medigraphic.com
ISSN 2395-8723 (Electronic)
ISSN 1405-888X (Print)
TIP Revista Especializada en Ciencias Químico-Biológicas

2020, Number 1

<< Back Next >>

TIP Rev Esp Cienc Quim Biol 2020; 23 (1)

Hepatocyte plasticity and its relevance in liver physiology and pathology

Ríos-López DG, Aranda-López Y, Sosa-Garrocho M, Macías-Silva M

Language: Spanish
References: 141
Page: 1-19
PDF size: 406.62 Kb.


ABSTRACT

The liver is one of the most important organs that contribute to maintain metabolic homeostasis in vertebrates, with a high regenerative capacity. Liver is constituted by diverse cellular types, which work together to accomplish the organ function. Hepatocytes are the main cellular type responsible for most of hepatic functions; they are a heterogeneous population with specialized metabolic functions. Several signaling pathways such as TGF-β/Smads, Hippo/YAP-TAZ and Wnt/ β-catenin, among others, regulate hepatocytes phenotype. These cells are normally in a quiescent state but they exhibit plasticity in response to liver damage; thus, they can proliferate or change their phenotype through process such as transdifferentiation or transformation in order to contribute to the maintenance of liver homeostasis or during the development of diverse pathologies.


REFERENCES

  1. Anfuso, B., El-Khobar, K. E., Sukowati, C. H. C. & Tiribelli, C. (2015). The multiple origin of cancer stem cells in hepatocellular carcinoma. Clinics and Research in Hepatology and Gastroenterology, 39, S92–S97. https:// doi.org/10.1016/j.clinre.2015.05.011.

  2. Bakiri, L. & Wagner, E. F. (2013). Mouse models for liver cancer. Molecular Oncology, 7(2), 206–223. https://doi. org/10.1016/j.molonc.2013.01.005.

  3. Ballatori, N., Henson, J. H., Seward, D. J., Cai, S. Y., Runnegar, M., Fricker, G. & Boyer, J. L. (2006). Retention of structural and functional polarity in cultured skate hepatocytes undergoing in vitro morphogenesis. Comparative Biochemistry and Physiology - B Biochemistry and Molecular Biology, 144(2), 167–179. https://doi.org/10.1016/j.cbpb.2006.02.005.

  4. Balogh, J., Victor III, D., Gordon, S., Li, X., Ghobrial, R. M. & Monsour Jr, H. P. (2016). Hepatocellular carcinoma: a review. Journal of Hepatocellular Carcinoma, 3, 41–53. https://doi.org/https://doi.org/10.2147/JHC.S61146.

  5. Benhamouche, S., Decaens, T., Godard, C., Chambrey, R., Rickman, D. S., Moinard, C. & Colnot, S. (2006). Apc Tumor Suppressor Gene Is the “Zonation-Keeper” of Mouse Liver. Developmental Cell, 10(6), 759–770. https://doi.org/10.1016/j.devcel.2006.03.015.

  6. Bird, T. G. & Forbes, S. J. (2015). Two Fresh Streams to Fill the Liver’s Hepatocyte Pool. Cell Stem Cell, 17(4), 377– 378. https://doi.org/10.1016/j.stem.2015.09.007.

  7. Böhm, F., Köhler, U. A., Speicher, T. & Werner, S. (2010). Regulation of liver regeneration by growth factors and cytokines. EMBO Molecular Medicine, 2(8), 294–305. https://doi.org/10.1002/emmm.201000085.

  8. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A. & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68(6), 394–424. https://doi. org/10.3322/caac.21492.

  9. Briscoe, J. & Thérond, P. P. (2013). The mechanisms of Hedgehog signalling and its roles in development and disease. Nature Reviews Molecular Cell Biology, 14(7), 416–429. https://doi.org/10.1038/nrm3598.

  10. Burke, Z. D., Reed, K. R., Yeh, S.-W., Meniel, V., Sansom, O. J., Clarke, A. R. & Tosh, D. (2018). Spatio temporal regulation of liver development by the Wnt/β-catenin pathway. Scientific Reports, 8(2735), 1–9. https://doi. org/10.1038/s41598-018-20888-y.

  11. Cassim, S., Raymond, V.-A., Lapierre, P. & Bilodeau, M. (2017). From in vivo to in vitro: Major metabolic alterations take place in hepatocytes during and following isolation. PLoS ONE, 12(12), 1–14. https://doi. org/10.1371/journal.pone.0190366.

  12. Celton-Morizur, S. & Desdouets, C. (2010). Polyploidization of liver cells. En Poon R.Y.C. (Eds) Polyploidization and Cancer. Advances in Experimental Medicine and Biology, 676, (pp.123–135). https://doi.org/10.1007/978-1-4419- 6199-0.

  13. Chen, Y., Zheng, S., Qi, D., Zheng, S., Guo, J., Zhang, S. & Weng, Z. (2012). Inhibition of Notch Signaling by a γ-Secretase Inhibitor Attenuates Hepatic Fibrosis in Rats. PLoS ONE, 7(10), 1–11. https://doi.org/10.1371/journal. pone.0046512.

  14. Choi, T. Y., Ninov, N., Stainier, D. Y. R. & Shin, D. (2014). Extensive conversion of hepatic biliary epithelial cells to hepatocytes after near total loss of hepatocytes in zebrafish. Gastroenterology, 146(3), 776–788. https://doi. org/10.1053/j.gastro.2013.10.019.

  15. Cicchini, C., Amicone, L., Alonzi, T., Marchetti, A., Mancone, C. & Tripodi, M. (2015). Molecular mechanisms controlling the phenotype and the EMT/MET dynamics of hepatocyte. Liver International, 35(2), 302–310. https://doi.org/10.1111/liv.12577.

