Cellular and Molecular Cascades during Liver Regeneration
DOI:
https://doi.org/10.17140/SROJ-2-110Keywords:
Liver, Regeneration, Hepatectomy, Stem cell, Healing, InflammationAbstract
The demand for organs such as the liver for patients with end stage disease is greater than what is currently available. Thus, there is a dire need to have alternative solutions, for which none exist at the moment. Investigating the key underlying mechanisms involved not only in liver regeneration and repair, but also in development, can give us a better under standing of how to promote a pro-regenerative phenotype in the liver. This review will focus on the cellular and molecular aspects of liver regeneration and address signaling mechanisms involved in liver development and how they are recapitulated in regeneration after a partial hepatectomy.
References
Michalopoulos GK, DeFrances MC. Liver regeneration. Sci-ence. 1997; 276(5309): 60-66.
Mitchell C, Willenbring H. A reproducible and well-tolerated method for 2/3 partial hepatectomy in mice. Nat Protoc. 2008. 3(7): 1167-1170. doi: 10.1038/nprot.2008.80
Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepa-tology. 2006; 43(2 Suppl 1): S45-S53.
Michalopoulos GK. Liver regeneration after partial hepatec-tomy: critical analysis of mechanistic dilemmas. Am J Pathol. 2010; 176(1): 2-13.
Miyajima A, Tanaka M, Itoh T. Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogram-ming. Cell Stem Cell. 2014; 14(5): 561-574. doi: 10.1016/j. stem.2014.04.010
Miyaoka Y, Ebato K, Kato H, Arakawa S, Shimizu S, Miya-jima A. Hypertrophy and unconventional cell division of hepato-cytes underlie liver regeneration. Curr Biol. 2012; 22(13): 1166- 1175. doi: 10.1016/j.cub.2012.05.016
Alison, MR, Islam S, Lim S. Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly. J Pathol. 2009; 217(2): 282-298. doi: 10.1002/path.2453
Su AI, Guidotti LG, Pezacki JP, Chisari FV, Schult PG. Gene expression during the priming phase of liver regeneration after partial hepatectomy in mice. Proc Natl Acad Sci USA. 2002; 99(17): 11181-11186. doi: 10.1073/pnas.122359899
Thomson AW, Knolle PA. Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol. 2010; 10(11): 753-766. doi: 10.1038/nri2858
Yin, C, Evason KJ, Asahina K, Stainier DY. Hepatic stellate cells in liver development, regeneration, and cancer. J Clin In-vest. 2013; 123(5): 1902-1910. doi: 10.1172/JCI66369
Tremblay KD, Zaret KS. Distinct populations of endoderm cells converge to generate the embryonic liver bud and ventral foregut tissues. Dev Biol. 2005; 280(1): 87-99. doi: 10.1016/j. ydbio.2005.01.003
Matsumoto K, Miki R, Nakayama M, Tatsumi N, Yokouchi Y. Wnt9a secreted from the walls of hepatic sinusoids is essential for morphogenesis, proliferation, and glycogen accumulation of chick hepatic epithelium. Dev Biol. 2008; 319(2): 234-247. doi: 10.1016/j.ydbio.2008.04.021
Houssaint E. Differentiation of the mouse hepatic primor-dium. I. An analysis of tissue interactions in hepatocyte differ-entiation. Cell Differ. 1980; 9(5): 269-279. doi: 10.1016/0045- 6039(80)90026-3
Medlock ES, Haar JL. The liver hemopoietic environment: II. Peroxidase reactive mouse fetal liver hemopoietic cells. Anat Rec. 1983; 207(1): 43-53.
Asahina K, Tsai SY, Li P, et al. Mesenchymal origin of he-patic stellate cells, submesothelial cells, and perivascular mes-enchymal cells during mouse liver development. Hepatology. 2009; 49(3): 998-1011. doi: 10.1002/hep.22721
Lemaigre FP. Development of the biliary tract. Mech Dev. 2003; 120(1): 81-87. doi: 10.1016/S0925-4773(02)00334-9
McLin VA, Rankin SA, Zorn AM. Repression of Wnt/beta-catenin signaling in the anterior endoderm is essential for liver and pancreas development. Development. 2007; 134(12): 2207- 2217. doi: 10.1242/dev.001230
Dessimoz J, Opokaa R, Kordicha JJ, Grapin-Bottonb A, Wells JM. FGF signaling is necessary for establishing gut tube domains along the anterior-posterior axis in vivo. Mech Dev. 2006; 123(1): 42-55. doi: 10.1016/j.mod.2005.10.001
Monga SP, Monga HK, Tan X, Mulé K, Pediaditakis P, Mi-chalopoulos GK. Beta-catenin antisense studies in embryonic liver cultures: role in proliferation, apoptosis, and lineage speci-fication. Gastroenterology. 2003; 124(1): 202-216.
