Skip to main content
Top
Published in: World Journal of Surgery 4/2007

01-04-2007

Platelets Promote Liver Regeneration in Early Period after Hepatectomy in Mice

Authors: Soichiro Murata, Nobuhiro Ohkohchi, Ryota Matsuo, Osamu Ikeda, Andriy Myronovych, Reiko Hoshi

Published in: World Journal of Surgery | Issue 4/2007

Login to get access

Abstract

Background

Platelets contain several growth factors, including platelet-derived growth factor and hepatocyte growth factor.

Materials and methods

We examined the effects of platelet increment on liver regeneration after 70% hepatectomy. Hepatectomies were carried out in male BALB/c mice, and subsequently divided into three groups: (i) untreated mice, (ii) thrombocytotic mice induced with thrombopoietin, and (iii) thrombocytopenic mice induced with anti-platelet antibody. Growth kinetics in the liver were analyzed as a function of the liver/body weight ratio, the mitotic index, the proliferating cell nuclear antigen labeling index and Ki-67 labeling index. Activation of signal transduction pathways relating to cell proliferation were examined, including the STAT3, Akt, and ERK1/2 pathways. Platelet accumulation in the residual liver was quantified by immunohistochemistry and transmission electron microscopy.

Results

In thrombocytotic and thrombocytopenic mice, liver/body weight ratios and Ki-67 labeling indices were significantly increased and significantly decreased, respectively, compared with untreated mice 48 hours post-hepatectomy. The Akt pathway was strongly activated, and platelet accumulation was significantly increased in thrombocytotic group 5 minutes post-hepatectomy compared with normal and thrombocytopenic groups. After hepatectomy platelets accumulated in the sinusoids of liver and promoted hepatocyte proliferation in early period after hepatectomy.