  16. Cicchini, C., Filippini, D., Coen, S., Marchetti, A., Cavallari, C., Laudadio, I. & Tripodi, M. (2006). Snail controls differentiation of hepatocytes by repressing HNF4α expression. Journal of Cellular Physiology, 209(1), 230– 238. https://doi.org/10.1002/jcp.20730.

  17. Cullen, J. M. (2010). Histologic patterns of Hepatotoxic Injury. En McQueen, C.A. (Ed)/ Comprehensive Toxicology (Second Edition), 9 (pp. 141–150). Elsevier Science. https://doi.org/10.1016/B978-0-08-046884-6.01007-1.

  18. Colnot, S. & Perret, C. (2011). Liver Zonation. En Monga, S. (Eds) Molecular Pathology of Liver Diseases. Molecular Pathology Library, Vol. 5, (pp. 7–16). Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-7107-4_2.

  19. De Santis Puzzonia, M., Cozzolino, A. M., Grassi, G., Bisceglia, F., Strippoli, R., Guarguaglini, G. & Amicone, L. (2016). TGFβ induces binucleation/polyploidization in hepatocytes through a src-dependent cytokinesis failure. PLoS ONE, 11(11), 1–18. https://doi.org/10.1371/journal. pone.0167158.

  20. Decaens, C. & Cassio, D. (2001). Spatio temporal expression of catenins, ZO-1, and occludin during early polarization of hepatic WIF-B9 cells. American Journal of Physiology-Cell Physiology, 49(3), C527–C539. https:// doi.org/10.1152/ajpcell.2001.280.3.c527.

  21. Deharde, D., Schneider, C., Hiller, T., Fischer, N., Kegel, V., Lübberstedt, M. & Damm, G. (2016). Bile canaliculi formation and biliary transport in 3D sandwich-cultured hepatocytes in dependence of the extracellular matrix composition. Archives of Toxicology, 90(10), 2497–2511. https://doi.org/10.1007/s00204-016-1758-z.

  22. Dooley, S. & ten Dijke, P. (2012). TGF-β in progression of liver disease. Cell Tissue Research, 347(1), 245–256. https://doi.org/10.1007/s00441-011-1246-y.

  23. Elmore, L. W., & Sirica, A. E. (1991). Phenotypic Characterization of Metaplastic Intestinal Glands and Ductular Hepatocytes in Cholangiofibrotic Lesions Rapidly Induced in the Caudate Liver Lobe of Rats Treated with Furan. Cancer Research, 51(20), 5752– 5759.

  24. Fabregat, I., Moreno-Càceres, J., Sánchez, A., Dooley, S., Dewidar, B., Giannelli, G. & ten Dijke, P. (2016). TGF-β signaling and liver disease. The FEBS Journal, 283, 2219–2232. https://doi.org/10.1111/febs.13665.

  25. Fan, B., Malato, Y., Calvisi, D. F., Naqvi, S., Razumilava, N., Ribback, S. & Willenbring, H. (2012). Cholangiocarcinomas can originate from hepatocytes in mice. The Journal of Clinical Investigation, 122(8), 2911–2915. https://doi.org/10.1172/JCI63212.

  26. Feldmann, G. (1989). The cytoskeleton of the hepatocyte. Structure and functions. Journal of Hepatology, 8(3), 380– 386. https://doi.org/10.1016/0168-8278(89)90038-X.

  27. Ferrini, J. B., Pichard, L., Domergue, J. & Maurel, P. (1997). Long-term primary cultures of adult human hepatocytes. Chemico-Biological Interactions, 107(1–2), 31–45. https://doi.org/10.1016/S0009-2797(97)00072-0.

  28. Firrincieli, D., Boissan, M. & Chignard, N. (2010). Epithelialmesenchymal transition in the liver. Gastroenterologie Clinique et Biologique, 34(10), 523–528. https://doi. org/10.1016/j.gcb.2010.04.017.

  29. Fitamant, J., Kottakis, F., Benhamouche, S., Helen, S. Tian, Chuvin, N., Parachoniak, C. A. & Bardeesy, N. (2015). YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression. Cell Reports, 10, 1692–1707. https://doi.org/10.1016/j. celrep.2015.02.027.

  30. Font-Burgada, J., Shalapour, S., Ramaswamy, S., Hsueh, B., Rossell, D., Umemura, A. & Karin, M. (2015). Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer. Cell, 162(4), 766–779. https://doi.org/10.1016/j.cell.2015.07.026.

  31. Fordyce, J. A. (2006). The evolutionary consequences of ecological interactions mediated through phenotypic plasticity. Journal of Experimental Biology, 209(12), 2377–2383. https://doi.org/10.1242/jeb.02271.

  32. Franco, D. L., Mainez, J., Vega, S., Sancho, P., Murillo, M. M., De Frutos, C. A. & Nieto, M. A. (2010). Snail1 suppresses TGF-β-induced apoptosis and is sufficient to trigger EMT in hepatocytes. Journal of Cell Science, 123(20), 3467–3477. https://doi.org/10.1242/jcs.068692.

  33. Furuyama, K., Kawaguchi, Y., Akiyama, H., Horiguchi, M., Kodama, S., Kuhara, T. & Uemoto, S. (2011). Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nature Genetics, 43(1), 34–41. https://doi.org/10.1038/ng.722.

