- freely available
Int. J. Mol. Sci. 2014, 15(4), 5412-5425; doi:10.3390/ijms15045412
Published: 28 March 2014
Abstract: Platelets contain three types of granules: alpha granules, dense granules, and lysosomal granules. Each granule contains various growth factors, cytokines, and other physiological substances. Platelets trigger many kinds of biological responses, such as hemostasis, wound healing, and tissue regeneration. This review presents experimental evidence of platelets in accelerating liver regeneration and improving liver fibrosis. The regenerative effect of liver by platelets consists of three mechanisms; i.e., the direct effect on hepatocytes, the cooperative effect with liver sinusoidal endothelial cells, and the collaborative effect with Kupffer cells. Many signal transduction pathways are involved in hepatocyte proliferation. One is activation of Akt and extracellular signal-regulated kinase (ERK)1/2, which are derived from direct stimulation from growth factors in platelets. The other is signal transducer and activator of transcription-3 (STAT3) activation by interleukin (IL)-6 derived from liver sinusoidal endothelial cells and Kupffer cells, which are stimulated by contact with platelets during liver regeneration. Platelets also improve liver fibrosis in rodent models by inactivating hepatic stellate cells to decrease collagen production. The level of intracellular cyclic adenosine monophosphate (cyclic AMP) is increased by adenosine through its receptors on hepatic stellate cells, resulting in inactivation of these cells. Adenosine is produced by the degradation of adenine nucleotides such as adenosine diphosphate (ADP) and adenosine tri-phosphate (ATP), which are stored in abundance within the dense granules of platelets.
1. Introduction: Cirrhosis
Cirrhosis is a serious and life-threatening major health problem worldwide. It is an advanced form of hepatic fibrosis in response to chronic liver injury . Up to 64% of patients with cirrhosis suffer thrombocytopenia [2–5]. Patients with thrombocytopenia sometimes cannot receive antiviral therapy with sufficient doses of interferon for hepatitis virus or curative surgery for hepatocellular carcinoma. When standard therapy has failed to control cirrhosis, liver transplantation is the only effective therapy . Unfortunately, liver transplantation is associated with donor shortage, surgical complications, organ rejection, and high cost [7–11]. Patients are often required to wait for many years for liver transplantation because of the shortage of donor organs, and some of them die while waiting. Therefore, alternative treatments are required to treat patients with cirrhosis. Treatment of cirrhosis consists of anti-inflammation, liver regeneration, and improvement of fibrosis. Each of these present very challenging problems in the clinical settings and no clear solutions have been found yet.
Platelets are derived from megakaryocytes (MKs). Megakaryocytes are derived from multipotent hematopoietic stem cells toward MK progenitors. Mature MK produces platelets by cytoplasmic fragmentation occurring through a dynamic and regulated process, called proplatelet formation, and consisting of long pseudopodial elongations that break in the blood flow . Platelets are discoid and have anucleate structures that contain a large number of secretary granules . Three types of secretary granules are recognized: alpha granules, dense granules, and lysosomal granules. Each granule contains secretory substances, such as platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), serotonin, adenosine diphosphate (ADP), adenosine tri-phosphate (ATP), epidermal growth factor (EGF), and transforming growth factor-β (TGF-β), etc. [13–16]. Platelets are activated by various types of stimulation and release active substances from the granules [13–19]. Several positive effects have been reported, such as hemostasis , wound healing [20–23], and tissue regeneration [24–29]. On the other hand, there are some negative effects of platelet degranulation, such as inflammation , malignancy [31,32], and immune response [33–36]. Platelets are reported to accumulate in the liver under pathological conditions such as ischemia/reperfusion [37–40], liver cirrhosis , cholestasis , viral hepatitis , and the residual liver after hepatectomy .
3. Platelets and Liver Regeneration
The proliferative effect of platelets in liver regeneration was first reported in 2006 by Lesurtel et al., who suggested platelet serotonin is important for liver regeneration . Our first study focused on liver regeneration under thrombocytotic conditions induced by thrombopoietin (TPO) . TPO is a growth factor that regulates the development of MK and platelet production . c-Mpl is a TPO receptor, and several novel agents that stimulate human c-Mpl and increase platelet levels, such as eltrombopag and romiplostim, are used for the treatment of chronic immune thrombocytopenia [46,47]. We used 0.5 μg of pegylated recombinant human MK growth and development factor (PEG-rHuMGDF) donated by Kirin Brewery Co. (Takasaki, Japan) as TPO . TPO was administered intraperitoneally five days before hepatectomy, which increases the peripheral platelet count two to three-fold over the pre-administration state in mice . Thrombocytotic conditions promote liver regeneration including the liver/total body weight ratio, hepatocyte Ki-67 labeling index and mitotic index [44,48], and improve the survival rates after 90% hepatectomy of mice . A significant increase in the hepatic concentrations of HGF and IGF-1 and early and strong phosphorylation of Akt and signal transducer and activator of transcription-3 (STAT3) are induced under thrombocytotic conditions [44,48]. Platelet-rich plasma transfusion was performed after partial hepatectomy, and liver regeneration was accelerated . These findings indicate that exogenous platelets also have an impact on liver regeneration through the early initiation of hepatocyte cell cycles after hepatectomy. The effect of TPO administration on liver regeneration under cirrhotic liver and its anti-fibrosis effects were evaluated after partial hepatectomy . TPO increased peripheral platelets and promoted liver regeneration, including increasing the hepatocyte-proliferating cell nuclear antigen (PCNA) labeling index and mitotic index in the cirrhotic liver, and improved fibrosis in the peri-portal regions . The proliferative effect on acute liver damage after hepatectomy by increasing platelets in a pig model was reported . Cholestasis, ballooning, and necrosis in the liver are decreased under thrombocytotic conditions and serum aspartate amino transferase and alkaline phosphatase levels are low after extended hepatectomy . Transmission microscopy revealed that the structure of the endothelial lining is well preserved in comparison with the structure observed with a normal platelet count . The increased number of platelets protects the sinusoidal lining and prevents acute liver damage after extended hepatectomy. Platelets also protect against Fas-mediated apoptosis of hepatocytes in murine acute hepatitis model induced by anti-Fas antibody . Platelets induce immediate activation of the Akt pathway, followed by an increase of B-cell lymphoma-extra large (BCl-xL) and a decrease of cleaved caspase-3 in hepatocytes .
