Potential mechanisms underlying platelet-mediated liver regeneration. (A) Platelets accumulate in the sinusoidal space of injured livers or livers that have been surgically reduced in size. From the sinusoidal space, some platelets migrate into the Space of Disse and some platelets are taken up by hepatocytes. These platelets have the potential to activate multiple pathways that may all contribute to platelet-mediated stimulation of liver regeneration. Which of these pathways occur in vivo has not been definitively established. (B) Platelets may release contents from their granules that either directly stimulate hepatocyte proliferation (serotonin, IGF, and HGF) or stimulate endothelial cells to release HGF (VEGF). Alternatively, the direct interaction of platelets with endothelial cells promotes release of interleukin 6 and VEGF that promote liver regeneration. (C) Platelets may transfer their RNA to hepatocytes, which promotes hepatocyte proliferation either by translation of mRNA or by the action of regulatory RNAs. (D) Platelets attract inflammatory cells, which are known to directly stimulate liver regeneration. Professional illustration by Patrick Lane, ScEYEnce Studios.