Update on the Mechanisms of Liver Regeneration

Morgan E. Preziosi; Satdarshan P. Monga

doi:10.1055/s-0037-1601351

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2017; 37(02): 141-151
DOI: 10.1055/s-0037-1601351

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA

Update on the Mechanisms of Liver Regeneration

Morgan E. Preziosi

¹Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

²Pittsburgh Liver Research Center, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

,

Satdarshan P. Monga

¹Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

²Pittsburgh Liver Research Center, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

³Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

› Author Affiliations

Abstract

Liver possesses many critical functions such as synthesis, detoxification, and metabolism. It continually receives nutrient-rich blood from gut, which incidentally is also toxin-rich. That may be why liver is uniquely bestowed with a capacity to regenerate. A commonly studied procedure to understand the cellular and molecular basis of liver regeneration is that of surgical resection. Removal of two-thirds of the liver in rodents or patients instigates alterations in hepatic homeostasis, which are sensed by the deficient organ to drive the restoration process. Although the exact mechanisms that initiate regeneration are unknown, alterations in hemodynamics and metabolism have been suspected as important effectors. Key signaling pathways are activated that drive cell proliferation in various hepatic cell types through autocrine and paracrine mechanisms. Once the prehepatectomy mass is regained, the process of regeneration is adequately terminated. This review highlights recent discoveries in the cellular and molecular basis of liver regeneration.

Keywords

partial hepatectomy - cellular and molecular basis - hepatocyte proliferation - inflammation - stellate cells - endothelial cells - initiation - signaling pathways - hepatocytes - nonparenchymal cells