4. Signal Transduction of Liver Regeneration by Platelets
In vivo: platelets accumulate in the liver immediately after hepatectomy. Under normal conditions, liver sinusoidal cavities show intact endothelial lining consisting of liver endothelial cells with flattened processes perforated by small pores . These small pores are reported to quickly enlarge within 10 min after hepatectomy [54,55]. In response to lipopolysaccharide administration, interleukin-1 or tumor necrosis factor, platelets accumulate in the liver sinusoidal space within a few minutes, stimulated by a different mechanism of aggregation, and large numbers of platelets are found in the space of Disse and even inside some hepatocytes [56–58]. In our study, platelet accumulation in the liver was observed in thrombocytotic groups in the early period after hepatectomy. In addition, platelets translocated into the space of Disse and had direct contact with hepatocytes 5 min after hepatectomy in the thrombocytosis group, which could be observed by transmission electron microscopy . Platelets are translocated from the liver sinusoids to the space of Disse, and growth factors such as HGF, IGF-1, and VEGF could be released through direct contact between platelets and hepatocytes (Figure 1). These soluble mediators lead to hepatocyte proliferation. Human platelets are reported to have a very limited amount of HGF , thus IGF-1 is considered to be the most important mediator for liver regeneration in human platelets. The Akt and ERK1/2 pathways in whole liver extracts are activated immediately after hepatectomy in thrombocytotic mice, compared with thrombocytopenic mice .
In vitro: the signal transduction of hepatocytes, which is activated by platelets, was analyzed. The phosphorylation of Akt and extracellular signal-regulated kinase (ERK)1/2 were analyzed in murine immortalized hepatocyte TLR2 and primary cultured murine hepatocytes stimulated by platelets . The Akt pathway and ERK1/2 pathway are activated within 10 min after adding platelets into the culture medium of hepatocyte in vitro . The Akt pathway, which is activated by growth factors, is known as a survival signaling pathway [61,62]. The ERK1/2 pathway, which is also activated by growth factors, is involved in growth and differentiation .
Liver sinusoidal endothelial cells (LSECs) enable contact between circulating blood and hepatocytes and help to exchange various soluble macromolecules and nano-particles, such as hyaluronic acid and lipoproteins . LSECs are known to produce growth factors, such as HGF and VEGF and pro-inflammatory cytokine interleukin (IL)-6 and promote liver regeneration after hepatectomy. Elevation of IL-6 concentration after hepatectomy activates the acute phase of protein synthesis by hepatocytes . IL-6 binds to the receptor on hepatocytes, which leads to phosphorylate STAT3 monomers. The relationship between platelets and LSECs is addressed in ischemia/reperfusion models [65,66], but there have been very few previous studies that focused on the relationship between platelets and LSECs during liver regeneration before our study . The role of platelets in liver regeneration in relation to LSECs was evaluated by co-culturing chamber systems in vitro. This study revealed that direct contact between platelets and LSECs induce IL-6 release from LSECs, and IL-6 derived from LSECs accelerates hepatocyte proliferation. In addition, sphingosine-1-phosphate (S1P) in platelets plays an important role in IL-6 secretion  (Figure 1). S1P is a lipid mediator that regulates many kinds of biological processes including proliferation, migration, and cytoskeletal reorganization . S1P is excreted from activated platelets and interacts with endothelial cells under the conditions of thrombosis, angiogenesis, atherosclerosis, and liver regeneration [67–69]. Zheng et al. revealed that S1P protects LSECs from alcohol-induced apoptosis via activation of eNOS . Isabel Fernández-Pisonero et al. revealed that S1P combined with lipopolysaccharide (LPS) activates human umbilical endothelial cells (HUVECs), famous endothelial cells, via NF-κB, ERK1/2, and p38 and activated HUVECs secrete IL-6 .
Kupffer cells play a role in the liver as resident macrophages that protect the liver from bacteria, endotoxins, and microbial debris derived from the gastrointestinal tract . Kupffer cells produce important cytokines that enable hepatocyte proliferation after hepatectomy . One of the most important events after hepatectomy is an increase in the plasma levels of tumor necrosis factor (TNF)-α. An experiment using an antibody against TNF-α demonstrated a significant reduction of hepatocyte proliferation , and mice lacking the TNF-α receptor showed severe impairment in liver regeneration after hepatectomy [75,76]. The activation of the TNF-α receptor increases hepatic expression of the NF-κB in both hepatocytes and non-parenchymal cells, and is followed by production and release of IL-6 from Kupffer cells . Kupffer cells are considered to be the most important source of both TNF-α and IL-6. Kupffer cell-depleted mice fail to increase TNF-α and IL-6 levels that are equivalent to the level in mice with Kupffer cells after hepatectomy . The collaborative effect of platelets with Kupffer cells on liver regeneration is thought to occur after hepatectomy, when activated Kupffer cells induce accumulation and activation of platelets in the liver, and the functions of Kupffer cells are enhanced by the accumulated platelets. Liver regeneration is promoted by the direct effect of growth factors released from platelets and by the paracrine effect of Kupffer cells enhanced by the platelets  (Figure 1).
