Megakaryocyte
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2008-07-01T13:01:35Z
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[[Image:Megakaryocyte.png|thumb|Megakaryocyte]]
[[Image:WVSOM Megakaryocytes.JPG|thumb|megakaryocytes in bone marrow]]
The '''megakaryocyte''' is a [[bone marrow]] [[cell (biology)|cell]] responsible for the production of blood [[platelet]]s necessary for normal blood [[clot]]ting. Megakaryocytes normally account for 1 out of 10,000 [[bone marrow]] cells but can increase in number nearly 10-fold in certain diseases.<ref name=Branehog>{{cite journal|author=Branehog I, Ridell B, Swolin B, Weinfeld A | date=1975 |title=Megakaryocyte quantifications in relation to thrombokinetics in primary thrombocythaemia and allied diseases |journal=Scand. J. Haematol.| volume=15 | pages=321–332}}</ref>
==Structure==
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]]. 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]].
== Megakaryocyte development ==
[[Image:Illu blood cell lineage.jpg|Blood cell lineage|left|200px]]
Megakaryocytes are derived from [[hematopoietic stem cell]] precursor cells in the bone marrow. These [[pluripotent]] 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 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]], and [[erythropoietin]].<ref name=Deutsch>{{cite journal | author=Deutsch VR, Torner A | title=Megakaryocyte development and platelet production | journal=Brit. J. Haem. | date=2006 September | volume=134 | issue=5 | pages=453–466 | doi=10.1111/j.1365-2141.2006.06215.x}}</ref> The megakaryocyte develops through the following lineage:
CFU-Me ([[pluripotential hemopoietic stem cell]] or hemocytoblast) -> [[megakaryoblast]] -> [[promegakaryocyte]] -> megakaryocyte.
The cell eventually reaches megakaryoblast stage and loses its ability to divide. However, it is still able to replicate its DNA and continue development, becoming [[polyploid]].<ref name=Deutsch/> The cytoplasm continues to expand and the DNA complement can increase up to 64N.
== Platelet release ==
Once the cell has completed differentiation and become a mature megakaryocyte, it begins the process of producing 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.<ref name=Choi>{{cite journal | author=Choi ES, Nichol JL, Hokom MM, et al | date=1995 | title=Platelets generated in vitro from proplatelet-displaying human megakaryocytes are functional | journal=Blood | volume=85 | issue=2 | pages=402–13}}</ref> 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.
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 macrophage]]s.
== Effects of cytokines ==
[[Cytokine]]s are signals used in the [[immune system]] for intercellular communication. There are many [[cytokine]]s which affect megakaryocytes. Certain cytokines such as [[IL-3]], [[IL-6]], [[IL-11]], [[LIF]], [[erythropoietin]], and [[thrombopoietin]] all stimulate the maturation of megakaryocytic progenitor cells.<ref name=Gordon>{{cite journal | author=Gordon MS, Hoffman R | date=1992 | title=Growth factors affecting human thrombocytopoiesis: potential agents for the treatment of thrombocytopenia | journal=Blood. | volume=80 | pages = 302–307}}</ref> Other signals such as [[PF4]], [[CXCL5]], [[CXCL7]], and [[CCL5]] inhibit platelet formation.<ref name=Pang>{{cite journal | author=Pang L, Weiss MJ, Poncz M | title=Megakaryocyte biology and related disorders | journal=J. Clin. Invest. | volume=115 | pages=3332–3338 | date=2005 | doi=10.1172/JCI26720 }}</ref>
===Thrombopoietin===
{{main|thrombopoietin}}
Thrombopoietin (TPO) is a 353-amino acid protein located on [[chromosome]] 3p27. TPO is primarily synthesized in the liver<ref name=Jelkmann>{{cite journal | author=Jelkmann W | date=2001 | title=The role of the liver in the production of thrombopoietin compared with erythropoietin | journal=Eur. J. Gastroenterol. Hepatol. | volume=13 | pages=791–801 | doi=10.1097/00042737-200107000-00006}}</ref> but can be made by kidneys, testes, brain, and even bone marrow stromal cells. It has high homology with [[erythropoietin]]. It is necessary but not required for the formation of platelets. Mice lacking TPO or the TPO receptor (Mpl) have a 90% reduction in circulating platelet number, although the platelets are normal in morphology and function.<ref name=Murone>{{cite journal|author=Murone M, Carpenter DA, de Sauvage FJ | date=1998 |title=Hematopoietic deficiencies in c-mpl and TPO knockout mice |journal=Stem Cells. | volume=16 |pages=1–6}}</ref>
== Disorders involving megakaryocytes ==
Megakaryocytes are directly responsible for producing platelets which are needed for the formation of a [[thrombus]], or blood clot. There are several diseases which are directly attributable to abnormal megakaryocyte function or abnormal platelet function.<ref name=Nurden>{{cite journal | author=Nurden AT | date=2005 | title=Qualitative disorders of platelets and megakaryocytes | journal=J. Thromb. and Haem. |volume=3 |issue=8 | pages=1773–1782 | doi=10.1111/j.1538-7836.2005.01428.x}}</ref>
