bone_marrow_barrier/4dfudk0H">bone marrow barrier</a> to the blood and is consumed in the <a href="/facts/Lung/gTWXI6Fj">lung</a> by <a href="/facts/Alveolar_macrophage/Hj8oxT3y">alveolar macrophages</a>. </p> <h3>Effects of cytokines</h3> <p><a href="/facts/Cytokine/SdWpWABH">Cytokines</a> are signals used in the <a href="/facts/Immune_system/HRCTf1pb">immune system</a> for intercellular communication. There are many <a href="/facts/Cytokine/SdWpWABH">cytokines</a> that affect megakaryocytes. Certain cytokines such as <a href="/facts/Interleukin_3/mXKTzRve">IL-3</a>, <a href="/facts/Interleukin_6/FVQeAWkt">IL-6</a>, <a href="/facts/Interleukin_11/fQ5UJws2">IL-11</a>, <a href="/facts/Leukemia_inhibitory_factor/AHsxb24a">LIF</a>, <a href="/facts/Erythropoietin/jgYFo1R6">erythropoietin</a>, and <a href="/facts/Thrombopoietin/0Whum9R8">thrombopoietin</a> all stimulate the maturation of megakaryocytic progenitor cells.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> Other signals such as <a href="/facts/PF4/ajLS8p75">PF4</a>, <a href="/facts/CXCL5/ausnxCUq">CXCL5</a>, <a href="/facts/CXCL7/sxQuVB62">CXCL7</a>, and <a href="/facts/CCL5/bfcYCrNH">CCL5</a> inhibit platelet formation.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> </p> <h2 id="clinical-significance">Clinical significance</h2> <p>Megakaryocytes are directly responsible for producing platelets, which are needed for the formation of a <a href="/facts/Thrombus/vH6FDIQG">thrombus</a>, or blood clot. There are several diseases that are directly attributable to abnormal megakaryocyte function or abnormal platelet function.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p> <h3>Essential thrombocythemia</h3> <p class="note">Main article: <a href="/facts/Essential_thrombocythemia/90PcPKUI">Essential thrombocythemia</a></p> <p><a href="/facts/Essential_thrombocythemia/90PcPKUI">Essential thrombocythemia</a> (ET) is a disorder characterized by elevated numbers of circulating platelets. The disease occurs in 1–2 per 100,000 people. The 2016 WHO requirements for diagnosis include > 450,000 platelets/μL of blood (normal 150,000–400,000) and characteristic findings in a <a href="/facts/Bone_marrow/4dfudk0H">bone marrow</a> biopsy. Some of the consequences of having such high numbers of platelets include <a href="/facts/Thrombosis/8Y3wh2UX">thrombosis</a> or clots in blood vessels. Thrombi form more frequently in arteries than veins. It seems ironic that having platelet counts above 1,000,000 platelets/μL can lead to <a href="/facts/Hemorrhage/CGyFMU0F">hemorrhagic</a> events.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> Approximately half ET cases are due to a mutation in the <a href="/facts/JAK2/yS2HKTU7">JAK2</a> protein, a member of the <a href="/facts/JAK-STAT_signaling_pathway/t31RBT3X">JAK-STAT signaling pathway</a>.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> This mutation induces an unregulated proliferative signal from the thrombopoietin (TPO) receptor in the absence of TPO causing clonal expansion of bone marrow cells, especially megakaryocytes. There is a low risk of transformation to <a href="/facts/Leukemia/WpEfW0Qh">leukemia</a> with this disorder. The primary treatment consists of <a href="/facts/Anagrelide/QXEo3lMS">anagrelide</a> or <a href="/facts/Hydroxyurea/lVlUYcy8">hydroxyurea</a> to lower platelet levels. </p> <h3>Congenital amegakaryocytic thrombocytopenia</h3> <p><a href="/facts/Thrombocytopenia/qMy4o0Rz">Congenital amegakaryocytic thrombocytopenia</a> (CAMT) is a rare <a href="/facts/Heredity/t0aMmRWx">inherited</a> disorder. The primary manifestations are <a href="/facts/Thrombocytopenia/qMy4o0Rz">thrombocytopenia</a> and megakaryocytopenia, for example low numbers of platelets and megakaryocytes. There is an absence of megakaryocytes in the bone marrow with no associated physical abnormalities.