5. Effect of Platelets and Thrombopoietin Receptor Agonist in Liver Cirrhosis
As mentioned previously, several novel agents that stimulate human c-Mpl and increase platelet levels, such as eltrombopag and romiplostim, are used for the treatment of chronic immune thrombocytopenia [46,47]. These agents are currently in development for the treatment of thrombocytopenia in patients with chronic liver disease and liver cirrhosis [80–82]. The ability to increase platelet count could facilitate the use of interferon-based antiviral therapy and other treatments for liver disease [3,83].
It was reported that the increment of platelets induced by TPO administration could improve liver fibrosis in experimental studies with rodents [51,84]. Dimetylnitrosamine was administered three times a week for three weeks to induce liver fibrosis in rats. Five days after administrating TPO intravenously, 70% hepatectomy was performed and liver fibrosis was compared 24 h after hepatectomy. The increase of platelets inhibited the activation of hepatic stellate cell (HSC) and reduced the fibrotic area of the cirrhotic liver, and these effects were diminished by administration of antiplatelet serum . Carbon tetrachloride (CCL4) was administered twice a week for eight weeks to induce liver fibrosis in mice. TPO was administered intraperitoneally once a week from five to eight weeks during the experiment . By administering TPO, liver fibrosis was decreased . Although the precise mechanisms between the increment of platelets and the liver anti-fibrotic effect are still unclear, one reason may be that platelets enhanced the expression of HGF by about 14% , whereas the matrix metalloproteinase 9 (MMP9) was enhanced by about three times, thereby stimulating fibrolysis, and decreased pro-fibrotic growth factor TGF-β . MMPs such as MMP-8, MMP-9, and MMP-13 possess the ability to degrade the extracellular matrix by breakdown of collagen type I [85–87]. MMP-9 may indirectly contribute to fibrolysis by accelerating HSC apoptosis . In murine bile duct ligation model, thrombocytopenia exacerbates liver fibrosis, and platelets have anti fibrotic role in suppressing type I collagen expression via the HGF–Met signaling pathway . Recently, Takahashi et al. reported that transfused human platelets improved liver fibrosis of severe combined immune deficiency (SCID) mice induced by CCL4 . An increase of murine HGF and a decrease of TGF-β were observed in the liver .
Based on these animal experiments, clinical trial was performed. Maruyama et al. recently reported the clinical trial to investigate whether platelet transfusion improves liver function in patients with chronic liver disease and cirrhosis (Child-Pugh class A or B), who all presented thrombocytopenia (platelet counts between 50,000 and 100,000/μL). The subjects received 10 units of platelet concentrate once a week for 12 weeks. One and three months after the last transfusion, significant improvement of serum albumin was observed. Serum cholinesterase improved for nine months after the last transfusion. Serum hyaluronic acid represents liver fibrosis, and that showed a tendency toward improvement after the last transfusion .
6. Signal Transduction of Liver Fibrolysis Induced by Platelets and Thrombopoietin (TPO)
In the long-term natural history of chronic liver injury, such as viral infection, alcohol, and non-alcoholic steatohepatitis, liver fibrosis occurs. Liver fibrosis is known to be part of a dynamic process of continuous extracellular matrix (ECM) remodeling, which leads to the excessive accumulation of several extracellular proteins, proteoglycans, and carbohydrates . Among the cellular populations in the liver, HSCs are reported to have the most involvement in liver fibrosis through the production of large amounts of ECM and the secretion of TGF-β, which appears to be a key mediator of liver fibrosis [93–95]. In the response to liver injury, HSCs are activated to convert from vitamin A storing star-like cells into contractile myofibroblastic cells . Recently, Ikeda et al. reported that human platelets contributed to the suppression of HSC activation and reduction of type I collagen production in vitro . The level of intracellular cyclic adenosine monophosphate (cyclic AMP) is increased by adenosine through its receptors on HSCs, and intracellular cyclic AMP is related to the inactivation of HSCs (Figure 2). Large amounts of adenosine around HSCs are produced by the degradation of adenine nucleotides such as ADP and ATP, which are stored in abundance within the dense granules of platelets. It is possible to say that activated HSCs are inactivated by adenosine and have a decreased ability to produce TGF-β and secrete ECM  (Figure 2). In rodents, platelet-derived HGF suppresses TGF-β and type I collagen gene expression in cultured HSCs  (Figure 2). These findings indicate that platelets suppress liver fibrosis by inactivating HSC.
This review discussed previous evidence of platelets promoting liver regeneration and improving liver fibrosis. There are three different mechanisms of liver regeneration induced by platelets: (i) direct effect on hepatocytes; (ii) a cooperative effect with LSECs; and (iii) a cooperation with Kupffer cells. There is significant evidence that platelets play a role in improving fibrosis. ATP and ADP inside platelets are degraded by HSCs and adenosine is incorporated into HSCs. Cyclic AMP is increased by adenosine and HSCs become inactivated by cyclic AMP. Therefore, platelet therapy, i.e., platelet transfusion and TPO receptor agonist administration would open a new avenue to develop novel strategies for the treatment of liver diseases for which there is currently no effective treatment except transplantation.