  34. Geiger, T., Northemann, W., Schmelzer, E., Gross, V., Gauthier, F. & Heinrich, P. C. (1982). Synthesis of α1‐ Antitrypsin in Rat‐Liver Hepatocytes and in a Cell‐Free System. European Journal of Biochemistry, 126(1), 189– 195. https://doi.org/10.1111/j.1432-1033.1982.tb06765.x.

  35. Gentric, G. & Desdouets, C. (2014). Polyploidization in liver tissue. American Journal of Pathology, 184(2), 322–331. https://doi.org/10.1016/j.ajpath.2013.06.035.

  36. Gissen, P. & Arias, I. M. (2015). Structural and functional hepatocyte polarity and liver disease. Journal of Hepatology, 63(4), 1023–1037. https://doi.org/10.1016/j. jhep.2015.06.015.

  37. Grijalva, J. L., Huizenga, M., Mueller, K., Rodriguez, S., Brazzo, J., Camargo, F. & Vakili, K. (2014). Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration. American Journal of Physiology-Gastrointestinal and Liver Physiology, 307(2), G196–G204. https://doi.org/10.1152/ ajpgi.00077.2014.

  38. Gu, X., Huang, D., Ci, L., Shi, J., Zhang, M., Yang, H. & Fei, J. (2017). Fate tracing of hepatocytes in mouse liver. Scientific Reports, 7(1), 1–10. https://doi.org/10.1038/ s41598-017-15973-7.

  39. Gupta, S. & Maitra, A. (2016). EMT: Matter of Life or Death? Cell, 164(5), 840–842. https://doi.org/10.1016/j. cell.2016.02.024.

  40. Hagenbeek, T. J., Webster, J. D., Kljavin, N. M., Chang, M. T., Pham, T., Lee, H. J. & Dey, A. (2018). The Hippo pathway effector TAZ induces TEAD-dependent liver inflammation and tumors. Science Signaling, 11(547), 1–11. https://doi.org/10.1126/scisignal.aaj1757.

  41. Hao, Y., Chun, A., Cheung, K., Rashidi, B. & Yang, X. (2008). Tumor Suppressor LATS1 Is a Negative Regulator of Oncogene YAP. The Journal of Biological Chemistry, 283(9), 5496–5509. https://doi.org/10.1074/jbc. M709037200

  42. Hewitt, N. J., Lechón, M. J. G., Houston, J. B., Hallifax, D., Brown, H. S., Maurel, P. & Hengstler, J. G. (2007). Primary hepatocytes: Current understanding of the regulation of metabolic enzymes and transporter proteins, and pharmaceutical practice for the use of hepatocytes in metabolism, enzyme induction, transporter, clearance, and hepatotoxicity studies. Drug Metabolism Reviews, 39(1), 159–234. https://doi.org/10.1080/03602530601093489.

  43. Hirose, Y., Itoh, T. & Miyajima, A. (2009). Hedgehog signal activation coordinates proliferation and differentiation of fetal liver progenitor cells. Experimental Cell Research, 315(15), 2648–2657. https://doi.org/10.1016/j. yexcr.2009.06.018.

  44. Huang, J. Y., Zhang, K., Chen, D. Q., Chen, J., Feng, B., Song, H. & Chen, L. B. (2015). MicroRNA-451: Epithelialmesenchymal transition inhibitor and prognostic biomarker of hepatocelluar carcinoma. Oncotarget, 6(21), 18613–18630. https://doi.org/10.18632/oncotarget.4317.

  45. Huch, M., Bonfanti, P., Boj, S. F., Sato, T., Loomans, C. J. M., Van De Wetering, M. & Clevers, H. (2013). Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. EMBO Journal, 32(20), 2708–2721. https://doi.org/10.1038/emboj.2013.204.

  46. Huh, D., Hamilton, G. A. & Ingber, D. E. (2011). From 3D cell culture to organs-on-chips. Trends in Cell Biology, 21(12), 745–754. https://doi.org/10.1016/j.tcb.2011.09.005.

  47. Itoh, Y., Saitoh, M. & Miyazawa, K. (2018). Smad3- STAT3 crosstalk in pathophysiological contexts. Acta Biochemica et Biophysica Sinica, 50(1), 82–90. https:// doi.org/10.1093/abbs/gmx118.

  48. Jeliazkova, P., Jörs, S., Lee, M., Zimber-Strobl, U., Ferrer, J., Schmid, R. M. & Geisler, F. (2013). Canonical Notch2 signaling determines biliary cell fates of embryonic hepatoblasts and adult hepatocytes independent of Hes1. Hepatology, 57(6), 2469–2479. https://doi.org/10.1002/ hep.26254.

  49. Jessen, K. R., Mirsky, R. & Arthur-Farraj, P. (2015). The role of cell plasticity in tissue repair: adaptive cellular reprogramming. Developmental Cell, 34(6), 613–620. https://doi.org/10.1016/j.devcel.2015.09.005.

  50. Jungermann, K. & Kietzmann, T. (1996). Zonation of parenchymal and non parenchymal metabolism in liver. Annual Review of Nutrition, 16, 179–203. https://doi. org/10.1146/annurev.nu.16.070196.001143.

  51. Kaimori, A., Potter, J., Kaimori, J. Y., Wang, C., Mezey, E. & Koteish, A. (2007). Transforming growth factor-β1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro. Journal of Biological Chemistry, 282(30), 22089–22101. https://doi. org/10.1074/jbc.M700998200.

  52. Kanai, F., Marignani, P. A., Sarbassova, D., Yagi, R., Hall, R. A., Donowitz, M. & Yaffe, M. B. (2000). Taz a Novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. The EMBO Journal, 19(24), 6778–6791. https://doi.org/10.1093/ emboj/19.24.6778.