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> The cause for this disorder appears to be a mutation in the gene for the TPO receptor, <i>c-mpl</i>, despite high levels of serum TPO.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a><a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> In addition, there may be abnormalities with the <a href="/facts/Central_nervous_system/k8I6To97">central nervous system</a> including the <a href="/facts/Cerebrum/zjpAVDgA">cerebrum</a> and <a href="/facts/Cerebellum/kBRS2Lou">cerebellum</a> that could cause symptoms.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> The primary treatment for CAMT is <a href="/facts/Bone_marrow_transplantation/rGYRsATD">bone marrow transplantation</a>. </p><p>Bone marrow/stem cell transplant is the only remedy for this genetic disease. Frequent platelet transfusions are required to keep the patient from bleeding to death until transplant has been completed, although this is not always the case. </p><p>There appears to be no generic resource for CAMT patients on the web and this is potentially due to the rarity of the disease. </p> <h2 id="history">History</h2> <p> In 1906, James Homer Wright provided evidence that megakaryocytes give rise to blood platelets.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> </p><p>Kelemen first coined the term "<a href="/facts/Thrombopoietin/0Whum9R8">thrombopoietin</a>" to describe the humoral substance responsible for the production of platelets.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/List_of_distinct_cell_types_in_the_adult_human_body/IjWXx31l">List of distinct cell types in the adult human body</a></li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="https://image.bloodline.net/mk2.html"><i>Megakaryocytes: Mature</i></a> Many microscopic images of mature megakaryocytes including in disease settings.</li> <li><a href="https://www.bloodline.net/imageatlas/megakaryocytes/"><i>Megakaryocytes</i></a></li> <li><a href="https://web.archive.org/web/20040328112742/http://wikibooks.org/wiki/Biology_Cell_biology_Introduction_Cell_size"><i>Cell size comparison</i></a></li> <li><a href="https://web.archive.org/web/20070404151527/http://www.haleysgiggle.com/">CAMT Specific Infant Bone Marrow Transplant Journal</a></li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Branehog I, Ridell B, Swolin B, Weinfeld A (1975). "Megakaryocyte quantifications in relation to thrombokinetics in primary thrombocythaemia and allied diseases". Scand. J. Haematol. 15 (5): 321–32. doi:10.1111/j.1600-0609.1975.tb01087.x. PMID 1060175. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Bunting S, Widmer R, Lipari T, Rangell L, Steinmetz H, Carver-Moore K, Moore MW, Keller GA, de Sauvage FJ (November 1997). "Normal platelets and megakaryocytes are produced in vivo in the absence of thrombopoietin". Blood. 90 (9): 3423–29. doi:10.1182/blood.V90.9.3423. 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PMID 10077649. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC15907" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC15907</a> <a href="#fnref:18" class="footnote-back-ref">↩</a></p></li> <li id="fn:19"><p>Wright, JH (June 7, 1906). "The origin and nature of the blood plates". Boston Medical and Surgical Journal. CLIV (23): 643–645. doi:10.1056/NEJM190606071542301. <a href="https://zenodo.org/record/1813919" target="_blank">https://zenodo.org/record/1813919</a> <a href="#fnref:19" class="footnote-back-ref">↩</a></p></li> <li id="fn:20"><p>Kelemen, E; Cserhati, I; Tanos, B (December 1958). "Demonstration and some properties of human thrombopoietin in thrombocythaemic sera". Acta Haematologica. 20 (6): 350–355. doi:10.1159/000205503. PMID 13616931. <a href="/wiki/Acta_Haematologica" target="_blank">/wiki/Acta_Haematologica</a> <a href="#fnref:20" class="footnote-back-ref">↩</a></p></li> </ol>