Full Text

References

References
1 Michalopoulos GK, DeFrances MC. Liver regeneration. Science 1997; 276 (5309): 60-66
2 Kuramitsu K, Sverdlov DY, Liu SB. , et al. Failure of fibrotic liver regeneration in mice is linked to a severe fibrogenic response driven by hepatic progenitor cell activation. Am J Pathol 2013; 183 (01) 182-194
3 Luedde T, Kaplowitz N, Schwabe RF. Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology 2014; 147 (04) 765-783.e4
4 Bernardi M, Gitto S, Biselli M. The MELD score in patients awaiting liver transplant: strengths and weaknesses. J Hepatol 2011; 54 (06) 1297-1306
5 Yagi S, Uemoto S. Small-for-size syndrome in living donor liver transplantation. Hepatobiliary Pancreat Dis Int 2012; 11 (06) 570-576
6 Ueno S, Sakoda M, Kubo F. , et al; Kagoshima Liver Cancer Study Group. Surgical resection versus radiofrequency ablation for small hepatocellular carcinomas within the Milan criteria. J Hepatobiliary Pancreat Surg 2009; 16 (03) 359-366
7 Golse N, Bucur PO, Adam R, Castaing D, Sa Cunha A, Vibert E. New paradigms in post-hepatectomy liver failure. J Gastrointest Surg 2013; 17 (03) 593-605
8 Michalopoulos GK. Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. Am J Pathol 2010; 176 (01) 2-13
9 Michalopoulos GK. Liver regeneration. J Cell Physiol 2007; 213 (02) 286-300
10 Monga SP, Pediaditakis P, Mule K, Stolz DB, Michalopoulos GK. Changes in WNT/beta-catenin pathway during regulated growth in rat liver regeneration. Hepatology 2001; 33 (05) 1098-1109
11 Tan X, Behari J, Cieply B, Michalopoulos GK, Monga SP. Conditional deletion of beta-catenin reveals its role in liver growth and regeneration. Gastroenterology 2006; 131 (05) 1561-1572
12 Yang J, Mowry LE, Nejak-Bowen KN. , et al. β-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation!. Hepatology 2014; 60 (03) 964-976
13 Ding BS, Nolan DJ, Butler JM. , et al. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature 2010; 468 (7321): 310-315
14 Paranjpe S, Bowen WC, Mars WM. , et al. Combined systemic elimination of MET and epidermal growth factor receptor signaling completely abolishes liver regeneration and leads to liver decompensation. Hepatology 2016; 64 (05) 1711-1724
15 Salehi S, Brereton HC, Arno MJ. , et al. Human liver regeneration is characterized by the coordinated expression of distinct microRNA governing cell cycle fate. Am J Transplant 2013; 13 (05) 1282-1295
16 Ng R, Song G, Roll GR, Frandsen NM, Willenbring H. A microRNA-21 surge facilitates rapid cyclin D1 translation and cell cycle progression in mouse liver regeneration. J Clin Invest 2012; 122 (03) 1097-1108
17 Cirera-Salinas D, Pauta M, Allen RM. , et al. Mir-33 regulates cell proliferation and cell cycle progression. Cell Cycle 2012; 11 (05) 922-933
18 Xu D, Yang F, Yuan JH. , et al. Long noncoding RNAs associated with liver regeneration 1 accelerates hepatocyte proliferation during liver regeneration by activating Wnt/β-catenin signaling. Hepatology 2013; 58 (02) 739-751
19 Nejak-Bowen KN, Orr AV, Bowen Jr WC, Michalopoulos GK. Gliotoxin-induced changes in rat liver regeneration after partial hepatectomy. Liver Int 2013; 33 (07) 1044-1055
20 Meijer C, Wiezer MJ, Diehl AM. , et al. Kupffer cell depletion by CI2MDP-liposomes alters hepatic cytokine expression and delays liver regeneration after partial hepatectomy. Liver 2000; 20 (01) 66-77
21 Takeishi T, Hirano K, Kobayashi T, Hasegawa G, Hatakeyama K, Naito M. The role of Kupffer cells in liver regeneration. Arch Histol Cytol 1999; 62 (05) 413-422
22 Nucera S, Biziato D, De Palma M. The interplay between macrophages and angiogenesis in development, tissue injury and regeneration. Int J Dev Biol 2011; 55 (4-5): 495-503
23 Melgar-Lesmes P, Edelman ER. Monocyte-endothelial cell interactions in the regulation of vascular sprouting and liver regeneration in mouse. J Hepatol 2015; 63 (04) 917-925
24 Tumanov AV, Koroleva EP, Christiansen PA. , et al. T cell-derived lymphotoxin regulates liver regeneration. Gastroenterology 2009; 136 (02) 694-704.e4
25 Dong Z, Wei H, Sun R, Tian Z. The roles of innate immune cells in liver injury and regeneration. Cell Mol Immunol 2007; 4 (04) 241-252
26 Hosoya S, Ikejima K, Takeda K. , et al. Innate immune responses involving natural killer and natural killer T cells promote liver regeneration after partial hepatectomy in mice. Am J Physiol Gastrointest Liver Physiol 2013; 304 (03) G293-G299
27 Graubardt N, Fahrner R, Trochsler M. , et al. Promotion of liver regeneration by natural killer cells in a murine model is dependent on extracellular adenosine triphosphate phosphohydrolysis. Hepatology 2013; 57 (05) 1969-1979
28 Besnard A, Julien B, Gonzales E, Tordjmann T. Innate immunity, purinergic system, and liver regeneration: a trip in complexity. Hepatology 2013; 57 (05) 1688-1690
29 Kudira R, Malinka T, Kohler A. , et al. P2X1-regulated IL-22 secretion by innate lymphoid cells is required for efficient liver regeneration. Hepatology 2016; 63 (06) 2004-2017