Ober EA, Verkade H, Field HA, Stainier DYR. Mesodermal Wnt2b signalling positively regulates liver specification. Nature. 2006; 442(7103): 688-691. doi: 10.1038/nature04888
Poulain M, Ober EA. Interplay between Wnt2 and Wnt2bb controls multiple steps of early foregut-derived organ develop-ment. Development. 2011; 138(16): 3557-3568. doi: 10.1242/ dev.055921
Itoh HYT, Miyajima A. Hedgehog signal activation coordi-nates proliferation and differentiation of fetal liver progenitor cells. Exp Cell Res. 2009; 315(15): 2648-2657. doi: 10.1016/j. yexcr.2009.06.018
Zong Y, Panikkar A, Xu J, et al. Notch signaling controls liver development by regulating biliary differentiation. Develop-ment. 2009; 136(10): 1727-1739. doi: 10.1242/dev.029140
Geisler F, Nagl F, Mazur PK, et al. Liver-specific inactiva-tion of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice. Hepatology. 2008; 48(2): 607-616. doi: 10.1002/hep.22381
Yanger K, Knigin D, Zong Y, et al. Adult hepatocytes are generated by self-duplication rather than stem cell differen-tiation. Cell Stem Cell. 2014; 15(3): 340-349. doi: 10.1016/j. stem.2014.06.003
Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol. 2004; 5(10): 836-847. doi: 10.1038/nrm1489
Gielchinsky Y, Laufer N, Weitman E, et al. Pregnancy re-stores the regenerative capacity of the aged liver via activation of an mTORC1-controlled hyperplasia/hypertrophy switch. Genes Dev. 2010; 24(6): 543-548. doi: 10.1101/gad.563110
Ding BS, Cao Z, Lis R, et al. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Na-ture. 2014; 505(7481): 97-102. doi: 10.1038/nature12681
Ding BS, Nolan DJ, Butler JM, et al. Inductive angiocrine signals from sinusoidal endothelium are required for liver re-generation. Nature. 2010; 468(7321): 310-315. doi: 10.1038/ nature09493
Hu J, Srivastava K, Wieland M, et al. Endothelial cell-de-rived angiopoietin-2 controls liver regeneration as a spatiotem-poral rheostat. Science. 2014; 343(6169): 416-419. doi: 10.1126/ science.1244880
Cressman DE, Greenbaum LE, DeAngelis RA, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science. 1996; 274(5291): 1379-1383. doi: 10.1126/science.274.5291.1379
Huang W, Ma K, Zhang J, et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Sci-ence. 2006; 312(5771): 233-236. doi: 10.1126/science.1121435
Weglarz TC, Sandgren EP. Timing of hepatocyte entry into DNA synthesis after partial hepatectomy is cell autonomous. Proc Natl Acad Sci USA. 2000; 97(23): 12595-12600. doi: 10.1073/pnas.220430497
Factor VM, Radaeva SA, Thorgeirsson SS. Origin and fate of oval cells in dipin-induced hepatocarcinogenesis in the mouse. Am J Pathol. 1994; 145(2): 409-422.
Shin D, Shin CH, Tucker J, et al. Bmp and Fgf signaling are essential for liver specification in zebrafish. Development. 2007; 134(11): 2041-2050. doi: 10.1242/dev.000281
Jung J, Zheng M, Goldfarb M, Zaret KS. Initiation of mam-malian liver development from endoderm by fibroblast growth factors. Science. 1999; 284(5422): 1998-2003. doi: 10.1126/sci-ence.284.5422.1998
Nejak-BowenK, Monga SP. Wnt/beta-catenin signaling in hepatic organogenesis. Organogenesis. 2008; 4(2): 92-99.
Tanimizu N, Miyajima A. Notch signaling controls hepato-blast differentiation by altering the expression of liver-enriched transcription factors. J Cell Sci. 2004; 117(Pt 15): 3165-3174. doi: 10.1242/ jcs.01169
Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet. 1997; 16(3): 243-251. doi: 10.1038/ng0797-
Godwin JW, Pinto AR, Rosenthal NA. Macrophages are re-quired for adult salamander limb regeneration. Proc Natl Acad Sci USA. 2013; 110(23): 9415-9420. doi: 10.1073/pnas.1300290110
Meijer C, Pintoa AR, 41. Rosenthal NA. Kupffer cell deple-tion by CI2MDP-liposomes alters hepatic cytokine expression and delays liver regeneration after partial hepatectomy. Liver. 2000; 20(1): 66-77. doi: 10.1034/j.1600-0676.2000.020001066.x
Yang J, Mowry LE, Nejak-Bowen KN, et al. beta-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation! Hepatology. 2014; 60(3): 964-976. doi: 10.1002/ hep.27082
Amini-Nik S, Elizabeth Cambridge, Winston Yu, et al. beta-Catenin-regulated myeloid cell adhesion and migration deter-mine wound healing. J Clin Invest. 2014; 124(6): 2599-2610.