This review article is based on works supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT).
Conflicts of Interest
The authors who have taken part in this study declare that they do not have anything to disclose regarding funding or conflicts of interest with respect to this manuscript.
- Author ContributionsSoichiro Murata wrote this manuscript. Takehito Maruyama, Takeshi Nowatari and Kazuhiro Takahashi performed some of the experiments and participated in a discussion. Nobuhiro Ohkohchi supervised this manuscript.
- Popper, H. Pathologic aspects of cirrhosis. A review. Am. J. Pathol 1977, 87, 228–264. [Google Scholar]
- Poordad, F. Review article: Thrombocytopenia in chronic liver disease. Aliment. Pharmacol. Ther 2007, 26, S5–S11. [Google Scholar]
- Afdhal, N.; McHutchison, J.; Brown, R.; Jacobson, I.; Manns, M.; Poordad, F.; Weksler, B.; Esteban, R. Thrombocytopenia associated with chronic liver disease. J. Hepatol 2008, 48, 1000–1007. [Google Scholar]
- Witters, P.; Freson, K.; Verslype, C.; Peerlinck, K.; Hoylaerts, M.; Nevens, F.; van Geet, C.; Cassiman, D. Review article: Blood platelet number and function in chronic liver disease and cirrhosis. Aliment. Pharmacol. Ther 2008, 27, 1017–1029. [Google Scholar]
- Bashour, F.N.; Teran, J.C.; Mullen, K.D. Prevalence of peripheral blood cytopenias (hypersplenism) in patients with nonalcoholic chronic liver disease. Am. J. Gastroenterol 2000, 95, 2936–2939. [Google Scholar]
- Merion, R.M.; Schaubel, D.E.; Dykstra, D.M.; Freeman, R.B.; Port, F.K.; Wolfe, R.A. The survival benefit of liver transplantation. Am. J. Transplant 2005, 5, 307–313. [Google Scholar]
- Neuberger, J.; James, O. Guidelines for selection of patients for liver transplantation in the era of donor-organ shortage. Lancet 1999, 354, 1636–1639. [Google Scholar]
- Guarrera, J.V.; Emond, J.C. Advances in segmental liver transplantation: Can we solve the donor shortage? Transplant. Proc 2001, 33, 3451–3455. [Google Scholar]
- Taylor, M.C.; Grieg, P.D.; Detsky, A.S.; McLeod, R.S.; Abdoh, A.; Krahn, M.D. Factors associated with the high cost of liver transplantation in adults. Can. J. Surg 2002, 45, 425–434. [Google Scholar]
- Mueller, A.R.; Platz, K.P.; Kremer, B. Early postoperative complications following liver transplantation. Best Pract. Res. Clin. Gastroenterol 2004, 18, 881–900. [Google Scholar]
- Porrett, P.M.; Hsu, J.; Shaked, A. Late surgical complications following liver transplantation. Liver Transplant 2009, 15, S12–S18. [Google Scholar]
- Chang, Y.; Bluteau, D.; Debili, N.; Vainchenker, W. From hematopoietic stem cells to platelets. J. Thromb. Haemost 2007, 5, S318–S327. [Google Scholar]
- Suzuki, H.; Yamazaki, H.; Tanoue, K. Immunocytochemical aspects of platelet adhesive proteins and membrane glycoproteins during activation. Prog. Histochem. Cytochem 1996, 30, 1–106. [Google Scholar]
- Blair, P.; Flaumenhaft, R. Platelet α-granules: Basic biology and clinical correlates. Blood Rev 2009, 23, 177–189. [Google Scholar]
- McNicol, A.; Israels, S.J. Platelet dense granules: Structure, function and implications for haemostasis. Thromb. Res 1999, 95, 1–18. [Google Scholar]
- Polasek, J. Platelet secretory granules or secretory lysosomes? Platelets 2005, 16, 500–501. [Google Scholar]
- Holmsen, H. Physiological functions of platelets. Ann. Med 1989, 21, 23–30. [Google Scholar]
- Broos, K.; Feys, H.B.; de Meyer, S.F.; Vanhoorelbeke, K.; Deckmyn, H. Platelets at work in primary hemostasis. Blood Rev 2011, 25, 155–167. [Google Scholar]
- Suzuki, H.; Nakamura, S.; Itoh, Y.; Tanaka, T.; Yamazaki, H.; Tanoue, K. Immunocytochemical evidence for the translocation of alpha granule membrane glycoprotein IIb/IIIa (integrin alpha IIb beta 3) of human platelets to the surface membrane during the release reaction. Histochemistry 1992, 97, 381–388. [Google Scholar]
- Mazzucco, L.; Borzini, P.; Gope, R. Platelet-derived factors involved in tissue repair-from signal to function. Transfus. Med. Rev 2010, 24, 218–234. [Google Scholar]
- Ranzato, E.; Balbo, V.; Boccafoschi, F.; Mazzucco, L.; Burlando, B. Scratch wound closure of C2C12 mouse myoblasts is enhanced by human platelet lysate. Cell Biol. Int 2009, 33, 911–917. [Google Scholar]