  53. Kang, L.-I., Mars, W. & Michalopoulos, G. (2012). Signals and Cells Involved in Regulating Liver Regeneration. Cells, 1(4), 1261–1292. https://doi.org/10.3390/cells1041261.

  54. Katoonizadeh, A. (2017). Liver regeneration. En Muriel, P. (Eds) Liver Pathophysiology. chapter 7 (pp. 113-123). Academic Press. http://dx.doi.org/10.1016/B978-0-12- 804274-8.00007-2.

  55. Katz, N., Teutsch, H. F., Jungermann, K. & Sasse, D. (1977). Heterogeneous reciprocal localization of fructose-1, 6-bis-phosphatase and of glucokinase in microdissected periportal and perivenous rat liver tissue. FEBS Letters, 83(2), 272–276. https://doi.org/10.1016/0014- 5793(77)81021-1.

  56. Kheolamai, P. & Dickson A. J. (2009). Liver-enriched transcription factors are critical for the expression of hepatocyte marker genes in mES-derived hepatocytelineage cells. BMC Molecular Biology, 10(35), 1–11. https://doi.org/10.1186/1471-2199-10-35.

  57. Kietzmann, T. (2017). Metabolic zonation of liver: the oxigen gradient revisited. Redox Biology, 11, 622–630. https:// doi.org/10.1016/j.redox.2017.01.012.

  58. Kmiec, Z. (2001). Cooperation of liver cells in health and disease. En Sutovsky, P. (Ed). Advances in Anatomy Embriology and Cell Biology (pp. 1–151). Springer- Verlag Berlin Heidelberg. https://doi.org/10.1007/978-3- 642-56553-3.

  59. Kreutz, C., MacNelly, S., Follo, M., Wäldin, A., Binninger- Lacour, P., Timmer, J. & Bartolomé-Rodríguez, M. M. (2017). Hepatocyte ploidy is a diversity factor for liver homeostasis. Frontiers in Physiology, 8(862), 1–15. https://doi.org/10.3389/fphys.2017.00862.

  60. Kuijk, E. W., Rasmussen, S., Blokzijl, F., Huch, M., Gehart, H., Toonen, P. & Cuppen, E. (2016). Generation and characterization of rat liver stem cell lines and their engraftment in a rat model of liver failure. Scientific Reports, 6(22154), 1–11. https://doi.org/10.1038/ srep22154.

  61. Leask, A. & Abraham, D. (2004). TGF-β signaling and the fibrotic response. The FASEB Journal, 18(7), 816–827. https://doi.org/10.1096/fj.03-1273rev.

  62. LeCluyse, E. L., Witek, R. P., Andersen, M. E. & Powers, M. J. (2012). Organotypic liver culture models: Meeting current challenges in toxicity testing. Critical Reviews in Toxicology, 42(6), 501–548. https://doi.org/10.3109/1040 8444.2012.682115.

  63. Lee, D., Park, J. O., Kim, T., Kim, S., Kim, T., Kim, M. & Lim, D. (2016). LATS-YAP/TAZ controls linage specification by regulating TGFβ signaling and Hnf4alpha expression during liver development. Nature Communications, 7, 1–14. https://doi.org/10.1038/ncomms11961.

  64. Lee, K., Lee, J., Kim, T., Kim, T., Park, H., Byun, J. & Lim, A.-S. (2010). The Hippo – Salvador pathway restrains hepatic oval cell proliferation , liver size , and liver tumorigenesis. Proceedings of the National Academy of Sciences of the USA, 107(18), 8248–8253. https://doi. org/10.1073/pnas.0912203107/-/DCSupplemental.www. pnas.org/cgi/doi/10.1073/pnas.0912203107.

  65. Liu, C. Y., Zha, Z. Y., Zhou, X., Zhang, H., Huang, W., Zhao, D. & Guan, K. L. (2010). The hippo tumor pathway promotes TAZ degradation by phosphorylating a phosphodegron and recruiting the SCFβ-TrCP E3 ligase. Journal of Biological Chemistry, 285(48), 37159–37169. https://doi.org/10.1074/jbc.M110.152942.

  66. Lu, L., Finegold, M. J. & Johnson, R. L. (2018). Hippo pathway coactivators Yap and Taz are required to coordinate mammalian liver regeneration. Experimental and Molecular Medicine, 50(1–8). https://doi.org/10.1038/ emm.2017.205.

  67. Lu, M., Jolly, M. K., Levine, H., Onuchic, J. N. & Ben-Jacob, E. (2013). MicroRNA-based regulation of epithelialhybrid- mesenchymal fate determination. Proceedings of the National Academy of Sciences of the USA, 110(45), 18144–18149. https://doi.org/10.1073/pnas.1318192110.

  68. Macías-Silva, M., Abdollah, S., Hoodless, P. A., Pirone, R., Attisano, L. & Wrana, J. L. (1996). MADR2 is a substrate of the TGFβ receptor and its phosphorylation is required for nuclear accumulation and signaling. Cell, 87(7), 1215– 1224. https://doi.org/10.1016/S0092-8674(00)81817-6.

  69. Macías-Silva, M., Li, W., Leu, J.I., Crissey, M.A.S. & Taub, R. (2002). Up-regulated transcriptional repressors SnoN and Ski bind Smad proteins to antagonize transforming growth factor-beta signals during liver regeneration. Journal of Biological Chemistry, 277(32), 28483–28490.

  70. Malato, Y., Naqvi, S., Schurmann, N., Ng, R., Wang, B., Zape, J. & Willenbring, H. (2011). Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration. Journal of Clinical Investigation, 121(12), 4850–4860. https://doi.org/10.1172/JCI59261DS1.

