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Ton Lisman - One of the best experts on this subject based on the ideXlab platform.
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intrahepatic fibrin ogen deposition drives Liver Regeneration after partial hepatectomy in mice and humans
Blood, 2019Co-Authors: Dafna Groeneveld, David Pereyra, Zwanida J Veldhuis, Jelle Adelmeijer, Petra J Ottens, Anna K Kopec, Patrick Starlinger, Ton Lisman, James P LuyendykAbstract:Platelets play a pivotal role in stimulating Liver Regeneration after partial hepatectomy in rodents and humans. Liver Regeneration in rodents is delayed when platelets are inhibited. However, the exact mechanisms whereby platelets accumulate and promote Liver Regeneration remain uncertain. Thrombin-dependent intrahepatic fibrin(ogen) deposition was recently reported after partial hepatectomy (PHx) in mice, but the role of fibrin(ogen) deposits in Liver Regeneration has not been investigated. We tested the hypothesis that fibrin(ogen) contributes to Liver Regeneration by promoting intrahepatic platelet accumulation and identified the trigger of rapid intrahepatic coagulation after PHx. PHx in wild-type mice triggered rapid intrahepatic coagulation, evidenced by intrahepatic fibrin(ogen) deposition. Intrahepatic fibrin(ogen) deposition was abolished in mice with Liver-specific tissue factor deficiency, pinpointing the trigger of coagulation after PHx. Direct thrombin activation of platelets through protease-activated receptor-4 did not contribute to hepatocyte proliferation after PHx, indicating that thrombin contributes to Liver Regeneration primarily by driving intrahepatic fibrin(ogen) deposition. Fibrinogen depletion with ancrod reduced both intrahepatic platelet accumulation and hepatocyte proliferation after PHx, indicating that fibrin(ogen) contributes to Liver Regeneration after PHx by promoting intrahepatic platelet accumulation. Consistent with the protective function of fibrin(ogen) in mice, low postoperative plasma fibrinogen levels were associated with Liver dysfunction and mortality in patients undergoing Liver resection. Moreover, increased intrahepatic fibrin(ogen) deposition was evident in Livers of patients after Liver resection but was remarkably absent in patients displaying hepatic dysfunction postresection. The results suggest a novel mechanism whereby coagulation-dependent intrahepatic fibrin(ogen) deposition drives platelet accumulation and Liver Regeneration after PHx.
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transient von willebrand factor mediated platelet influx stimulates Liver Regeneration after partial hepatectomy in mice
Liver International, 2017Co-Authors: Marc Kirschbaum, Zwanida J Veldhuis, Craig N Jenne, Klaas A Sjollema, Peter J Lenting, Ben N G Giepmans, Robert J Porte, Paul Kubes, Cecile V Denis, Ton LismanAbstract:BACKGROUND & AIMS: In addition to their function in thrombosis and hemostasis, platelets play an important role in the stimulation of Liver Regeneration. It has been suggested that platelets deLiver mitogenic cargo to the regenerating Liver, and accumulation of platelets in the regenerating Liver has been demonstrated. We studied kinetics of platelet influx in the regenerating Liver and investigated the signal that initiates platelet influx. METHODS: We visualized platelets in the Liver remnant after partial hepatectomy in mice using intravital microscopy and assessed Liver Regeneration by examination of Liver/body weight ratio and the number of proliferating hepatocytes examined by immunohistochemistry. RESULTS: We demonstrated rapid but transient platelet influx into the Liver remnant after a partial Liver resection. Liver Regeneration in thrombocytopenic mice was substantially impaired as evidenced by a reduced Liver-to-body weight ratio and decreased numbers of proliferating hepatocytes at day 3 compared to mice with normal platelet counts. In contrast, Liver Regeneration was only mildly impaired when thrombocytopenia was induced 2 hours after partial Liver resection. Platelet influx into the Liver remnant was virtually absent in the presence of an antibody to von Willebrand factor (VWF) suggesting that VWF release from Liver sinusoidal endothelial cells mediates platelet influx. Additionally, Liver Regeneration in mice deficient in VWF was markedly impaired. CONCLUSIONS: A rapid but transient VWF-dependent platelet influx into the Liver remnant drives platelet-mediated Liver Regeneration. This article is protected by copyright. All rights reserved.
