期刊
PLATELETS
卷 25, 期 1, 页码 62-68出版社
INFORMA HEALTHCARE
DOI: 10.3109/09537104.2012.761686
关键词
Megakaryocyte; PKC; proplatelet formation; polyploidy
资金
- British Heart Foundation [RG/10/006/28299, PG/08/049]
- British Heart Foundation [RG/10/006/28299] Funding Source: researchfish
Proplatelet formation is a part of the intricate process by which platelets are generated by their precursor cell, the megakaryocyte. The processes that drive megakaryocyte maturation and platelet production are however still not well understood. The protein kinase C (PKC) family of serine/threonine kinases has been demonstrated as an important regulator of megakaryocyte maturation and proplatelet formation, but little investigation has been made on the individual isoforms. We have previously shown, in mouse models, that PKC alpha plays a vital role in regulating platelet function, so in this study we aimed to investigate the role of PKC alpha in megakaryocyte function using the same Prkca(-/-) mice. We assessed the role of global PKC and specifically PKC alpha in proplatelet formation in vitro, analyzed polyploidy in Prkca(-/-)-derived megakaryocytes and followed platelet recovery in platelet-depleted Prkca(-/-) mice. We show reduced proplatelet formation in the presence of global PKC blockade. However, in the presence of a selective classical PKC isoform inhibitor, Go6976, proplatelet formation was conversely enhanced. PKC alpha null megakaryocytes also showed enhanced proplatelet formation, as well as a shift to greater polyploidy. In vivo, platelet production was enhanced in response to experimentally induced immune thrombocytopenia. In conclusion, our data indicate that classical PKC isoforms, and more specifically PKC alpha, are negative regulators of proplatelet formation. PKC alpha appears to negatively regulate endomitosis, with the enhanced polyploidy observed in Prkca(-/-)-derived megakaryocytes. In vivo, these observations may culminate in the observed ability of Prkca(-/-) mice to recover more rapidly from a thrombocytopenic insult.
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