Lesage G, Glaser SS, Gubba S, et al. Regrowth of the rat bili-ary tree after 70% partial hepatectomy is coupled to increased secretin-induced ductal secretion. Gastroenterology. 1996; 111(6): 1633-1644.
Boulter L, Govaere O, Bird TG, et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med. 2012; 18(4): 572-579. doi: 10.1038/nm.2667
Kordes C, Haussinger D. Hepatic stem cell niches. J Clin Invest. 2013; 123(5): 1874-1880. doi: 10.1172/JCI66027
Kordes C, Sawitza I, Müller-Marbach A, et al. CD133+ hepat-ic stellate cells are progenitor cells. Biochem Biophys Res Com-mun. 2007; 352(2): 410-417. doi: 10.1016/j.bbrc.2006.11.029
Yang, L, Jung Y, Omenetti A, et al. Fate-mapping evidence that hepatic stellate cells are epithelial progenitors in adult mouse livers. Stem Cells. 2008; 26(8): 2104-2113. doi: 10.1634/ stemcells.2008-0115
Krizhanovsky V, Yon M, Dickins RA, et al. Senescence of activated stellate cells limits liver fibrosis. Cell. 2008; 134(4): 657-667. doi: 10.1016/j.cell.2008.06.049
Kalinichenko VV, Bhattacharyya D, Zhou Y, et al. Foxf1 +/-mice exhibit defective stellate cell activation and abnormal liver regeneration following CCl4 injury. Hepatology. 2003; 37(1): 107-117. doi: 10.1053/jhep.2003.50005
Pintilie DG, Shupe TD, Oh SH, et al. Hepatic stellate cells’ involvement in progenitor-mediated liver regeneration. Lab In-vest. 2010; 90(8): 1199-1208. doi: 10.1038/labinvest.2010.88
Ochoa B, Syn WK, Delgado I, et al. Hedgehog signaling is critical for normal liver regeneration after partial hepatectomy in mice. Hepatology. 2010; 51(5): 1712-1723. doi: 10.1002/ hep.23525
Hadem J, Bockmeyer CL, Lukasz A, et al. Angiopoietin-2 in acute liver failure. Crit Care Med. 2012; 40(5): 1499-1505. doi: 10.1097/CCM.0b013e318241e34e
Simmonds PC, Primrose JN, Colquitt JL, et al. Surgical re-section of hepatic metastases from colorectal cancer: a system-atic review of published studies. Br J Cancer. 2006; 94(7): 982- 999. doi: 10.1038/sj.bjc.6603033
Clavien PA, Petrowsky H, DeOliveira ML, Graf R. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med. 2007; 356(15): 1545-1559. doi: 10.1056/NEJMra065156
Van Cutsem E, Nordlinger B, Adam R, et al. Towards a pan-European consensus on the treatment of patients with colorectal liver metastases. Eur J Cancer. 2006; 42(14): 2212-2221.
Kishi Y, Abdalla EK, Chun YS, et al. Three hundred and one consecutive extended right hepatectomies: evaluation of outcome based on systematic liver volumetry. Ann Surg. 2009; 250(4): 540-548. doi: 10.1097/SLA.0b013e3181b674df
Kopetz S, e Chang GJ, Overman MJ, t al. Improved survival in metastatic colorectal cancer is associated with adoption of he-patic resection and improved chemotherapy. J Clin Oncol. 2009; 27(22): 3677-3683. doi: 10.1200/JCO.2008.20.5278
Abdalla EK, Adam R, Bilchik AJ, Jaeck D, Vauthey JN, Mahvi D. Improving resectability of hepatic colorectal metasta-ses: expert consensus statement. Ann Surg Oncol. 2006; 13(10): 1271-1280. doi: 10.1245/s10434-006-9045-5
Jeschke MG. The hepatic response to thermal injury: is the liver important for postburn outcomes? Mol Med. 2009; 15(9- 10): 337-351. doi: 10.2119/molmed.2009.00005
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