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evidence against a role for platelet derived molecules in Liver Regeneration after partial hepatectomy in humans
Journal of Clinical and Translational Research, 2016Co-Authors: Marc Kirschbaum, Jelle Adelmeijer, Robert J Porte, Edris M Alkozai, Ton LismanAbstract:Background and Aim: Blood platelets have been shown to stimulate Liver Regeneration after partial hepatectomy in animal models and humans, but the molecular mechanisms involved are unclear. It has been proposed that growth factors and angiogenic molecules stored within platelets drive platelet-mediated Liver Regeneration, but little direct evidence in support of this mechanism is available. Methods: We assessed levels of relevant platelet-derived proteins (vascular endothelial growth factor, hepatocyte growth factor, fibroblast growth factor, platelet-derived growth factor, thrombospondin, and endostatin) in platelet-rich and platelet-poor plasma taken at various perioperative time points from patients undergoing a (extended) right partial hepatectomy (n = 17) or a pylorus-preserving pancreatico-duodenectomy (n = 10). In addition, we collected intraoperative samples from the efferent and afferent Liver veins prior to and after completion of Liver resection. Twenty-four healthy controls were included to establish reference ranges for the various tests. Results and Conclusions: Although we demonstrate perioperative changes in platelet and plasma levels of the proteins assessed, the changes observed in patients undergoing partial hepatectomy largely mirror the changes observed in patients undergoing a pylorus-preserving pancreatico-duodenectomy. In addition, no change in the growth factor levels in platelet-rich plasma between afferent and efferent Liver veins was observed. Thus, the absence of an intra- or postoperative consumption of platelet-derived proteins in patients undergoing partial hepatectomy argues against a role of release of these molecules in stimulation of Liver Regeneration. Relevance for patients: In depth knowledge of the mechanism underlying platelet-mediated Liver Regeneration may facilitate development of targeted therapeutic interventions for patients with failing Liver Regeneration, which for example may occur following a partial hepatectomy. Although the prevailing dogma is that platelet stimulate Liver Regeneration by release of growth factors stored within platelets, data in this manuscript argue against this mechanism and suggest other pathways to be responsible.
Marc Kirschbaum - One of the best experts on this subject based on the ideXlab platform.
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transient von willebrand factor mediated platelet influx stimulates Liver Regeneration after partial hepatectomy in mice
Liver International, 2017Co-Authors: Marc Kirschbaum, Zwanida J Veldhuis, Craig N Jenne, Klaas A Sjollema, Peter J Lenting, Ben N G Giepmans, Robert J Porte, Paul Kubes, Cecile V Denis, Ton LismanAbstract:BACKGROUND & AIMS: In addition to their function in thrombosis and hemostasis, platelets play an important role in the stimulation of Liver Regeneration. It has been suggested that platelets deLiver mitogenic cargo to the regenerating Liver, and accumulation of platelets in the regenerating Liver has been demonstrated. We studied kinetics of platelet influx in the regenerating Liver and investigated the signal that initiates platelet influx. METHODS: We visualized platelets in the Liver remnant after partial hepatectomy in mice using intravital microscopy and assessed Liver Regeneration by examination of Liver/body weight ratio and the number of proliferating hepatocytes examined by immunohistochemistry. RESULTS: We demonstrated rapid but transient platelet influx into the Liver remnant after a partial Liver resection. Liver Regeneration in thrombocytopenic mice was substantially impaired as evidenced by a reduced Liver-to-body weight ratio and decreased numbers of proliferating hepatocytes at day 3 compared to mice with normal platelet counts. In contrast, Liver Regeneration was only mildly impaired when thrombocytopenia was induced 2 hours after partial Liver resection. Platelet influx into the Liver remnant was virtually absent in the presence of an antibody to von Willebrand factor (VWF) suggesting that VWF release from Liver sinusoidal endothelial cells mediates platelet influx. Additionally, Liver Regeneration in mice deficient in VWF was markedly impaired. CONCLUSIONS: A rapid but transient VWF-dependent platelet influx into the Liver remnant drives platelet-mediated Liver Regeneration. This article is protected by copyright. All rights reserved.
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evidence against a role for platelet derived molecules in Liver Regeneration after partial hepatectomy in humans
Journal of Clinical and Translational Research, 2016Co-Authors: Marc Kirschbaum, Jelle Adelmeijer, Robert J Porte, Edris M Alkozai, Ton LismanAbstract:Background and Aim: Blood platelets have been shown to stimulate Liver Regeneration after partial hepatectomy in animal models and humans, but the molecular mechanisms involved are unclear. It has been proposed that growth factors and angiogenic molecules stored within platelets drive platelet-mediated Liver Regeneration, but little direct evidence in support of this mechanism is available. Methods: We assessed levels of relevant platelet-derived proteins (vascular endothelial growth factor, hepatocyte growth factor, fibroblast growth factor, platelet-derived growth factor, thrombospondin, and endostatin) in platelet-rich and platelet-poor plasma taken at various perioperative time points from patients undergoing a (extended) right partial hepatectomy (n = 17) or a pylorus-preserving pancreatico-duodenectomy (n = 10). In addition, we collected intraoperative samples from the efferent and afferent Liver veins prior to and after completion of Liver resection. Twenty-four healthy controls were included to establish reference ranges for the various tests. Results and Conclusions: Although we demonstrate perioperative changes in platelet and plasma levels of the proteins assessed, the changes observed in patients undergoing partial hepatectomy largely mirror the changes observed in patients undergoing a pylorus-preserving pancreatico-duodenectomy. In addition, no change in the growth factor levels in platelet-rich plasma between afferent and efferent Liver veins was observed. Thus, the absence of an intra- or postoperative consumption of platelet-derived proteins in patients undergoing partial hepatectomy argues against a role of release of these molecules in stimulation of Liver Regeneration. Relevance for patients: In depth knowledge of the mechanism underlying platelet-mediated Liver Regeneration may facilitate development of targeted therapeutic interventions for patients with failing Liver Regeneration, which for example may occur following a partial hepatectomy. Although the prevailing dogma is that platelet stimulate Liver Regeneration by release of growth factors stored within platelets, data in this manuscript argue against this mechanism and suggest other pathways to be responsible.
