Regular Article PLATELETS AND THROMBOPOIESIS Horizontal RNA transfer mediates platelet-induced hepatocyte proliferation

Blood platelets have essential roles in hemostasis and thrombosis, inflammation, host defense, and wound healing. Emerging evidence from recent in vitro and in vivo studies suggests that platelets have a pivotal role in liver regeneration. In experimental animal models in which platelets were depleted or functionally impaired, liver regeneration after a partial liver resection was substantially delayed. Conversely, following a partial liver resection in animals with a drug-induced thrombocytosis, liver regeneration was accelerated. In a clinical study, we showed that a low platelet count is an independent predictor of delayed postoperative liver function recovery following a partial liver resection, suggesting that platelets stimulate liver regeneration also in humans. Themolecularmechanisms of platelet-mediated stimulation of liver regeneration are largely unexplored. Platelets contain 2 distinct types of storageorganelles:agranulesanddensegranules.Thea granulescontain, among many proteins, a number of growth factors that have an established role in liver regeneration (platelet-derived growth factor [PDGF], hepatocyte growth factor [HGF], insulin-like growth factor [IGF], and vascular endothelial growth factor [VEGF]). In addition, the dense granules contain serotonin, which is also an established mediator of liver regeneration. It seems plausible that local release of these factors following stimulation of the platelets contributes to platelet-mediated stimulation of regeneration. Indeed, it has been demonstrated that platelets stimulate hepatocyte proliferation in vitro, and it has been suggested that direct contact of platelets and hepatocytes is required for this effect. Also, in vivo studies have demonstrated that platelets accumulate in the liver parenchyma following partial liver resection. Recently, a novel mechanism by which platelets may communicate with their environment has been described, which involves de novo protein synthesis. Although platelets lack a nucleus, they do contain a wide array of (pre–) messenger RNAs, which may be translated to protein. Protein synthesis by platelets may occur in particular following stimulation of the platelet. In addition, it has been convincingly demonstrated that platelets are capable of transferring their messenger RNA (mRNA) to other cell types, including monocytic and endothelial cells. It was shown that the recipient cell is capable of translating platelet-derived mRNA, which may have biologically relevant effects on the recipient cell. Platelet also contain microRNAs (miRNAs), and functional transfer of platelet miRNA to endothelial cells has recently been described. Here, we studied the fate of platelets during platelet-mediated stimulation of hepatocyte proliferation in vitro. We observed that platelets were internalized by hepatocytes. Based on our observation that platelets are, after internalization, directed toward the hepatocyte nucleus,we hypothesized that platelets deliver theirRNAcontent to the hepatocyte and that this RNA transfer contributes to platelet-mediated hepatocyte proliferation.