Myosin-II repression favors pre/proplatelets but shear activation generates platelets and fails in macrothrombocytopenia.

摘要: Megakaryocyte ploidy and the generation of pre/proplatelets are both increased in culture by pharmacologic inhibition myosin-II, but nonmuscle myosin-IIA (MIIA) mutations paradoxically cause MYH9-related diseases (MYH9-RD) that adversely affect platelets. In marrow, megakaryocytes extend projections into microcirculation, where shear facilitates fragmentation to large pre/proplatelets, suggesting fluid stresses myosin-II activity somehow couple platelet biogenesis. Here, bulk shear, plateletlike particles generated from maximized at a stress typical microcirculation after treatment with inhibitor. MIIA static cells is naturally repressed through phosphorylation Serine-1943, decreases phosphorylation, consistent activation localization cortex. Micropipette aspiration shows accumulates stressed sites, its prevents such mechanoactivation CD41(+) fragments similar size pre/proplatelets. MYH9-RD mutants phenocopy inhibition, revealing dominant negative effect. diffuse platelets patient macrothrombocytopenia also normal treated inhibitor blocks vitro division small The findings explain near-normal thrombocrit patients. Myosin-II regulation thus controls number.