Conclusion

By increasing or decreasing the platelet, marked changes in liver regeneration can occur, due to differences in cellular signaling and mitosis.
Literature
3.
4.
go back to reference Behrens A, Sibilia M, David JP, et al. Impaired postnatal hepatocyte proliferation and liver regeneration in mice lacking c-jun in the liver. EMBO J 2002;21:1782–1790PubMedCrossRef Behrens A, Sibilia M, David JP, et al. Impaired postnatal hepatocyte proliferation and liver regeneration in mice lacking c-jun in the liver. EMBO J 2002;21:1782–1790PubMedCrossRef
5.
go back to reference DeAngelis RA, Kovalovich K, Cressman DE, et al. Normal liver regeneration in p50/ nuclear factor κB1 knockout mice. Hepatology 2001;33:915–924PubMedCrossRef DeAngelis RA, Kovalovich K, Cressman DE, et al. Normal liver regeneration in p50/ nuclear factor κB1 knockout mice. Hepatology 2001;33:915–924PubMedCrossRef
6.
go back to reference Li W, Liang X, Kellendonk C, et al. STAT3 contributes to mitogenic response of hepatocytes during liver regeneration. J Biol Chem 2002;277:28411–28417PubMedCrossRef Li W, Liang X, Kellendonk C, et al. STAT3 contributes to mitogenic response of hepatocytes during liver regeneration. J Biol Chem 2002;277:28411–28417PubMedCrossRef
7.
go back to reference Spector MS, Auer KL, Jarvis WD, et al. Differential regulation of the mitogen-activated protein and stress-activated protein kinase cascades by adrenergic agonists in quiescent and regenerating adult rat hepatocytes. Mol Cell Biol 1997;17:3556–3565PubMed Spector MS, Auer KL, Jarvis WD, et al. Differential regulation of the mitogen-activated protein and stress-activated protein kinase cascades by adrenergic agonists in quiescent and regenerating adult rat hepatocytes. Mol Cell Biol 1997;17:3556–3565PubMed
8.
go back to reference Hong F, Nguyen VA, Shen X, et al. Rapid activation of protein kinase B/Akt has a key role in antiapoptotic signaling during liver regeneration. Biochem Biophys Res Commun 2000;279:974–979PubMedCrossRef Hong F, Nguyen VA, Shen X, et al. Rapid activation of protein kinase B/Akt has a key role in antiapoptotic signaling during liver regeneration. Biochem Biophys Res Commun 2000;279:974–979PubMedCrossRef
9.
go back to reference Albrecht JH, Hansen LK. Cyclin D1 promotes mitogen-independent cell cycle progression in hepatocytes. Cell Growth Differ 1999;10:397–404PubMed Albrecht JH, Hansen LK. Cyclin D1 promotes mitogen-independent cell cycle progression in hepatocytes. Cell Growth Differ 1999;10:397–404PubMed
10.
go back to reference Ueda J, Chijiwa K, Nakano K. Cyclin expression in the atrophying and proliferating lobes of the liver after portal vein branch ligation and hepatectomy in rats. J Surg Res 2004;120:89–96PubMedCrossRef Ueda J, Chijiwa K, Nakano K. Cyclin expression in the atrophying and proliferating lobes of the liver after portal vein branch ligation and hepatectomy in rats. J Surg Res 2004;120:89–96PubMedCrossRef
11.
go back to reference Borowiak M, Garratt AN, Wüstefeld T, et al. Met provides essential signals for liver regeneration. Proc Natl Acad Sci USA 2004;101:10608–10613PubMedCrossRef Borowiak M, Garratt AN, Wüstefeld T, et al. Met provides essential signals for liver regeneration. Proc Natl Acad Sci USA 2004;101:10608–10613PubMedCrossRef
12.
go back to reference Fausto N, Laird AD, Webber EM. Role of growth factors and cytokines in hepatic regeneration. FASEB J 1995;9:1527–1536PubMed Fausto N, Laird AD, Webber EM. Role of growth factors and cytokines in hepatic regeneration. FASEB J 1995;9:1527–1536PubMed
13.
go back to reference Akerman P, Cote P, Yang SQ, et al. Antibodies to tumor necrosis factor–α inhibit liver regeneration after partial hepatectomy. Am J Physiol 1992;263:G579–G585PubMed Akerman P, Cote P, Yang SQ, et al. Antibodies to tumor necrosis factor–α inhibit liver regeneration after partial hepatectomy. Am J Physiol 1992;263:G579–G585PubMed
14.
go back to reference Blindenbacher A, Wang X, Langer I, et al. Interleukin 6 is important for survival after partial hepatectomy in mice. Hepatology 2003;38:674–682PubMedCrossRef Blindenbacher A, Wang X, Langer I, et al. Interleukin 6 is important for survival after partial hepatectomy in mice. Hepatology 2003;38:674–682PubMedCrossRef
15.
go back to reference Nakamura T, Teramoto H, Ichihara A. Purification and characterization of a growth factor from rat platelets for mature parenchymal hepatocytes in primary cultures. Proc Natl Acad Sci USA 1986;83:6489–6493PubMedCrossRef Nakamura T, Teramoto H, Ichihara A. Purification and characterization of a growth factor from rat platelets for mature parenchymal hepatocytes in primary cultures. Proc Natl Acad Sci USA 1986;83:6489–6493PubMedCrossRef
16.
go back to reference Oka Y, Orth DN. Human plasma epidermal growth factor/β-urogastrone is associated with blood platelets. J Clin Invest 1983;72:249–259PubMedCrossRef Oka Y, Orth DN. Human plasma epidermal growth factor/β-urogastrone is associated with blood platelets. J Clin Invest 1983;72:249–259PubMedCrossRef