- Rozman, P.; Bolta, Z. Use of platelet growth factors in treating wounds and soft-tissue injuries. Acta Dermatovenerol. Alp. Panon. Adriat 2007, 16, 156–165. [Google Scholar]
- Yamaguchi, R.; Terashima, H.; Yoneyama, S.; Tadano, S.; Ohkohchi, N. Effects of platelet-rich plasma on intestinal anastomotic healing in rats: PRP concentration is a key factor. J. Surg. Res 2012, 173, 258–266. [Google Scholar]
- Radice, F.; Yánez, R.; Gutiérrez, V.; Rosales, J.; Pinedo, M.; Coda, S. Comparison of magnetic resonance imaging findings in anterior cruciate ligament grafts with and without autologous platelet derived growth factors. Arthroscopy 2010, 26, 50–57. [Google Scholar]
- Dugrillon, A.; Eichler, H.; Kern, S.; Klüter, H. Autologous concentrated platelet-rich plasma (cPRP) for local application in bone regeneration. Int. J. Oral Maxillofac. Surg 2002, 31, 615–619. [Google Scholar]
- Hartmann, E.K.; Heintel, T.; Morrison, R.H.; Weckbach, A. Influence of platelet-rich plasma on the anterior fusion in spinal injuries: A qualitative and quantitative analysis using computer tomography. Arch. Orthop. Trauma Surg 2010, 130, 909–914. [Google Scholar]
- De Vos, R.J.; Weir, A.; van Schie, H.T.; Bierma-Zeinstra, S.M.; Verhaar, J.A.; Weinans, H.; Tol, J.L. Platelet-rich plasma injection for chronic Achilles tendinopathy: A randomized controlled trial. JAMA 2010, 303, 144–149. [Google Scholar]
- Rodeo, S.A.; Delos, D.; Weber, A.; Ju, X.; Cunningham, M.E.; Fortier, L.; Maher, S. What’s new in orthopaedic research. J. Bone Jt. Surg. Am 2010, 92, 2491–2501. [Google Scholar]
- Nocito, A.; Georgiev, P.; Dahm, F.; Jochum, W.; Bader, M.; Graf, R.; Clavien, P.A. Platelets and platelet-derived serotonin promote tissue repair after normothermic hepatic ischemia in mice. Hepatology 2007, 45, 369–376. [Google Scholar]
- McNicol, A.; Israels, S.J. Beyond hemostasis: The role of platelets in inflammation, malignancy and infection. Cardiovasc. Hematol. Disord. Drug Targets 2008, 8, 99–117. [Google Scholar]
- Mehta, P. Potential role of platelets in the pathogenesis of tumor metastasis. Blood 1984, 63, 55–63. [Google Scholar]
- Nash, G.F.; Turner, L.F.; Scully, M.F.; Kakkar, A.K. Platelets and cancer. Lancet Oncol 2002, 3, 425–430. [Google Scholar]
- Elzey, B.D.; Sprague, D.L.; Ratliff, T.L. The emerging role of platelets in adaptive immunity. Cell. Immunol 2005, 238, 1–9. [Google Scholar]
- Sowa, J.M.; Crist, S.A.; Ratliff, T.L.; Elzey, B.D. Platelet influence on T- and B-cell responses. Arch. Immunol. Ther. Exp 2009, 57, 235–241. [Google Scholar]
- Klinger, M.H.; Jelkmann, W. Role of blood platelets in infection and inflammation. J. Interf. Cytokine Res 2002, 22, 913–922. [Google Scholar]
- Sprague, D.L.; Elzey, B.D.; Crist, S.A.; Waldschmidt, T.J.; Jensen, R.J.; Ratliff, T.L. Platelet-mediated modulation of adaptive immunity: Unique delivery of CD154 signal by platelet-derived membrane vesicles. Blood 2008, 111, 5028–5036. [Google Scholar]
- Khandoga, A.; Hanschen, M.; Kessler, J.S.; Krombach, F. CD4+ T cells contribute to postischemic liver injury in mice by interacting with sinusoidal endothelium and platelets. Hepatology 2006, 43, 306–315. [Google Scholar]
- Khandoga, A.; Biberthaler, P.; Messmer, K.; Krombach, F. Platelet-endothelial cell interactions during hepatic ischemia-reperfusion in vivo: A systematic analysis. Microvasc. Res 2003, 65, 71–77. [Google Scholar]
- Pak, S.; Kondo, T.; Nakano, Y.; Murata, S.; Fukunaga, K.; Oda, T.; Sasaki, R.; Ohkohchi, N. Platelet adhesion in the sinusoid caused hepatic injury by neutrophils after hepatic ischemia reperfusion. Platelets 2010, 21, 282–288. [Google Scholar]
- Nakano, Y.; Kondo, T.; Matsuo, R.; Hashimoto, I.; Kawasaki, T.; Kohno, K.; Myronovych, A.; Tadano, S.; Hisakura, K.; Ikeda, O.; et al. Platelet dynamics in the early phase of postischemic liver in vivo. J. Surg. Res. 2008, 149, 192–198. [Google Scholar]
- Zaldivar, M.M.; Pauels, K.; von Hundelshausen, P.; Berres, M.L.; Schmitz, P.; Bornemann, J.; Kowalska, M.A.; Gassler, N.; Streetz, K.L.; Weiskirchen, R.; et al. CXC chemokine ligand 4 (Cxcl4) is a platelet-derived mediator of experimental liver fibrosis. Hepatology 2010, 51, 1345–1353. [Google Scholar]