30 Park O, Wang H, Weng H. , et al. In vivo consequences of liver-specific interleukin-22 expression in mice: Implications for human liver disease progression. Hepatology 2011; 54 (01) 252-261
31 Ren X, Hu B, Colletti LM. IL-22 is involved in liver regeneration after hepatectomy. Am J Physiol Gastrointest Liver Physiol 2010; 298 (01) G74-G80
32 Furuya S, Kono H, Hara M, Hirayama K, Tsuchiya M, Fujii H. Interleukin-17A plays a pivotal role after partial hepatectomy in mice. J Surg Res 2013; 184 (02) 838-846
33 DeAngelis RA, Markiewski MM, Kourtzelis I. , et al. A complement-IL-4 regulatory circuit controls liver regeneration. J Immunol 2012; 188 (02) 641-648
34 Rao R, Graffeo CS, Gulati R. , et al. Interleukin 17-producing γδT cells promote hepatic regeneration in mice. Gastroenterology 2014; 147 (02) 473-84.e2
35 Goh YP, Henderson NC, Heredia JE. , et al. Eosinophils secrete IL-4 to facilitate liver regeneration. Proc Natl Acad Sci U S A 2013; 110 (24) 9914-9919
36 Loke P, Gallagher I, Nair MG. , et al. Alternative activation is an innate response to injury that requires CD4+ T cells to be sustained during chronic infection. J Immunol 2007; 179 (06) 3926-3936
37 Wang X, Kiyokawa H, Dennewitz MB, Costa RH. The Forkhead Box m1b transcription factor is essential for hepatocyte DNA replication and mitosis during mouse liver regeneration. Proc Natl Acad Sci U S A 2002; 99 (26) 16881-16886
38 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 (04) 808-816
39 Matsuo R, Nakano Y, Ohkohchi N. Platelet administration via the portal vein promotes liver regeneration in rats after 70% hepatectomy. Ann Surg 2011; 253 (04) 759-763
40 Lesurtel M, Graf R, Aleil B. , et al. Platelet-derived serotonin mediates liver regeneration. Science 2006; 312 (5770): 104-107
41 Matondo RB, Punt C, Homberg J. , et al. Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration. Am J Physiol Gastrointest Liver Physiol 2009; 296 (04) G963-G968
42 Abshagen K, Eipel C, Vollmar B. A critical appraisal of the hemodynamic signal driving liver regeneration. Langenbecks Arch Surg 2012; 397 (04) 579-590
43 Kirschbaum M, Karimian G, Adelmeijer J, Giepmans BN, Porte RJ, Lisman T. Horizontal RNA transfer mediates platelet-induced hepatocyte proliferation. Blood 2015; 126 (06) 798-806
44 Jenne CN, Kubes P. Platelets in inflammation and infection. Platelets 2015; 26 (04) 286-292
45 Mabuchi A, Mullaney I, Sheard PW. , et al. Role of hepatic stellate cell/hepatocyte interaction and activation of hepatic stellate cells in the early phase of liver regeneration in the rat. J Hepatol 2004; 40 (06) 910-916
46 Benyon RC, Arthur MJ. Extracellular matrix degradation and the role of hepatic stellate cells. Semin Liver Dis 2001; 21 (03) 373-384
47 Gallai M, Sebestyén A, Nagy P, Kovalszky I, Onody T, Thorgeirsson SS. Proteoglycan gene expression in rat liver after partial hepatectomy. Biochem Biophys Res Commun 1996; 228 (03) 690-694
48 Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol 2004; 5 (10) 836-847
49 Kocabayoglu P, Zhang DY, Kojima K, Hoshida Y, Friedman SL. Induction and contribution of beta platelet-derived growth factor signalling by hepatic stellate cells to liver regeneration after partial hepatectomy in mice. Liver Int 2016; 36 (06) 874-882
50 Mederacke I, Hsu CC, Troeger JS. , et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun 2013; 4: 2823
51 Shimizu H, Miyazaki M, Wakabayashi Y. , et al. Vascular endothelial growth factor secreted by replicating hepatocytes induces sinusoidal endothelial cell proliferation during regeneration after partial hepatectomy in rats. J Hepatol 2001; 34 (05) 683-689
52 Greene AK, Wiener S, Puder M. , et al. Endothelial-directed hepatic regeneration after partial hepatectomy. Ann Surg 2003; 237 (04) 530-535
53 Hu J, Srivastava K, Wieland M. , et al. Endothelial cell-derived angiopoietin-2 controls liver regeneration as a spatiotemporal rheostat. Science 2014; 343 6169 416-419
54 Fujii H, Hirose T, Oe S. , et al. Contribution of bone marrow cells to liver regeneration after partial hepatectomy in mice. J Hepatol 2002; 36 (05) 653-659
55 Wang L, Wang X, Xie G, Wang L, Hill CK, DeLeve LD. Liver sinusoidal endothelial cell progenitor cells promote liver regeneration in rats. J Clin Invest 2012; 122 (04) 1567-1573
56 Ping C, Xiaoling D, Jin Z, Jiahong D, Jiming D, Lin Z. Hepatic sinusoidal endothelial cells promote hepatocyte proliferation early after partial hepatectomy in rats. Arch Med Res 2006; 37 (05) 576-583
57 Xu C, Chen X, Chang C. , et al. Transcriptional profiles of biliary epithelial cells from rat regenerating liver after partial hepatectomy. Genes Genomics 2012; 34 (03) 245-256
58 Wen Y, Feng D, Wu H. , et al. Defective initiation of liver regeneration in osteopontin-deficient mice after partial hepatectomy due to insufficient activation of IL-6/Stat3 pathway. Int J Biol Sci 2015; 11 (10) 1236-1247