Nobuhiro Ohkohchi - One of the best experts on this subject based on the ideXlab platform.
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platelet administration via the portal vein promotes Liver Regeneration in rats after 70 hepatectomy
Annals of Surgery, 2011Co-Authors: Ryota Matsuo, Yoritaka Nakano, Nobuhiro OhkohchiAbstract:Objective: This study examines the applicability of platelet infusion therapy for Liver Regeneration in vivo. Background: We recently reported that platelets accumulate in the Liver immediately after extended hepatectomy and promote residual Liver Regeneration. Liver Regeneration depends on the number of accumulated platelets in the sinusoids. Methods: Male Sprague-Dawley rats underwent 70% hepatectomy and were then assigned to groups that were infused with 1 mL of either platelet-rich plasma (PRP; 1 × 109 platelets/mL) in normal saline (NS) or NS via the portal vein. We then analyzed Liver Regeneration and the signaling pathways that are related to Liver Regeneration and function. The dynamics of platelets infused via the portal vein were visualized before and after hepatectomy. Results: The Liver/body weight ratio after 70% hepatectomy was significantly higher and the Ki-67 labeling index was higher in the PRP, than in the NS group. The Akt pathway was activated earlier in the PRP, than in the NS group with concurrent ERK1/2 pathway activation, but this was prolonged in the PRP group. Many more platelets infused via the portal vein accumulated in the sinusoid after 70% hepatectomy, and serum Liver function tests and histological findings revealed that portal infusion did not cause Liver damage. Conclusions: Platelets infused via the portal vein promoted Liver Regeneration after 70% hepatectomy in rats without Liver damage. These findings indicate that PRP administration could be a useful part of Liver Regeneration therapy.
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platelets promote Liver Regeneration under conditions of kupffer cell depletion after hepatectomy in mice
World Journal of Surgery, 2008Co-Authors: Soichiro Murata, Ryota Matsuo, Osamu Ikeda, Andriy Myronovych, Motonobu Watanabe, Katsuji Hisakura, Yoritaka Nakano, Ikuka Hashimoto, Nobuhiro OhkohchiAbstract:Platelets have been proven to promote Liver Regeneration after hepatectomy. Kupffer cells produce inflammatory cytokines and also promote Liver Regeneration. In the present study, we examined whether platelets promote Liver Regeneration after hepatectomy under conditions of Kupffer cell depletion. Seventy percent hepatectomy was carried out in mice, which were subsequently divided into four groups: (1) a normal group without any treatment, (2) a Kupffer cell depleted (KD) group, (3) a thrombocytotic group, and (4) a combined thrombocytotic and Kupffer cell depleted (TKD) group. Growth kinetics in the Liver Regeneration, growth factors, inflammatory cytokines, and signal transduction relating to hepatocyte proliferation were analyzed. In the KD group, Liver Regeneration was significantly delayed compared to the normal group 48 h after hepatectomy. On the other hand, Liver Regeneration of the TKD group increased significantly compared to KD group, to a level that was the same as that recorded in the normal group. In the thrombocytotic group, Liver Regeneration increased significantly compared to the normal group. Tumor necrosis factor alpha (TNF-α) expression was lower in the KD and TKD groups than in the normal group after hepatectomy, but, in the TKD group, hepatocyte growth factor and Akt phosphorylation were higher than in the normal and KD groups. After hepatectomy, Liver Regeneration in the Kupffer cell depleted group was delayed because of lower TNF-α expression. Platelets promote Liver Regeneration even under condition of Kupffer cell depletion by stimulating hepatocyte growth factor and insulin-like growth factor-1 expression, and they activate Akt.
Robert J Porte - One of the best experts on this subject based on the ideXlab platform.
