Platelets Strongly Induce Hepatocyte Proliferation with IGF-1 and HGF In Vitro Platelets strongly induce hepatocyte proliferation with IGF-1 and HGF in vitro
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Background. It is well known that platelets have athrombotic effect. However, platelets play an importantrole not only in hemostasis but also in woundhealing and tissue regeneration. Platelets have beenreported to accumulate in the liver and promote liverregeneration after an extended hepatectomy, but themechanism is unclear. The present study was designedto clarify the mechanism by which plateletshave a direct proliferative effect on hepatocytes invitro.Materials and methods. Hepatocytes obtained frommale BALB/c mice by collagenase digestion and immortalizedhepatocytes (TLR2) were used. To elucidatethe mechanism of the proliferative effect of platelets,DNA synthesis of hepatocytes was measuredunder various conditions and the related cellular signalswere analyzed. Chromatographic analysis wasalso performed to clarify which elements of plateletshave mitogenic activity.Results. DNA synthesis significantly increased in thehepatocytes cultured with platelets (P < 0.001). However,when the platelets and hepatocytes were separated,the platelets did not have a proliferative effect.Whole disrupted platelets, the supernatant fraction,and fresh isolated platelets had a similar proliferativeeffect, while the membrane fraction did not. After theaddition of platelets, both Akt and extracellularsignal-regulated kinases ERK1/2 were activated, butextracellular signal-regulated kinase STAT3 was not activated. Some mitogenic fractions were obtainedfrom the platelet extracts by gel exclusion chromatography;the fractions were rich in hepatocyte growthfactor and IGF-1.Conclusions. Direct contact between platelets andhepatocytes was necessary for the proliferative effect.The direct contact initiated signal transduction involvedin growth factor activation. Hepatocyte growthfactor, vascular endothelial growth factor, and insulin-like growth factor-1, rather than platelet-derivedgrowth factor, mainly contributed to hepatocyteproliferation.
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