59 Delahunty TJ, Rubinstein D. Accumulation and release of triglycerides by rat liver following partial hepatectomy. J Lipid Res 1970; 11 (06) 536-543
60 Schofield PS, Sugden MC, Corstorphine CG, Zammit VA. Altered interactions between lipogenesis and fatty acid oxidation in regenerating rat liver. Biochem J 1987; 241 (02) 469-474
61 Tijburg LB, Nyathi CB, Meijer GW, Geelen MJ. Biosynthesis and secretion of triacylglycerol in rat liver after partial hepatectomy. Biochem J 1991; 277 (Pt 3): 723-728
62 Weymann A, Hartman E, Gazit V. , et al. p21 is required for dextrose-mediated inhibition of mouse liver regeneration. Hepatology 2009; 50 (01) 207-215
63 Newberry EP, Kennedy SM, Xie Y. , et al. Altered hepatic triglyceride content after partial hepatectomy without impaired liver regeneration in multiple murine genetic models. Hepatology 2008; 48 (04) 1097-1105
64 Huang J, Schriefer AE, Cliften PF. , et al. Postponing the hypoglycemic response to partial hepatectomy delays mouse liver regeneration. Am J Pathol 2016; 186 (03) 587-599
65 Nelsen CJ, Rickheim DG, Tucker MM. , et al. Amino acids regulate hepatocyte proliferation through modulation of cyclin D1 expression. J Biol Chem 2003; 278 (28) 25853-25858
66 Csanaky IL, Aleksunes LM, Tanaka Y, Klaassen CD. Role of hepatic transporters in prevention of bile acid toxicity after partial hepatectomy in mice. Am J Physiol Gastrointest Liver Physiol 2009; 297 (03) G419-G433
67 Doignon I, Julien B, Serrière-Lanneau V. , et al. Immediate neuroendocrine signaling after partial hepatectomy through acute portal hyperpressure and cholestasis. J Hepatol 2011; 54 (03) 481-488
68 Sainz GR, Monte MJ, Barbero ER, Herrera MC, Marin JJ. Bile secretion by the rat liver during synchronized regeneration. Int J Exp Pathol 1997; 78 (02) 109-116
69 Modica S, Gadaleta RM, Moschetta A. Deciphering the nuclear bile acid receptor FXR paradigm. Nucl Recept Signal 2010; 8: e005
70 Huang W, Ma K, Zhang J. , et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 2006; 312 (5771): 233-236
71 Fernández-Barrena MG, Monte MJ, Latasa MU. , et al. Lack of Abcc3 expression impairs bile-acid induced liver growth and delays hepatic regeneration after partial hepatectomy in mice. J Hepatol 2012; 56 (02) 367-373
72 Keitel V, Reinehr R, Gatsios P. , et al. The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology 2007; 45 (03) 695-704
73 Péan N, Doignon I, Garcin I. , et al. The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice. Hepatology 2013; 58 (04) 1451-1460
74 Gonzales E, Julien B, Serrière-Lanneau V. , et al. ATP release after partial hepatectomy regulates liver regeneration in the rat. J Hepatol 2010; 52 (01) 54-62
75 Besnard A, Gautherot J, Julien B. , et al. The P2X4 purinergic receptor impacts liver regeneration after partial hepatectomy in mice through the regulation of biliary homeostasis. Hepatology 2016; 64 (03) 941-953
76 Schoen JM, Wang HH, Minuk GY, Lautt WW. Shear stress-induced nitric oxide release triggers the liver regeneration cascade. Nitric Oxide 2001; 5 (05) 453-464
77 Maeno H, Ono T, Dhar DK, Sato T, Yamanoi A, Nagasue N. Expression of hypoxia inducible factor-1alpha during liver regeneration induced by partial hepatectomy in rats. Liver Int 2005; 25 (05) 1002-1009
78 Yu ZY, Bai YN, Luo LX, Wu H, Zeng Y. Expression of microRNA-150 targeting vascular endothelial growth factor-A is downregulated under hypoxia during liver regeneration. Mol Med Rep 2013; 8 (01) 287-293
79 Yu J, Yin S, Zhang W. , et al. Hypoxia preconditioned bone marrow mesenchymal stem cells promote liver regeneration in a rat massive hepatectomy model. Stem Cell Res Ther 2013; 4 (04) 83
80 Liu HX, Keane R, Sheng L, Wan YJ. Implications of microbiota and bile acid in liver injury and regeneration. J Hepatol 2015; 63 (06) 1502-1510
81 Wu X, Sun R, Chen Y. , et al. Oral ampicillin inhibits liver regeneration by breaking hepatic innate immune tolerance normally maintained by gut commensal bacteria. Hepatology 2015; 62 (01) 253-264
82 Nakashima H, Inui T, Habu Y. , et al. Activation of mouse natural killer T cells accelerates liver regeneration after partial hepatectomy. Gastroenterology 2006; 131 (05) 1573-1583
83 Yin S, Wang H, Bertola A. , et al. Activation of invariant natural killer T cells impedes liver regeneration by way of both IFN-γ- and IL-4-dependent mechanisms. Hepatology 2014; 60 (04) 1356-1366
84 Alvarado TF, Puliga E, Preziosi M. , et al. Thyroid hormone receptor β agonist induces β-catenin-dependent hepatocyte proliferation in mice: implications in hepatic regeneration. Gene Expr 2016; 17 (01) 19-34
85 Fanti M, Singh S, Ledda-Columbano GM, Columbano A, Monga SP. Tri-iodothyronine induces hepatocyte proliferation by protein kinase A-dependent β-catenin activation in rodents. Hepatology 2014; 59 (06) 2309-2320
86 Gebhardt R. Speeding up hepatocyte proliferation: how triiodothyronine and β-catenin join forces. Hepatology 2014; 59 (06) 2074-2076