=== Essential Thrombocythemia===
[[essential thrombocythemia| Essential thrombocythemia]] (ET) is a disorder characterized by extremely high numbers of circulating platelets. The disease occurs in 1-2 per 100,000 people. The current WHO requirements for diagnosis include > 600,000 platelets/μL of blood (normal 150,000-400,000) and a [[bone marrow]] biopsy. Some of the consequences of having such high numbers of platelets include [[thrombosis]] or clots throughout the body. Thrombi form more frequently in arteries than veins. Ironically, having platelet counts above 1,000,000 platelets/μL can lead to [[hemorrhage|hemorrhagic]] events.<ref name=Michiels>{{cite journal |author=Michiels JJ, Berneman ZN, Schroyens W, Van Vliet HH | title=Pathophysiology and treatment of platelet-mediated microvascular disturbances, major thrombosis and bleeding complications in essential thrombocythaemia and polycythaemia vera |journal=Platelets |date=2004 |volume=15|pages=67–84 |doi=10.1080/09537100310001646969}}</ref> Recent evidence suggests that the majority of ET cases are due to a mutation in the [[JAK2]] protein, a member of the [[JAK]]-[[STAT]] pathway.<ref name=Kralovics>{{cite journal | author=Kralovics R, Passamonti F, Buser AS, Teo SS, et al |title=A gain-of-function mutation of JAK2 in myeloproliferative disorders| journal=N Engl J Med |date=2005 Apr 28 |volume=352|issue=17 |pages=1779–90 | doi=10.1056/NEJMoa051113 |pmid=15858187}}</ref> Evidence suggests this mutation renders the megakaryocyte hypersensitive to thrombopoietin and causes clonal proliferation of megakaryocytes. There is a significant risk of transformation to [[leukemia]] with this disorder. The primary treatment consists of [[anegrelide]] or [[hydroxyurea]] to lower platelet levels.
===Congenital amegakaryocytic thrombocytopenia (CAMT)===
[[Thrombocytopenia|Congenital amegakaryocytic thrombocytopenia]] (CAMT) is a rare [[inherited]] disorder. The primary manifestations are [[thrombocytopenia]] and [[megakaryocytopenia]], or low numbers of platelets and megakaryocytes. There is an absence of megakaryocytes in the bone marrow with no associated physical abnormalities.<ref name=Freedman>{{cite journal | author=Freedman MH, Estrov Z| title= Congenital amegakaryocytic thrombocytopenia: an intrinsic hematopoietic stem cell defect | date=1990 |journal=Am. J. Pediatr. Hematol. Oncol. |volume=12 | pages=225–230}}</ref> The cause for this disorder appears to be a mutation in the gene for the TPO receptor, ''c-mpl'', despite high levels of serum TPO.<ref name=Ihara>{{cite journal | author=Ihara K, Ishii E, Eguchi M, Takada H, Suminoe A, Good RA, Hara T |title=Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia |journal=Proc. Natl. Acad. Sci. |date=1999 |volume=96 |pages=3133–6 | doi=10.1073/pnas.96.6.3132 |pmid=10077649}}</ref><ref name=Ballmaier>{{cite journal | author=Ballmaier M, Germeshausen M, Schulze H, Cherkaoui K, Lang S, Gaudig A, Krukemeier S, Eilers M, Strauss G, Welte K | title=C-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia |journal=Blood. |date=2001 |volume=97|pages=139–46 | doi=10.1182/blood.V97.1.139 | pmid=11133753}}</ref> In addition, there may be abnormalities with the [[central nervous system]] including the [[cerebrum]] and [[cerebellum]] which could cause symptoms.<ref name=Ihara/> The primary treatment for CAMT is [[bone marrow transplantation]].
Bone Marrow/Stem Cell Transplant is the only thing that ultimately cures this genetic disease. Frequent platelet transfusions are required to keep the patient from bleeding to death until transplant is done, although this is not always the case.
One of the few non Medical Research related sources on the web with some information on CAMT is;
*[http://haleysgiggle.com/ CAMT Specific Infant Bone Marrow Transplant Journal]
There appears to be no generic resource for CAMT patients on the web, and this is potentially due to the rariety of the disease.
== External links ==
*[http://www.healthsystem.virginia.edu/internet/hematology/HessEDD/Normal-hematopoietic-cells/Immature-Megakaryocyte.cfm Immature megakaryocyte] Presented by the University of Virginia
* [http://image.bloodline.net/mk2 ''Megakaryocytes: Mature''] Many microscopic images of mature megakaryocytes including in disease settings.
* [http://wikibooks.org/wiki/Biology_Cell_biology_Introduction_Cell_size ''Cell size comparison'']
*[http://haleysgiggle.com/ CAMT Specific Infant Bone Marrow Transplant Journal]
== References ==
{{reflist|2}}
{{Blood}}
[[Category:Leukocytes]]
[[Category:Human cells]]
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