  71. Mannaerts, I., Leite, S. B., Verhulst, S., Claerhout, S., Eysackers, N., Thoen, L. F. R. & Van Grunsven, L. A. (2015). The Hippo pathway effector YAP controls mouse hepatic stellate cell activation. Journal of Hepatology, 63(3), 679–688. https://doi.org/10.1016/j. jhep.2015.04.011.

  72. Massagué, J. (1998). TGF-β Signal Transduction. Annual Review of Biochemistry, 67, 753–791. https://doi. org/10.1146/annurev.biochem.67.1.753.

  73. Maurel, P. (2010). Hepatocytes Methods and Protocols. En Methods in Molecular Biology, 640. Springer Sciences Business Media. LLC 2010. https://doi.org/10.1007/978- 1-60761-688-7.

  74. Merrell, A. J. & Stanger, B. Z. (2016). Adult cell plasticity in vivo: De-differentiation and transdifferentiation are back in style. Nature Reviews Molecular Cell Biology, 17(7), 413–425. https://doi.org/10.1038/nrm.2016.24.

  75. Michalopoulos, G. K. (2010). Liver regeneration after partial hepatectomy: Critical analysis of mechanistic dilemmas. American Journal of Pathology, 176(1), 2–13. https://doi. org/10.2353/ajpath.2010.090675.

  76. Michalopoulos, G. K., Barua, L. & Bowen, W. C. (2005). Transdifferentiation of rat hepatocytes into biliary cells after bile duct ligation and toxic biliary injury. Hepatology, 41(3), 535–544. https://doi.org/10.1002/hep.20600.

  77. Moghe, P. V., Berthiaume, F., Ezzell, R. M., Toner, M., Tompkins, R. G. & Yarmush, M. L. (1996). Culture matrix configuration and composition in the maintenance of hepatocyte polarity and function. Biomaterials, 17(3), 373–385. https://doi.org/10.1016/0142- 9612(96)85576-1.

  78. Monga, S. P. (2015). Β-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis. Gastroenterology, 148(7), 1294–1310. https://doi. org/10.1053/j.gastro.2015.02.056.

  79. Morell, C. M., Fiorotto, R., Fabris, L. & Strazzabosco, M. (2013). Notch signalling beyond liver development: Emerging concepts in liver repair and oncogenesis. Clinics and Research in Hepatology and Gastroenterology, 37(5), 447–454. https://doi.org/10.1016/j.clinre.2013.05.008.

  80. Moroishi, T., Hayashi, T., Pan, W. W., Fujita, Y., Holt, M. V., Qin, J. & Guan, K. L. (2016). The Hippo Pathway Kinases LATS1/2 Suppress Cancer Immunity. Cell, 167(6), 1525– 1539. https://doi.org/10.1016/j.cell.2016.11.005.

  81. Moustakas, A. & Heldin, CH. (2016). Mechanisms of TGF- β-induced epithelial-mesenchymal transition. Journal of Clinical Medicine, 5(63), 1–34. https://doi.org/10.3390/ jcm5070063.

  82. Ni, M-m, Wang, Y-r, Wu, W-w, Xia, C-c, Zhang, Y-h, Xu, J., Xu, T. & Li, J. (2018). Novel Insights on Notch signaling pathways in liver fibrosis. European Journal of Pharmacology, 826, 66–74. https://doi.org/10.1016/j. ejphar.2018.02.051.

  83. Nieto, M. A., Huang, R. Y. Y. J., Jackson, R. A. A. & Thiery, J. P. P. (2016). EMT: 2016. Cell, 166(1), 21–45. https://doi. org/10.1016/j.cell.2016.06.028.

  84. Nitta, T., Kim, J.-S., Mohuczy, D. & Behrns, K. E. (2008). Murine Cirrhosis induces hepatocyte epithelial mesenchymal transition and alterations in survival signaling pathways. Hepatology, 48(3), 909–919. https:// doi.org/10.1002/hep.22397.

  85. No D.Y., Lee, KH., Lee, J. & Lee, SH. (2015). 3D liver models on a microplatform: well-defined culture, engineering of liver tissue and liver-on-a-chip. Lab on a Chip, 15(19), 3822–3837. https://doi.org/10.1039/c5lc00611b.

  86. Ochoa, B., Syn, W. K., Delgado, I., Karaca, G. F., Jung, Y., Wang, J. & Diehl, A. M. (2010). Hedgehog signaling is critical for normal liver regeneration after partial hepatectomy in mice. Hepatology, 51(5), 1712–1723. https://doi.org/10.1002/hep.23525.

  87. Oh, S. H., Swiderska-Syn, M., Jewell, M. L., Premont, R. T. & Diehl, A. M. (2018). Liver regeneration requires Yap1- TGFβ-dependent epithelial-mesenchymal transition in hepatocytes. Journal of Hepatology, 69(2), 359–367. https://doi.org/10.1016/j.jhep.2018.05.008.

  88. Omenetti, A., Choi, S., Michelotti, G. & Diehl, A. M. (2011). Hedgehog Signaling in the liver. Journal of Hepatology, 2354(12), 366–373. https://doi.org/10.1016/j. jhep.2010.10.003.

  89. Pan, D. (2010). The Hippo signaling pathway in development and cancer. Developmental Cell, 19(4), 491–505. https:// doi.org/10.1016/j.devcel.2010.09.011.

  90. Patel, S. H., Camargo, F. D. & Yimlamai, D. (2017). Hippo Signaling in the Liver Regulates Organ Size, Cell Fate, and Carcinogenesis. Gastroenterology, 152(3), 533–545. https://doi.org/10.1053/j.gastro.2016.10.047.

