Megakaryocytopoiesis is the cellular development process that leads to platelet production. The protein encoded by this gene is a humoral growth factor necessary formegakaryocyte proliferation and maturation, as well as for thrombopoiesis. This protein is the ligand for MLP/C_MPL, the product of myeloproliferative leukemia virus oncogene.[6]
Thrombopoietin is produced in the liver by both parenchymal cells andsinusoidal endothelial cells, as well as in the kidney by proximal convoluted tubule cells. Small amounts are also made bystriated muscle and bone marrow stromal cells.[5] In the liver, its production is augmented byinterleukin 6 (IL-6).[5] However, the liver and the kidney are the primary sites of thrombopoietin production.
Thrombopoietin regulates the differentiation ofmegakaryocytes andplatelets, but studies on the removal of the thrombopoietin receptor show that its effects onhematopoiesis are more versatile.[5]
Its negative feedback is different from that of most hormones inendocrinology: The effector regulates the hormone directly. Thrombopoietin is bound to the surface of platelets and megakaryocytes by the mpl receptor (CD 110). Inside the platelets it gets destroyed, while inside the megakaryocytes it gives the signal of their maturation and consecutively more platelet production. The bounding of the hormone at these cells thereby reduces further megakaryocyte exposure to the hormone.[5] Therefore, the rising and dropping platelet and megakaryocyte concentrations regulate the thrombopoietin levels. Low platelets and megakaryocytes lead a higher degree of thrombopoietin exposure to the undifferentiated bone marrow cells, leading to differentiation intomegakaryocytes and further maturation of these cells. On the other hand, high platelet and megakaryocyte concentrations lead to more thrombopoetin destruction and thus less availability of thrombopoietin to bone marrow.
TPO, likeEPO, plays a role in brain development. It promotesapoptosis of newly generated neurons, an effect counteracted by EPO andneurotrophins.[8]
Despite numerous trials, thrombopoietin has not been found to be useful therapeutically. Theoretical uses include the procurement of platelets for donation,[9] and recovery of platelet counts after myelosuppressivechemotherapy.[5]
Trials of a modified recombinant form, megakaryocyte growth and differentiation factor (MGDF), were stopped when healthy volunteers developed autoantibodies to endogenous thrombopoietin and then developed thrombocytopenia.[10]Romiplostim andEltrombopag, compounds that are structurally different to thrombopoietin but stimulate the same pathway by binding to and activating the thrombopoietin receptor, are used instead.[11]
A quadrivalent peptide analogue is being investigated, as well as severalsmall-molecule agents,[5] and several non-peptide ligands ofc-Mpl, which act as thrombopoietin analogues.[12][13]
Thrombopoietin was cloned by five independent teams in 1994. Before its identification, its function has been hypothesized for as much as 30 years as being linked to thecell surface receptorc-Mpl, and in older publicationsthrombopoietin is described asc-Mpl ligand (the agent that binds to the c-Mpl molecule). Thrombopoietin is one of the Class I hematopoietic cytokines.[5]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^abcdefghKaushansky K (May 2006). "Lineage-specific hematopoietic growth factors".The New England Journal of Medicine.354 (19):2034–45.doi:10.1056/NEJMra052706.PMID16687716.
^Imbach P, Crowther M (August 2011). "Thrombopoietin-receptor agonists for primary immune thrombocytopenia".The New England Journal of Medicine.365 (8):734–41.doi:10.1056/NEJMct1014202.PMID21864167.
