Liver regeneration (LR) involves a complex interplay of growth factors and antagonists. In this context, platelet-derived serotonin (5-HT) has been identified as a critical inducer of LR in mice. Clinical evidence for a role of 5-HT in LR in humans is lacking. Accordingly, serum and plasma 5-HT was monitored perioperatively in 60 patients undergoing liver resection, of which 35 served as exploration and 25 as validation sets. Intraplatelet (IP) levels of 5-HT were calculated by subtraction of plasma 5-HT from serum values. Serum markers of liver function were used to evaluate LR and liver dysfunction (LD). In the exploration setting, IP 5-HT levels significantly decreased after liver resection (P < 0.001) and gradually recovered during the first week. IP 5-HT measured before surgery specifically predicted LD in the subsequent 7 days (area under the curve: 0.721; P 5 0.029). Patients suffering from postoperative LD and morbidity were found to have reduced IP 5-HT levels during the entire perioperative period. Furthermore, we validated that reduced preoperative IP 5-HT (<73 ng/mL) was associated with an increased incidence of postoperative LD and morbidity (P 50.045 and P 5 0.021) and were able to demonstrate that IP 5-HT levels were an independent predictor of poor clinical outcome. Conclusions: These findings provide evidence that IP 5-HT correlates with LR in humans: Patients with low IP 5-HT before liver resection suffered from delayed hepatic regeneration. Therefore, IP 5-HT levels may prove a helpful clinical marker to predict postoperative LD and clinical outcome before hepatic resection and initiate suitable interventions. (HEPATOLOGY 2014;60:257-266)

Platelets promote liver regeneration through site-specific serotonin release from dense granules, triggering proliferative signaling in hepatocytes. However, the effects of factors derived from platelet a-granules on liver regeneration are unclear, because a-granules contain bioactive molecules with opposing functions. Because a-granule molecules are stored in separate compartments, it has been suggested that platelets selectively release their a-granule content dependent on the environmental stimulus. Therefore, we investigated the pattern of circulating a-granule molecules during liver regeneration in 157 patients undergoing partial hepatectomy. We measured plasma levels of a-granule-derived factors in the liver vein at the end of liver resection, as well as on the first postoperative day. We observed a rapid accumulation of platelets within the liver after induction of liver regeneration. Platelet count and P-selectin (a ubiquitous cargo of a-granules) were not associated with postoperative liver dysfunction. However, low plasma levels of vascular endothelial growth factor (VEGF), but high levels of thrombospondin 1 (TSP-1), predicted liver dysfunction after resection. Patients with an unfavorable postoperative a-granule release profile (high TSP-1/low VEGF) showed substantially worse postoperative clinical outcomes. The unfavorable postoperative a-granule release profile was associated with increased postoperative portal venous pressure and von Willebrand factor antigen levels as a marker for intrahepatic endothelial dysfunction. Conclusion: The postoperative profile of circulating platelet-derived factors correlates with the ability of the remnant liver to regenerate. Portal venous pressure and intrahepatic endothelial dysfunction might account for the selective granule release profile. Selective modulation of platelet a-granule release in patients may represent an attractive target for therapeutic interventions to improve liver regeneration and clinical outcomes after partial hepatectomy. (HEPATOLOGY 2016;63:1675-1688 P latelets are critically involved not only in hemostasis, but also in inflammation, wound healing and angiogenesis. Through release of their granule content, they orchestrate signal responses in a plethora of target cells, including hepatocytes. Platelets are potent inducers of liver regeneration (LR) after partial hepatectomy and platelet activation as well as granule release increase after liver resection.(1,2) Platelet activation results in the release of dense granules, followed by secretion of a-granule content.(3) Exocytosis of a-granules represents a highly regulated process, involving distinct packaging

Paracrine signalling mediated by cytokine secretion is essential for liver regeneration after hepatic resection, yet the mechanisms of cellular crosstalk between immune and parenchymal cells are still elusive. is released by immune cells and mediates strong hepatoprotective functions. However, it remains unclear whether IL-22 is critical for the crosstalk between liver lymphocytes and parenchymal cells during liver regeneration after partial hepatectomy (PH). Here, we found that plasma levels of IL-22 and its upstream cytokine, IL-23, are highly elevated in patients after major liver resection. In a mouse model of PH, deletion of IL-22 was associated with significantly delayed hepatocellular proliferation and an increase of hepatocellular injury and endoplasmic reticulum stress. Using Rag1 2/2 and Rag2 2/2 cc 2/2 mice, we show that the main producers of IL-22 post-PH are conventional natural killer cells and innate lymphoid cells type 1. Extracellular adenosine triphosphate (ATP), a potent danger molecule, is elevated in patients immediately after major liver resection. Antagonism of the P2-type nucleotide receptors, P2X1 and P2Y6, significantly decreased IL-22 secretion ex vivo. In vivo, specific inhibition of P2X1 was associated with decreased IL-22 secretion, elevated liver injury, and impaired liver regeneration. Conclusion: This study shows that innate immune cell-derived IL-22 is required for efficient liver regeneration and that secretion of IL-22 in the regenerating liver is modulated by the ATP receptor, P2X1. (HEPATOLOGY 2016;63:2004-2017 C ellular crosstalk, including secretion of cytokines and paracrine signaling via dangerassociated molecular patterns, is essential for liver regeneration after hepatic resection. The cytokine, interleukin-22 (IL-22), is released by immune cells and acts primarily on nonhematopoietic cells, such as epithelial cells, unlike most other cytokines, which target hematopoietic cells.(1) In the liver, IL-22 acts on hepatocytes and stellate cells and exhibits hepatoprotective properties by reducing liver fibrosis and ameliorating acute liver injury. (2)(3)(4)(5) In response to partial hepatectomy (PH), levels of IL-22 are elevated in the regenerating liver and exogenous administration of IL-22 as well as transgenic (Tg) expression is associated with improved outcome.(5) Yet, it remains unclear what the source and triggering factors of