- Laschke, M.W.; Dold, S.; Menger, M.D.; Jeppsson, B.; Thoelacius, H. Platelet-dependent accumulation of leukocytes in sinusoids mediates hepatocellular damage in bile duct ligation-induced cholestasis. Br. J. Pharmacol 2008, 153, 148–156. [Google Scholar]
- Lang, P.A.; Contalado, C.; Gergiev, P.; El-Bardy, A.M.; Recher, M.; Kurrer, M.; Cervantes-Barragan, L.; Ludewig, B.; Calzascia, T.; Bolinger, B.; et al. Aggravation of viral hepatitis by platelet-derived serotonin. Nat. Med 2008, 14, 756–761. [Google Scholar]
- Murata, S.; Ohkohchi, N.; Matsuo, R.; Ikeda, O.; Myronovych, A.; Hoshi, R. Platelets promote liver regeneration in early period after hepatectomy in mice. World J. Surg 2007, 31, 808–816. [Google Scholar]
- Lesurtel, M.; Graf, R.; Aleil, B.; Walther, D.J.; Tian, Y.; Jochum, W.; Gachet, C.; Bader, M.; Clavien, P.A. Platelet-derived serotonin mediates liver regeneration. Science 2006, 312, 104–107. [Google Scholar]
- Wolber, E.M.; Jelkmann, W. Thrombopoietin: The novel hepatic hormone. News Physiol. Sci 2002, 17, 6–10. [Google Scholar]
- Cheng, G. Eltrombopag, a thrombopoietin-receptor agonist in the treatment of adult chronic immune thrombocytopenia: A review of the efficacy and safety profile. Ther. Adv. Hematol 2012, 3, 155–164. [Google Scholar]
- Murata, S.; Matsuo, R.; Ikeda, O.; Myronovych, A.; Watanabe, M.; Hisakura, K.; Nakano, Y.; Hashimoto, I.; Ohkohchi, N. Platelets promote liver regeneration under conditions of kupffer cell depletion after hepatectomy in mice. World J. Surg 2008, 32, 1088–1096. [Google Scholar]
- Myronovych, A.; Murata, S.; Chiba, M.; Matsuo, R.; Ikeda, O.; Watanabe, M.; Hisakura, K.; Nakano, Y.; Kohno, K.; Kawasaki, T.; et al. Role of platelets on liver regeneration after 90% hepatectomy in mice. J. Hepatol 2008, 49, 363–372. [Google Scholar]
- Matsuo, R.; Nakano, Y.; Ohkohchi, N. Platelet administration via the portal vein promotes liver regeneration in rats after 70% hepatectomy. Ann. Surg 2011, 253, 759–763. [Google Scholar]
- Murata, S.; Hashimoto, I.; Nakano, Y.; Myronovych, A.; Watanabe, M.; Ohkohchi, N. Single administration of thrombopoietin prevents progression of liver fibrosis and promotes liver regeneration after partial hepatectomy in cirrhotic rats. Ann. Surg 2008, 248, 821–828. [Google Scholar]
- Hisakura, K.; Murata, S.; Fukunaga, K.; Myronovych, A.; Tadano, S.; Kawasaki, T.; Kohno, K.; Kobayashi, E.; Saito, T.; Yasue, H.; et al. Platelets prevent acute liver damage after extended hepatectomy in pigs. J. Hepatobiliary Pancreat. Sci 2010, 17, 855–864. [Google Scholar]
- Hisakura, K.; Murata, S.; Takahashi, K.; Matsuo, R.; Pak, S.; Ikeda, N.; Kawasaki, T.; Kohno, K.; Myronovych, A.; Nakano, Y.; et al. Platelets prevent acute hepatitis induced by anti-Fas antibody. J. Gastroenterol. Hepatol 2011, 26, 348–355. [Google Scholar]
- Braet, F.; Wisse, E. Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: A review. Comp. Hepatol 2002, 23, 1:1–1:17. [Google Scholar]
- Wack, K.E.; Ross, M.A.; Zegarra, V.; Sysko, L.R.; Watkins, S.C.; Stolz, D.B. Sinusoidal ultrastructure evaluated during the revascularization of regenerating rat liver. Hepatology 2001, 33, 363–378. [Google Scholar]
- Nakamura, M.; Shibasaki, M.; Nitta, Y.; Endo, Y. Translocation of platelets into Disse space and their entry into hepatocytes in response to lipopolysaccharides, interleukin-1 and tumour necrosis factor: The role of Kupffer cells. J. Hepatol 1998, 28, 991–999. [Google Scholar]
- Endo, Y.; Nakamura, M. The effect of lipopolysaccharide, interleukin-1 and tumour necrosis factor on the hepatic accumulation of 5-hydroxytryptamine and platelets in the mouse. Br. J. Pharmacol 1992, 105, 613–619. [Google Scholar]
- Ohtaki, Y.; Shimauchi, H.; Yokochi, T.; Endo, Y. In vivo platelet response to lipopolysaccharide in mice: Proposed method for evaluating new antiplatelet drugs. Thromb. Res 2003, 108, 303–309. [Google Scholar]
- Nakamura, T.; Nishizawa, T.; Hagiya, M.; Seki, T.; Shimonishi, M.; Sugimura, A.; Tashiro, K.; Shimizu, S. Molecular cloning and expression of human hepatocyte growth factor. Nature 1989, 342, 440–443. [Google Scholar]
- Matsuo, R.; Ohkohchi, N.; Murata, S.; Ikeda, O.; Nakano, Y.; Watanabe, M.; Hisakura, K.; Myronovych, A.; Kubota, T.; Narimatsu, H.; et al. Platelets strongly induce hepatocyte proliferation with IGF-1 and HGF in vitro. J. Surg. Res. 2008, 145, 279–286. [Google Scholar]