  91. Perugorria, M. J., Olaizola, P., Labiano, I., Esparza-Baquer, A., Marzioni, M., Marin, J. J. G. & Banales, J. M. (2019). Wnt–β-catenin signalling in liver development, health and disease. Nature Reviews Gastroenterology and Hepatology, 16(2), 121–136. https://doi.org/10.1038/ s41575-018-0075-9.

  92. Petersen, B. E., Zajac, V. F. & Michalopoulos, G. K. (1998). Hepatic oval cell activation in response to injury following chemically induced periportal or pericentral damage in rats. Hepatology, 27(4), 1030–1038. https:// doi.org/10.1002/hep.510270419.

  93. Pigliucci, M., Murren, C. J. & Schlichting, C. D. (2006). Phenotypic plasticity and evolution by genetic assimilation. Journal of Experimental Biology, 209(12), 2362–2367. https://doi.org/10.1242/jeb.02070.

  94. Pösö, A. R., Penttila, K. E., Suolinna, E. M. & Lindros, K. O. (1986). Urea synthesis in freshly isolated and in cultured periportal and perivenous hepatocytes. Biochemical Journal, 239(2), 263–267. https://doi.org/10.1042/ bj2390263.

  95. Pritchard, M. T. & Apte, U. (2015). Models to Study Liver Regeneration. En Apte, U. (Ed). Liver Regeneration: Basic Mechanisms, Relevant Models and Clinical Applications. (pp.15–40) USA: Academic Press. https:// doi.org/10.1016/B978-0-12-420128-6.00002-6.

  96. Roberts, A. B., Lamb, L. C., Newton, D. L., Sporn, M. B., De Larco, J. E. & Todaro, G. J. (1980). Transforming growth factors: isolation of polypeptides from virally and chemically transformed cells by acid/ethanol extraction. Proceedings of the National Academy of Sciences of USA, 77(6), 3494–3498. https://doi.org/10.1073/ pnas.77.6.3494.

  97. Rodgarkia-Dara, C., Vejda, S., Erlach, N., Losert, A., Bursch, W., Berger, W. & Grusch, M. (2006). The activin axis in liver biology and disease. Reviews in Mutation Research, 613(2–3), 123–137. https://doi.org/10.1016/j. mrrev.2006.07.002.

  98. Runge, D., Runge, D. M., Jäger, D., Lubecki, K. A., Beer Stolz, D., Karathanasis, S. & Michalopoulos, G. K. (2000). Serum-free, long-term cultures of human hepatocytes: Maintenance of cell morphology, transcription factors, and liver-specific functions. Biochemical and Biophysical Research Communications, 269(1), 46–53. https://doi. org/10.1006/bbrc.2000.2215.

  99. Russell, J. O. & Monga, S. P. (2018). Wnt/β-Catenin Signaling in Liver Development, Homeostasis, and Pathobiology. Annual Review of Pathology: Mechanisms of Disease, 13, 351–378. https://doi.org/10.1146/annurevpathol- 020117-044010.

  100. Schmidt-Arras, D. & Rose-John, S. (2016). IL-6 pathway in the liver: from physiopathology to therapy. Journal of Hepatology, 64(6), 1403–1415. https://doi.org/10.1016/j. jhep.2016.02.004.

  101. Sekiya, S. & Suzuki, A. (2012). Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes. Journal of Clinical Investigation, 122(11), 3914–3918. https://doi.org/10.1172/JCI63065DS1.

  102. Sell, S. (2002). Cellular origin of hepatocellular carcinomas. Seminars in Cell and Developmental Biology, 13(6), 419–424. https://doi.org/10.1016/S1084952102001295.

  103. Shaub, J. R., Huppert, K. A., Kurial, S. N., Hsu, B.Y., Cast, A. E., Donnelly, B., Karns, R. A., Chen, F., Rezvani, M., Luu, H.,Y., Mattis, A. N., Rougemont, A.,L., Rosenthal, P., Huppert, S. S. & Willenbring, H. (2018). De novo formation of the biliary system by TGF-β- mediated hepatocyte transdifferentiation. Nature, 557(7704), 247– 251. https://doi.org/10.1038/s41586-018-0075-5.

  104. Shulman, M. & Nahmias Y. (2013). Long-term culture and coculture of primary rat and human hepatocytes. Methods in Molecular Biology, 945, 287–302. https://doi. org/10.1007/978-1-62703-125-7_17.

  105. Sicklick, J. K., Li, Y. X., Melhem, A., Schmelzer, E., Zdanowicz, M., Huang, J. & Diehl, A. M. (2006). Hedgehog signaling maintains resident hepatic progenitors throughout life. American Journal of Physiology- Gastrointestinal and Liver Physiology, 290(5), G859– G870. https://doi.org/10.1152/ajpgi.00456.2005.

  106. Sierra-Santoyo, A., López, M. L., Hernández, A. & Mendoza- Figueroa, T. (1994). Urea production in long-term cultures of adult rat hepatocytes. Toxicology in Vitro, 8(2), 293– 299. https://doi.org/10.1016/0887-2333(94)90196-1.

  107. Sigal, S. H., Rajvanshi, P., Gorla, G. R., Sokhi, R. P., Saxena, R., David, R. Gebhard, J. & Gupta, A. (1999). Partial hepatectomy-induced polyploidy attenuates hepatocyte replication and activates cell aging events. American Journal of Physiology-Gastrointestinal and Liver Physiology, 276(39), G1260–G1272. https://doi. org/10.1152/ajpgi.1999.276.5.G1260.