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transient von willebrand factor mediated platelet influx stimulates Liver Regeneration after partial hepatectomy in mice
Liver International, 2017Co-Authors: Marc Kirschbaum, Zwanida J Veldhuis, Craig N Jenne, Klaas A Sjollema, Peter J Lenting, Ben N G Giepmans, Robert J Porte, Paul Kubes, Cecile V Denis, Ton LismanAbstract:BACKGROUND & AIMS: In addition to their function in thrombosis and hemostasis, platelets play an important role in the stimulation of Liver Regeneration. It has been suggested that platelets deLiver mitogenic cargo to the regenerating Liver, and accumulation of platelets in the regenerating Liver has been demonstrated. We studied kinetics of platelet influx in the regenerating Liver and investigated the signal that initiates platelet influx. METHODS: We visualized platelets in the Liver remnant after partial hepatectomy in mice using intravital microscopy and assessed Liver Regeneration by examination of Liver/body weight ratio and the number of proliferating hepatocytes examined by immunohistochemistry. RESULTS: We demonstrated rapid but transient platelet influx into the Liver remnant after a partial Liver resection. Liver Regeneration in thrombocytopenic mice was substantially impaired as evidenced by a reduced Liver-to-body weight ratio and decreased numbers of proliferating hepatocytes at day 3 compared to mice with normal platelet counts. In contrast, Liver Regeneration was only mildly impaired when thrombocytopenia was induced 2 hours after partial Liver resection. Platelet influx into the Liver remnant was virtually absent in the presence of an antibody to von Willebrand factor (VWF) suggesting that VWF release from Liver sinusoidal endothelial cells mediates platelet influx. Additionally, Liver Regeneration in mice deficient in VWF was markedly impaired. CONCLUSIONS: A rapid but transient VWF-dependent platelet influx into the Liver remnant drives platelet-mediated Liver Regeneration. This article is protected by copyright. All rights reserved.
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evidence against a role for platelet derived molecules in Liver Regeneration after partial hepatectomy in humans
Journal of Clinical and Translational Research, 2016Co-Authors: Marc Kirschbaum, Jelle Adelmeijer, Robert J Porte, Edris M Alkozai, Ton LismanAbstract:Background and Aim: Blood platelets have been shown to stimulate Liver Regeneration after partial hepatectomy in animal models and humans, but the molecular mechanisms involved are unclear. It has been proposed that growth factors and angiogenic molecules stored within platelets drive platelet-mediated Liver Regeneration, but little direct evidence in support of this mechanism is available. Methods: We assessed levels of relevant platelet-derived proteins (vascular endothelial growth factor, hepatocyte growth factor, fibroblast growth factor, platelet-derived growth factor, thrombospondin, and endostatin) in platelet-rich and platelet-poor plasma taken at various perioperative time points from patients undergoing a (extended) right partial hepatectomy (n = 17) or a pylorus-preserving pancreatico-duodenectomy (n = 10). In addition, we collected intraoperative samples from the efferent and afferent Liver veins prior to and after completion of Liver resection. Twenty-four healthy controls were included to establish reference ranges for the various tests. Results and Conclusions: Although we demonstrate perioperative changes in platelet and plasma levels of the proteins assessed, the changes observed in patients undergoing partial hepatectomy largely mirror the changes observed in patients undergoing a pylorus-preserving pancreatico-duodenectomy. In addition, no change in the growth factor levels in platelet-rich plasma between afferent and efferent Liver veins was observed. Thus, the absence of an intra- or postoperative consumption of platelet-derived proteins in patients undergoing partial hepatectomy argues against a role of release of these molecules in stimulation of Liver Regeneration. Relevance for patients: In depth knowledge of the mechanism underlying platelet-mediated Liver Regeneration may facilitate development of targeted therapeutic interventions for patients with failing Liver Regeneration, which for example may occur following a partial hepatectomy. Although the prevailing dogma is that platelet stimulate Liver Regeneration by release of growth factors stored within platelets, data in this manuscript argue against this mechanism and suggest other pathways to be responsible.
Peter G Schultz - One of the best experts on this subject based on the ideXlab platform.
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gene expression during the priming phase of Liver Regeneration after partial hepatectomy in mice
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Andrew I Su, Luca G Guidotti, John Paul Pezacki, Francis V Chisari, Peter G SchultzAbstract:Understanding the gene-expression patterns during Liver Regeneration may help to reveal how regenerative processes are initiated and controlled as well as shed new light onto processes that lead to Liver disease. Using high-density oligonucleotide arrays, we have examined the gene-expression program in the Livers of mice after partial hepatectomy. A time course was constructed for gene expression between 0 and 4 h after partial hepatectomy, corresponding to the priming phase of Liver Regeneration. The genomic program for Liver Regeneration involves transcription-factor generation, stress and inflammatory responses, cytoskeletal and extracellular matrix modification, and regulation of cell-cycle entry. The genome-wide changes that are observed provide a detailed and comprehensive map of the initial priming stage of Liver Regeneration.