- Ozaki, M.; Haga, S.; Zhang, H.Q.; Irani, K.; Suzuki, S. Inhibition of hypoxia/reoxygenation-induced oxidative stress in HGF-stimulated antiapoptotic signaling: Role of PI3-K and Akt kinase upon rac1. Cell Death Differ 2003, 10, 508–515. [Google Scholar]
- Conery, A.R.; Cao, Y.; Thompson, E.A.; Townsend, C.M., Jr.; Ko, T.C.; Luo, K. Akt interacts directly with Smad3 to regulate the sensitivity to TGF-β induced apoptosis. Nat. Cell Biol 2004, 6, 366–372. [Google Scholar]
- Pearson, G.; Robinson, F.; Beers Gibson, T.; Xu, B.E.; Karandikar, M.; Berman, K.; Cobb, M.H. Mitogen-activated protein (MAP) kinase pathways: Regulation and physiological functions. Endocr. Rev 2001, 22, 153–183. [Google Scholar]
- Gauldie, J.; Richards, C.; Baumann, H. IL-6 and the acute phase reaction. Res. Immunol 1992, 143, 755–759. [Google Scholar]
- Montalvo-Jave, E.E.; Escalante-Tattersfield, T.; Ortega-Salgado, J.A.; Piña, E.; Geller, D.A. Factors in the pathophysiology of the liver ischemia-reperfusion injury. J. Surg. Res 2008, 147, 153–159. [Google Scholar]
- Croner, R.S.; Hoerer, E.; Kulu, Y.; Hackert, T.; Gebhard, M.M.; Herfarth, C.; Klar, E. Hepatic platelet and leukocyte adherence during endotoxemia. Crit. Care 2006, 10, R15:1–R15:6. [Google Scholar]
- Kawasaki, T.; Murata, S.; Takahashi, K.; Nozaki, R.; Ohshiro, Y.; Ikeda, N.; Pak, S.; Myronovych, A.; Hisakura, K.; Fukunaga, K.; et al. Activation of human liver sinusoidal endothelial cell by human platelets induces hepatocyte proliferation. J. Hepatol 2010, 53, 648–654. [Google Scholar]
- Yatomi, Y.; Ohmori, T.; Rile, G.; Kazama, F.; Okamoto, H.; Sano, T.; Satoh, K.; Kume, S.; Tigyi, G.; Igarashi, Y.; et al. Sphingosine-1-phosphate as a major bioactive lysophospholipid that is released from platelets and interacts with endothelial cells. Blood 2000, 96, 3431–3438. [Google Scholar]
- Takuwa, Y.; Okamoto, Y.; Yoshioka, K.; Takuwa, N. Sphingosine-1-phosphate signaling and biological activities in the cardiovascular system. Biochim. Biophys. Acta 2008, 1781, 483–488. [Google Scholar]
- Zheng, D.M.; Kitamura, T.; Ikejima, K.; Enomoto, N.; Yamashina, S.; Suzuki, S.; Takei, Y.; Sato, N. Sphingosine-1-phosphate protects rat liver sinusoidal endothelial cells from ethanol-induced apoptosis: Role of intracellular calcium and nitric oxide. Hepatology 2006, 44, 1278–1287. [Google Scholar]
- Fernández-Pisonero, I.; Dueňas, A.I.; Barreiro, O.; Montero, O.; Sánchez-Madrid, F.; Garcia-Rodriguez, C. Lipopolysaccharide and sphingosine-1-phosphate cooperate to induce inflammatory molecules and leukocyte adhesion in endothelial cells. J. Immunol 2012, 189, 5402–5410. [Google Scholar]
- Bilzer, M.; Roggel, F.; Gerbes, A.L. Role of Kupffer cells in host defense and liver disease. Liver Int 2006, 26, 1175–1186. [Google Scholar]
- Meijer, C.; Wiezer, M.J.; Diehl, A.M.; Schouten, H.J.; Schouten, H.J.; Meijer, S.; van Rooijen, N.; van Lambalgen, A.A.; Dijkstra, C.D.; van Leeuwen, P.A. Kupffer cell depletion by CI2MDP-liposomes alters hepatic cytokine expression and delays liver regeneration after partial hepatectomy. Liver 2000, 20, 66–77. [Google Scholar]
- Akerman, P.; Cote, P.; Yang, S.Q.; McClain, C.; Nelson, S.; Bagby, G.J.; Diehl, A.M. Antibodies to tumor necrosis factor-α inhibit liver regeneration after partial hepatectomy. Am. J. Physiol 1992, 263, G579–G585. [Google Scholar]
- Yamada, Y.; Webber, E.M.; Kirillova, I.; Peschon, J.J.; Fausto, N. Analysis of liver regeneration in mice lacking type 1 or type 2 tumor necrosis factor receptor: Requirement for type 1 but not type 2 receptor. Hepatology 1998, 28, 959–970. [Google Scholar]
- Yamada, Y.; Kirillova, I.; Peschon, J.J.; Fausto, N. Initiation of liver growth by tumor necrosis factor: Deficient liver regeneration in mice lacking type I tumor necrosis factor receptor. Proc. Natl. Acad. Sci. USA 1997, 94, 1441–1446. [Google Scholar]
- Malik, R.; Selden, C.; Hodgson, H. The role of non-parenchymal cells in liver growth. Semin. Cell Dev. Biol 2002, 13, 425–431. [Google Scholar]
- Abshagen, K.; Eipel, C.; Kalff, J.C.; Menger, M.D.; Vollmar, B. Loss of NF-κB activation in Kupffer cell-depleted mice impairs liver regeneration after partial hepatectomy. Am. J. Physiol. Gastrointest. Liver Physiol 2007, 292, G1570–G1577. [Google Scholar]