  108. Snykers, S., De Kock, J., Rogiers, V. & Vanhaecke, T. (2009). In Vitro Differentiation of Embryonic and Adult Stem Cells into Hepatocytes: State of the Art. Stem Cells, 27(3), 577–605. https://doi.org/10.1634/stemcells.2008-0963.

  109. Stanger, B. Z. (2015). Cellular Homeostasis and Repair in the Mammalian Liver. Annual Review of Physiology, 77(1), 179–200. https://doi.org/10.1146/annurevphysiol- 021113-170255.

  110. Tan, X., Behari, J., Cieply, B., Michalopoulos, G. K. & Monga, S. P. S. (2006). Conditional Deletion of β-Catenin Reveals Its Role in Liver Growth and Regeneration. Gastroenterology, 131(5), 1561–1572. https://doi. org/10.1053/j.gastro.2006.08.042.

  111. Tanami, S., Ben-Moshe, S., Elkayam, A., Mayo, A., Bahar Halpern, K. & Itzkovitz, S. (2017). Dynamic zonation of liver polyploidy. Cell and Tissue Research, 368(2), 405–410. https://doi.org/10.1007/s00441-016-2427-5.

  112. Taub, R. (2004). Liver regeneration: From myth to mechanism. Nature Reviews Molecular Cell Biology, 5(10), 836–847. https://doi.org/10.1038/nrm1489.

  113. Taura, K., Miura, K., Iwaisako, K., Österreicher, C. H., Kodama, Y., Penz-Österreicher, M. & Brenner, D. A. (2010). Hepatocytes do not undergo epithelialmesenchymal transition in liver fibrosis in mice. Hepatology 51(3), 1027–1036. https://doi.org/10.1002/ hep.23368.

  114. Treyer, A. & Müsch, A. (2013). Hepatocyte polarity. Comprehensive Physiology, 3(1), 243–287. https://doi. org/10.1002/cphy.c120009.

  115. Tsai, W. C., Hsu, P. W. C., Lai, T. C., Chau, G. Y., Lin, C. W., Chen, C. M. & Tsou, A. P. (2009). MicroRNA-122, a tumor suppressor MicroRNA that regulates intrahepatic metastasis of hepatocellular carcinoma. Hepatology, 49(5), 1571–1582. https://doi.org/10.1002/hep.22806.

  116. Tsutsui, M., Ogawa, S., Inada, Y., Tomioka, E., Kamiyoshi, A., Tanaka, S. & Tagawa, Y. I. (2006). Characterization of cytochrome P450 expression in murine embryonic stem cell-derived hepatic tissue system. Drug Metabolism and Disposition, 34(4), 696–701. https://doi.org/10.1124/ dmd.105.007674.

  117. Tsutsumi, V., Nakamura, T., Ueno, T., Torimura, T., & Aguirre-García, J. (2017). Structure and ultrastructure of the normal and diseased liver. En Muriel, P. (Eds) Liver Pathophysiology. Chapter 2 (pp. 23-44). Academic Press. http://dx.doi.org/10.1016/B978-0-12-804274-8.00002-3.

  118. Tummala, K. S., Brandt, M., Teijeiro, A., Graña, O., Schwabe, R. F., Perna, C. & Djouder, N. (2017). Hepatocellular Carcinomas Originate Predominantly from Hepatocytes and Benign Lesions from Hepatic Progenitor Cells. Cell Reports, 19(3), 584–600. https://doi.org/10.1016/j. celrep.2017.03.059.

  119. Tunissiolli, N. M., Castanhole-Nunes, M. M. U., Biselli- Chicote, P. M., Pavarino, E. C., da Silva, R. F., da Silva, R. C. & Goloni-Bertollo, E. M. (2017). Hepatocellular Carcinoma: a Comprehensive Review of Biomarkers, Clinical Aspects, and Therapy. Asian Pacific Journal of Cancer Prevention, 18(4), 863–872. https://doi. org/10.22034/APJCP.2017.18.4.863.

  120. Varga, J. & Greten, F. R. (2017). Cell plasticity in epithelial homeostasis and tumorigenesis. Nature Cell Biology, 19(10), 1133–1141. https://doi.org/10.1038/ncb3611.

  121. Vázquez-Victorio, G., Caligaris, C., Del Valle-Espinosa, E., Sosa-Garrocho, M., González-Arenas, N. R., Reyes- Cruz, G., Briones-Orta, M. A. & Macías-Silva, M. (2015). Novel regulation of Ski protein stability and endosomal sorting by actin cytoskeleton dynamics in hepatocytes. Journal of Biological Chemistry, 290(7), 4487–4499.

  122. Villanueva, A., Alsinet, C., Yanger, K., Hoshida, Y., Zong, Y., Toffanin, A. & Llovet, J. M. (2012). Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology, 143(6), 1660–1669. https://doi.org/10.1053/j.gastro.2012.09.002.

  123. Wang, B., Zhao, L., Fish, M., Logan, C. Y. & Nusse, R. (2015). Self-renewing diploid Axin2 + cells fuel homeostatic renewal of the liver. Nature, 524(7564), 180–185. https:// doi.org/10.1038/nature14863.

  124. Wang, H., Lafdil, F., Kong, X. & Gao, B. (2011). Signal transducer and activator of transcription 3 in liver diseases: A novel therapeutic target. International Journal of Biological Sciences, 7(5), 536–550. https:// doi.org/10.7150/ijbs.7.536.