17.
go back to reference Lesurtel M, Graf R, Aleil B, et al. Platelet-derived serotonin mediates liver regeneration. Science 2006;312:104–107PubMedCrossRef Lesurtel M, Graf R, Aleil B, et al. Platelet-derived serotonin mediates liver regeneration. Science 2006;312:104–107PubMedCrossRef
18.
go back to reference Murata S, Ohkohchi N, Abe T, et al. Platelets promote G1-S progression of liver regeneration after hepatectomy. In: Antoniou E, Vagianos C, Kouraklis G (editors). The 39th congress of the European Society for Surgical Research. Bologna, Italy, Medimond S.R.L., 2004. 107–112 Murata S, Ohkohchi N, Abe T, et al. Platelets promote G1-S progression of liver regeneration after hepatectomy. In: Antoniou E, Vagianos C, Kouraklis G (editors). The 39th congress of the European Society for Surgical Research. Bologna, Italy, Medimond S.R.L., 2004. 107–112
19.
go back to reference Shibuya K, Akahori H, Takahashi K, et al. Multilineage hematopoietic recovery by a single injection of pegylated recombinant human megakaryocyte growth and development factor in myelosuppressed mice. Blood 1998;91:37–45PubMed Shibuya K, Akahori H, Takahashi K, et al. Multilineage hematopoietic recovery by a single injection of pegylated recombinant human megakaryocyte growth and development factor in myelosuppressed mice. Blood 1998;91:37–45PubMed
20.
go back to reference Skomorovski K, Harpak H, Ianovski A, et al. New TPO treatment schedules of increased safety and efficacy: pre-clinical validation of a thrombopoiesis simulation model. Br J Haematol 2003;123:683–691PubMedCrossRef Skomorovski K, Harpak H, Ianovski A, et al. New TPO treatment schedules of increased safety and efficacy: pre-clinical validation of a thrombopoiesis simulation model. Br J Haematol 2003;123:683–691PubMedCrossRef
21.
go back to reference Nagata Y, Nagahisa H, Aida Y, et al. Thrombopoietin induces megakaryocyte differentiation in hematopoietic progenitor FDC-P2 cells. J Biol Chem 1995;270:19673–19675PubMedCrossRef Nagata Y, Nagahisa H, Aida Y, et al. Thrombopoietin induces megakaryocyte differentiation in hematopoietic progenitor FDC-P2 cells. J Biol Chem 1995;270:19673–19675PubMedCrossRef
22.
go back to reference Nagata Y, Shozaki Y, Nagahisa H, et al. Serum thrombopoietin level is not regulated by transcription but by the total counts of both megakaryocytes and platelets during thrombocytopenia and thrombocytosis. Thromb Haemost 1997;77(5):808–814PubMed Nagata Y, Shozaki Y, Nagahisa H, et al. Serum thrombopoietin level is not regulated by transcription but by the total counts of both megakaryocytes and platelets during thrombocytopenia and thrombocytosis. Thromb Haemost 1997;77(5):808–814PubMed
23.
go back to reference Higgins GM, Anderson RM. Experimental pathology of the liver. Arch Pathol 1931;12:186–202 Higgins GM, Anderson RM. Experimental pathology of the liver. Arch Pathol 1931;12:186–202
24.
go back to reference Selzner N, Selzner M, Odermatt B, et al. ICAM-1 triggers liver regeneration through leukocyte recruitment and Kupffer cell-dependent release of TNF-α/IL-6 in mice. Gastroenterology 2003;124:692–700PubMedCrossRef Selzner N, Selzner M, Odermatt B, et al. ICAM-1 triggers liver regeneration through leukocyte recruitment and Kupffer cell-dependent release of TNF-α/IL-6 in mice. Gastroenterology 2003;124:692–700PubMedCrossRef
25.
go back to reference Ozaki M, Haga S, Zhang H, et al. Inhibition of hypoxia/reoxygenetion-induced oxidative stress in HGF-stimulated antiapoptotic signaling: role of PI3-K and Akt kinase upon rac 1. Cell Death Differ 2003;10:508–515PubMedCrossRef Ozaki M, Haga S, Zhang H, et al. Inhibition of hypoxia/reoxygenetion-induced oxidative stress in HGF-stimulated antiapoptotic signaling: role of PI3-K and Akt kinase upon rac 1. Cell Death Differ 2003;10:508–515PubMedCrossRef
26.
go back to reference Conery A, Cao Y, Thompson E, et al. Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nat Cell Biol 2004;6:366–372PubMedCrossRef Conery A, Cao Y, Thompson E, et al. Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nat Cell Biol 2004;6:366–372PubMedCrossRef
27.
go back to reference Gardai S, Hildeman D, Frankel S, et al. Phosphorylation of Bax Ser 184 by Akt regulates its activity and apoptosis in neutrophils. J Biol Chem 2004;279:21085–21095PubMedCrossRef Gardai S, Hildeman D, Frankel S, et al. Phosphorylation of Bax Ser 184 by Akt regulates its activity and apoptosis in neutrophils. J Biol Chem 2004;279:21085–21095PubMedCrossRef
28.
go back to reference Tanaka Y, Gavrielides M, Mitsuuchi Y, et al. Protein kinase C promotes apoptosis in LNCaP prostate cancer cells through activation of p38 MAPK and inhibition of the Akt survival pathway. J Biol Chem 2003;278:33753–33762PubMedCrossRef Tanaka Y, Gavrielides M, Mitsuuchi Y, et al. Protein kinase C promotes apoptosis in LNCaP prostate cancer cells through activation of p38 MAPK and inhibition of the Akt survival pathway. J Biol Chem 2003;278:33753–33762PubMedCrossRef