- Takahashi, K.; Kozuma, Y.; Suzuki, H.; Tamura, T.; Maruyama, T.; Fukunaga, K.; Murata, S.; Ohkohchi, N. Human platelets promote liver regeneration with Kupffer cells in SCID mice. J. Surg. Res 2013, 180, 62–72. [Google Scholar]
- Cooper, K.L.; Fitzgerald, P.; Dillingham, K.; Helme, K.; Akehurst, R. Romiplostim and eltrombopag for immune thrombocytopenia: Methods for indirect comparison. Int. J. Technol. Assess. Health Care 2012, 28, 249–258. [Google Scholar]
- McHutchison, J.G.; Dusheiko, G.; Shiffman, M.L.; Rodriguez-Torres, M.; Sigal, S.; Bourliere, M.; Berg, T.; Gordon, S.C.; Campbell, F.M.; Theodore, D.; et al. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N. Engl. J. Med 2007, 357, 2227–2236. [Google Scholar]
- Afdhal, N.H.; Giannini, E.G.; Tayyab, G.; Mohsin, A.; Lee, J.W.; Andriulli, A.; Jeffers, L.; McHutchison, J.; Chen, P.J.; Han, K.H.; et al. Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N. Engl. J. Med 2012, 367, 716–724. [Google Scholar]
- Kawaguchi, T.; Komori, A.; Seike, M.; Fujiyama, S.; Watanabe, H.; Tanaka, M.; Sakisaka, S.; Nakamuta, M.; Sasaki, Y.; Oketani, M.; et al. Efficacy and safety of eltrombopag in Japanese patients with chronic liver disease and thrombocytopenia: A randomized, open-label, phase II study. J. Gastroenterol 2012, 47, 1342–1351. [Google Scholar]
- Watanabe, M.; Murata, S.; Hashimoto, I.; Nakano, Y.; Ikeda, O.; Aoyagi, Y.; Matsuo, R.; Fukunaga, K.; Yasue, H.; Ohkohchi, N. Platelets contribute to the reduction of liver fibrosis in mice. J. Gastroenterol. Hepatol 2009, 24, 78–89. [Google Scholar]
- Arthur, M.J.; Fibrogenesis, I.I. Metalloproteinases and their inhibitors in liver fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol 2000, 279, G245–G249. [Google Scholar]
- Benyon, R.C.; Arthur, M.J. Extracellular matrix degradation and the role of hepatic stellate cells. Semin. Liver Dis 2001, 21, 373–384. [Google Scholar]
- Winwood, P.J.; Schuppan, D.; Iredale, J.P.; Kawser, C.A.; Docherty, A.J.; Arthur, M.J.P. Kupffer cell-derived 95-kd type IV collagenase/gelatinase B: Characterization and expression in cultured cells. Hepatology 1995, 22, 304–315. [Google Scholar]
- Hemmann, S.; Graf, J.; Roderfeld, M.; Roeb, E. Expression of MMPs and TIMPs in liver fibrosis—A systematic review with special emphasis on anti-fibrotic strategies. J. Hepatol 2007, 46, 955–975. [Google Scholar]
- Kodama, T.; Takehara, T.; Hikita, H.; Shimizu, S.; Li, W.; Miyagi, T.; Hosui, A.; Tatsumi, T.; Ishida, H.; Tadokoro, S.; et al. Thrombocytopenia exacerbates cholestasis-induced liver fibrosis in mice. Gastroenterology 2010, 138, 2487–2498. [Google Scholar]
- Takahashi, K.; Murata, S.; Fukunaga, K.; Ohkohchi, N. Human platelets inhibit liver fibrosis in severe combined immunodeficiency mice. World J. Gastroenterol 2013, 19, 5250–5260. [Google Scholar]
- Maruyama, T.; Murata, S.; Takahashi, K.; Tamura, T.; Nozaki, R.; Ikeda, N.; Fukunaga, K.; Oda, T.; Sasaki, R.; Ohkohchi, N. Platelet transfusion improves liver function in patients with chronic liver disease and cirrhosis. Tohoku J. Exp. Med 2013, 229, 213–220. [Google Scholar]
- Gressner, A.M.; Weiskirchen, R. Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-β as major players and therapeutic targets. J. Cell. Biol. Med 2006, 10, 76–99. [Google Scholar]
- Friedman, S.L. The cellular basis of hepatic fibrosis—Mechanisms and treatment strategies. N. Engl. J. Med 1993, 328, 1828–1835. [Google Scholar]
- Friedman, S.L.; Maher, J.J.; Bissell, D.M. Mechanisms and therapy of hepatic fibrosis: Report of the AASLD single topic basic research conference. Hepatology 2000, 32, 1403–1408. [Google Scholar]
- Friedman, S.L. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008, 134, 1655–1669. [Google Scholar]
- Ikeda, N.; Murata, S.; Maruyama, T.; Tamura, T.; Nozaki, R.; Kawasaki, T.; Fukunaga, K.; Oda, T.; Sasaki, R.; Homma, M.; et al. Platelet-derived adenosine 5′-triphosphate suppresses activation of human hepatic stellate cell: In vitro study. Hepatol. Res 2012, 42, 91–102. [Google Scholar]
© 2014 by the authors; licensee MDPI, Basel, Switzerland This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).