  125. Wang, L. & Boyer, J. L. (2004). The maintenance and generation of membrane polarity in hepatocytes. Hepatology, 39(4), 892–899. https://doi.org/10.1002/ hep.20039. . Weinstein, M., Monga, S. P. S., Liu, Y., Brodie, S. G., Tang, Y., Li, C. & Deng, C.-X. (2001). Smad Proteins and Hepatocyte Growth Factor Control Parallel Regulatory Pathways That Converge on 1-Integrin To Promote Normal Liver Development. Molecular and Cellular Biology, 21(15), 5122–5131. https://doi.org/10.1128/ mcb.21.15.5122-5131.2001.

  126. Wells, R. G. (2010). The epithelial to mesenchymal transition in liver fibrosis: Here today, gone tomorrow? Hepatology, 51(3), 737–740. https://doi.org/10.1002/hep.23529.

  127. Whitman, D. W. & Agrawal, A. A. (2009). What is Phenotypic Plasticity and Why is it Important? En Whithman, D. W. & Ananthakrishnan, T. N. (Ed). Phenotypic Plasticity of Insects: Mechanisms and Consequences. (pp. 1-63) New Hampshire: Science Publishers. DOIhttps://doi. org/10.1201/9780367803568.

  128. Yagi, R., Chen, L., Shigesada, K., Murakami, Y. & Ito, Y. (1999). A WW domain-containing Yes-associated protein (YAP) is a novel transcriptional co-activator. EMBO Journal, 18(9), 2551–2562. https://doi.org/10.1093/ emboj/18.9.2551.

  129. Yang, M. H., Chen, C. L., Chau, G. Y., Chiou, S. H., Su, C. W., Chou, T. Y. & Wu, J. C. (2009). Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma. Hepatology, 50(5), 1464–1474. https://doi.org/10.1002/hep.23221.

  130. Yanger, K., Zong, Y., Maggs, L. R., Shapira, S. N., Maddipati, R., Aiello, N. M. & Stanger, en Z. (2013). Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes and Development, 27, 719–724. https://doi.org/10.1101/gad.207803.112.

  131. Yimlamai, D., Fowl, B. H. & Camargo, F. D. (2015). Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer. Journal of Hepatology, 63(6), 1491–1501. https://doi.org/10.1016/j.jhep.2015.07.008.

  132. Yimlamai, D., Christodoulou, C., Galli, G. G., Yanger, K., Pepe-Mooney, B., Shrestha, K., Cahan, P., Stanger, B. Z. & Camargo, F. D. (2016). Hippo pathway activity influences liver cell fate. Cell, 157, 1324–1338. https:// dx.doi.org/10.1016/j.cell.2014.03.060.

  133. Yoshida, K., Murata, M., Yamaguchi, T., Matsuzaki, K. & Okazaki, K. (2016). Reversible Human TGF-β Signal Shifting between Tumor Suppression and Fibro- Carcinogenesis: Implications of Smad Phospho-Isoforms for Hepatic Epithelial-Mesenchymal Transitions. Journal of Clinical Medicine, 5(7), 1–19. https://doi.org/10.3390/ jcm5010007.

  134. Yu, K., Li, Q., Shi, G. & Li, N. (2018). Involvement of epithelial-mesenchymal transition in liver fibrosis. Saudi Journal of Gastroenterology. 24, 5–11. https://doi. org/10.4103/sjg.SJG_297_17.

  135. Zajicek, G., Oren, R. & Weinreb, M. (1985). The streaming liver. Liver, 5(6), 293–300. https://doi. org/10.1111/j.1600-0676.1985.tb00252.x.

  136. Zeisberg, M., Yang, C., Martino, M., Duncan, M. B., Rieder, F., Tanjore, H. & Kalluri, R. (2007). Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. Journal of Biological Chemistry, 282(32), 23337–23347. https://doi.org/10.1074/jbc.M700194200.

  137. Zhang, J., Zhang, H., Liu, J., Tu, X., Zang, Y., Zhu, J. & Zhang, J. (2012). MiR-30 inhibits TGF-β1-induced epithelial-to-mesenchymal transition in hepatocyte by targeting Snail1. Biochemical and Biophysical Research Communications, 417(3), 1100–1105. https://doi. org/10.1016/j.bbrc.2011.12.121.

  138. Zhang, N., Bai, H., David, K. K., Dong, J., Zheng, Y., Cai, J. & Pan, D. (2010). The Merlin/NF2 Tumor Suppressor Functions through the YAP Oncoprotein to Regulate Tissue Homeostasis in Mammals. Developmental Cell, 19(1), 27–38. https://doi.org/10.1016/j.devcel.2010.06.015.

  139. Zhao, J., Tang, N., Wu, K., Dai, W., Ye, C., Shi, J. & Lin, Y. (2014). MiR-21 simultaneously regulates ERK1 signaling in HSC activation and hepatocyte EMT in hepatic fibrosis. PLoS ONE, 9(10), 1–10. https://doi.org/10.1371/journal. pone.0108005.

  140. Zhao, S., Zhang, Y., Zheng, X., Tu, X., Li, H., Chen, J. & Zhang, J. (2015). Loss of MicroRNA-101 Promotes Epithelial to Mesenchymal Transition in Hepatocytes. Journal of Cellular Physiology, 230(11), 2706–2717. https://doi.org/10.1002/jcp.24995.

  141. Zhou, D., Conrad, C., Xia, F., Park, J., Payer, B., Yin, Y. & Bardeesy, N. (2009). Mst1 and Mst2 Maintain Hepatocyte Quiescence and Suppress Hepatocellular Carcinoma Development through Inactivation of the Yap1 Oncogene. Cancer Cell, 16(5), 425–438. https://doi.org/10.1016/j. ccr.2009.09.026.




2020     |     www.medigraphic.com