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Platelets and liver sinusoidal endothelial cells (LSEC) are both known to independently regulate liver regeneration. Our aim was to investigate the role of interactions between platelets and LSEC in a model of liver regeneration.Platelet and LSEC interactions were analyzed in vivo by intravital confocal microscopy in partially hepatectomized mice. Then, highly purified primary mouse LSEC were co-incubated with increasing concentrations of resting platelets, activated platelets, or platelet releasates, and secretion of growth factors was measured. The active fraction of platelet releasates was characterized and its effect on hepatocyte proliferation assessed. Finally, IL-6 serum concentrations were measured in mice with varying platelet counts after partial hepatectomy.Following partial hepatectomy, in vivo adhesion of platelets to LSEC was significantly increased, when compared to sham-operated mice. Co-incubation of increasing numbers of resting or activated platelets with LSEC resulted in significantly enhanced IL-6 secretion by LSEC. IL-6 release by LSEC was the highest after incubation with ADP-activated platelets. The effect of platelet releasates on LSEC was similar to that seen with intact, whole platelets. Further, the effect of platelets on LSEC was mediated by a platelet factor, whose action was synergistically enhanced by ADP. ADP-activated platelet releasates increased proliferation of hepatocytes co-cultured with LSEC. Decreased platelet counts resulted in decreased serum levels of IL-6 after partial hepatectomy in vivo.We show that platelets modulate LSEC to constitutively secrete IL-6, a key player in liver regeneration. After partial hepatectomy, platelets adhere to LSEC and serum IL-6 levels depend on platelet concentration. Interactions between platelets and LSEC modulate IL-6 release by LSEC and increase hepatocyte proliferation. This effect is dependent on ADP.