29.
go back to reference Haga S, Ogawa W, Todo S, et al. Compensatory recovery of liver mass by Akt-mediated hepatocellular hypertrophy in liver-specific STAT3-deficient mice. J Hepatol 2005;43:799–807PubMedCrossRef Haga S, Ogawa W, Todo S, et al. Compensatory recovery of liver mass by Akt-mediated hepatocellular hypertrophy in liver-specific STAT3-deficient mice. J Hepatol 2005;43:799–807PubMedCrossRef
30.
go back to reference Chen B, Pan H, Zhu L, et al. Progesterone inhibits the estrogen-induced phosphoinositide 3-kinase→AKT→GSK3β→cyclin D1→pRB pathway to block uterine epithelial cell proliferation. Mol Endocrinol 2005;19(8):1978–1990PubMedCrossRef Chen B, Pan H, Zhu L, et al. Progesterone inhibits the estrogen-induced phosphoinositide 3-kinase→AKT→GSK3β→cyclin D1→pRB pathway to block uterine epithelial cell proliferation. Mol Endocrinol 2005;19(8):1978–1990PubMedCrossRef
31.
go back to reference Faridi J, Fawcett J, Wang L, et al. Akt promotes increased mammalian cell size by stimulating protein synthesis and inhibiting protein degradation. Am J Physiol Endocrinol Metab 2003;285:E964–E972PubMed Faridi J, Fawcett J, Wang L, et al. Akt promotes increased mammalian cell size by stimulating protein synthesis and inhibiting protein degradation. Am J Physiol Endocrinol Metab 2003;285:E964–E972PubMed
32.
go back to reference Braet F, Shleper M, Paizi M, et al. Liver sinusoidal endothelial cell modulation upon resection and shear stress in vitro. Comp Hepatol 2004;3:7PubMedCrossRef Braet F, Shleper M, Paizi M, et al. Liver sinusoidal endothelial cell modulation upon resection and shear stress in vitro. Comp Hepatol 2004;3:7PubMedCrossRef
33.
go back to reference Wack KE, Ross MA, Zegarra V, et al. Sinusoidal ultrastructure evaluated during the revascularization of regenerating rat liver. Hepatology 2001;33:363–378PubMedCrossRef Wack KE, Ross MA, Zegarra V, et al. Sinusoidal ultrastructure evaluated during the revascularization of regenerating rat liver. Hepatology 2001;33:363–378PubMedCrossRef
34.
go back to reference Nakamura M, Shibasaki M, Nitta Y, et al. 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;28:991–999PubMedCrossRef Nakamura M, Shibasaki M, Nitta Y, et al. 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;28:991–999PubMedCrossRef
35.
go back to reference 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;105:613–619PubMed 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;105:613–619PubMed
36.
go back to reference Ohtaki Y, Shimauchi H, Yokochi T, et al. In vivo platelet response to lipopolysaccharide in mice: proposed method for evaluating new antiplatelet drugs. Thromb Res 2003;108:303–309CrossRef Ohtaki Y, Shimauchi H, Yokochi T, et al. In vivo platelet response to lipopolysaccharide in mice: proposed method for evaluating new antiplatelet drugs. Thromb Res 2003;108:303–309CrossRef
37.
go back to reference Klintman D, Li X, Thorlacius H. Important role of P-selection for leukocyte recruitment, hepatocellular injury, and apoptosis in endotoxemic mice. Clin Diagn Lab Immunol 2004;11:56–62PubMedCrossRef Klintman D, Li X, Thorlacius H. Important role of P-selection for leukocyte recruitment, hepatocellular injury, and apoptosis in endotoxemic mice. Clin Diagn Lab Immunol 2004;11:56–62PubMedCrossRef
38.
go back to reference Peck-Radosavlijevic M, Wichlas M, Zacherl J, et al. Thrombopoietin induces rapid resolution of thrombocytopenia after orthotopic liver transplantation through increased platelet production. Blood 2000;95:795–801 Peck-Radosavlijevic M, Wichlas M, Zacherl J, et al. Thrombopoietin induces rapid resolution of thrombocytopenia after orthotopic liver transplantation through increased platelet production. Blood 2000;95:795–801
39.
go back to reference Cardier JE, Dempsey J. Thrombopoietin and its receptor, c-mpl, are constitutively expressed by mouse liver endothelial cells: evidence of thrombopoietin as a growth factor for liver endothelial Cells. Blood 1998;91:923–929PubMed Cardier JE, Dempsey J. Thrombopoietin and its receptor, c-mpl, are constitutively expressed by mouse liver endothelial cells: evidence of thrombopoietin as a growth factor for liver endothelial Cells. Blood 1998;91:923–929PubMed
Metadata
Title
Platelets Promote Liver Regeneration in Early Period after Hepatectomy in Mice
Authors
Soichiro Murata
Nobuhiro Ohkohchi
Ryota Matsuo
Osamu Ikeda
Andriy Myronovych
Reiko Hoshi
Publication date
01-04-2007
Publisher
Springer-Verlag
Published in
World Journal of Surgery / Issue 4/2007
Print ISSN: 0364-2313
Electronic ISSN: 1432-2323
DOI
https://doi.org/10.1007/s00268-006-0772-3

Other articles of this Issue 4/2007

World Journal of Surgery 4/2007 Go to the issue