Home Liver Research Liver regeneration: biological and pathological mechanisms and implications

Liver regeneration: biological and pathological mechanisms and implications

Credits to the Source Link Daniel
Liver regeneration: biological and pathological mechanisms and implications
  • 1.

    Michalopoulos, G. K. Liver regeneration. J. Cell Physiol. 213, 286–300 (2007).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 2.

    Michalopoulos, G. K. & DeFrances, M. C. Liver regeneration. Science 276, 60–66 (1997).

    CAS 
    PubMed 

    Google Scholar
     

  • 3.

    Michalopoulos, G. K. Principles of liver regeneration and growth homeostasis. Compr. Physiol. 3, 485–513 (2013).

    PubMed 

    Google Scholar
     

  • 4.

    Fausto, N., Campbell, J. S. & Riehle, K. J. Liver regeneration. Hepatology 43, S45–S53 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • 5.

    Higgins, G., Anderson, R. E., Higgins, G. M. & Anderson, R. M. Experimental pathology of the liver, 1: restoration of the liver of the white rat following partial surgical removal. Arch. Pathol. 12, 186–202 (1931).


    Google Scholar
     

  • 6.

    Demetriou, A. A. et al. Transplantation of microcarrier-attached hepatocytes into 90% partially hepatectomized rats. Hepatology 8, 1006–1009 (1988).

    CAS 
    PubMed 

    Google Scholar
     

  • 7.

    Demetris, A. J. et al. Pathophysiologic observations and histopathologic recognition of the portal hyperperfusion or small-for-size syndrome. Am. J. Surg. Pathol. 30, 986–993 (2006).

    PubMed 

    Google Scholar
     

  • 8.

    Miyaoka, Y. & Miyajima, A. To divide or not to divide: revisiting liver regeneration. Cell Div. 8, 8 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 9.

    DeLeve, L. D., Wang, X. & Wang, L. VEGF-sdf1 recruitment of CXCR7+ bone marrow progenitors of liver sinusoidal endothelial cells promotes rat liver regeneration. Am. J. Physiol. Gastrointest. Liver Physiol 310, G739–G746 (2016).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 10.

    Fujii, H. et al. Contribution of bone marrow cells to liver regeneration after partial hepatectomy in mice. J. Hepatol. 36, 653–659 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • 11.

    Bonnardel, J. et al. Stellate cells, hepatocytes, and endothelial cells imprint the Kupffer Cell identity on monocytes colonizing the liver macrophage niche. Immunity 51, 638–654.e9 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 12.

    Marubashi, S. et al. Effect of portal hemodynamics on liver regeneration studied in a novel portohepatic shunt rat model. Surgery 136, 1028–1037 (2004).

    PubMed 

    Google Scholar
     

  • 13.

    Preziosi, M., Okabe, H., Poddar, M., Singh, S. & Monga, S. P. Endothelial Wnts regulate β-catenin signaling in murine liver zonation and regeneration: a sequel to the Wnt-Wnt situation. Hepatol. Commun. 2, 845–860 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 14.

    Russell, J. O. & Monga, S. P. Wnt/β-catenin signaling in liver development, homeostasis, and pathobiology. Annu. Rev. Pathol. 13, 351–378 (2018).

    CAS 
    PubMed 

    Google Scholar
     

  • 15.

    Rappaport, A. M. The microcirculatory hepatic unit. Microvasc. Res. 6, 212–228 (1973).

    CAS 
    PubMed 

    Google Scholar
     

  • 16.

    Wake, K. Hepatic stellate cells: three-dimensional structure, localization, heterogeneity and development. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 82, 155–164 (2006).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 17.

    Oda, M., Yokomori, H. & Han, J. Y. Regulatory mechanisms of hepatic microcirculatory hemodynamics: hepatic arterial system. Clin. Hemorheol. Microcirc. 34, 11–26 (2006).

    PubMed 

    Google Scholar
     

  • 18.

    Mars, W. M. et al. Immediate early detection of urokinase receptor after partial hepatectomy and its implications for initiation of liver regeneration. Hepatology 21, 1695–1701 (1995).

    CAS 
    PubMed 

    Google Scholar
     

  • 19.

    Kim, T. H., Mars, W. M., Stolz, D. B. & Michalopoulos, G. K. Expression and activation of pro-MMP-2 and pro-MMP-9 during rat liver regeneration. Hepatology 31, 75–82 (2000).

    CAS 
    PubMed 

    Google Scholar
     

  • 20.

    Kim, T. H., Mars, W. M., Stolz, D. B., Petersen, B. E. & Michalopoulos, G. K. Extracellular matrix remodeling at the early stages of liver regeneration in the rat. Hepatology 26, 896–904 (1997).

    CAS 
    PubMed 

    Google Scholar
     

  • 21.

    Nejak-Bowen, K., Orr, A., Bowen, W. C. Jr. & Michalopoulos, G. K. Conditional genetic elimination of hepatocyte growth factor in mice compromises liver regeneration after partial hepatectomy. PLoS ONE 8, e59836 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 22.

    Mars, W. M., Kim, T. H., Stolz, D. B., Liu, M. L. & Michalopoulos, G. K. Presence of urokinase in serum-free primary rat hepatocyte cultures and its role in activating hepatocyte growth factor. Cancer Res. 56, 2837–2843 (1996).

    CAS 
    PubMed 

    Google Scholar
     

  • 23.

    Lindroos, P. M., Zarnegar, R. & Michalopoulos, G. K. Hepatocyte growth factor (hepatopoietin A) rapidly increases in plasma before DNA synthesis and liver regeneration stimulated by partial hepatectomy and carbon tetrachloride administration. Hepatology 13, 743–750 (1991).

    CAS 
    PubMed 

    Google Scholar
     

  • 24.

    Saegusa, S., Isaji, S. & Kawarada, Y. Changes in serum hyaluronic acid levels and expression of CD44 and CD44 mRNA in hepatic sinusoidal endothelial cells after major hepatectomy in cirrhotic rats. World J. Surg. 26, 694–699 (2002).

    PubMed 

    Google Scholar
     

  • 25.

    Roselli, H. T. et al. Liver regeneration is transiently impaired in urokinase-deficient mice. Am. J. Physiol. 275, G1472–G1479 (1998).

    CAS 
    PubMed 

    Google Scholar
     

  • 26.

    Lieber, A. et al. Adenovirus-mediated urokinase gene transfer induces liver regeneration and allows for efficient retrovirus transduction of hepatocytes in vivo. Proc. Natl Acad. Sci. USA 92, 6210–6214 (1995).

    CAS 
    PubMed 

    Google Scholar
     

  • 27.

    Mohammed, F. F. & Khokha, R. Thinking outside the cell: proteases regulate hepatocyte division. Trends Cell Biol. 15, 555–563 (2005).

    CAS 
    PubMed 

    Google Scholar
     

  • 28.

    Rudolph, K. L. et al. Differential regulation of extracellular matrix synthesis during liver regeneration after partial hepatectomy in rats. Hepatology 30, 1159–1166 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • 29.

    Gallai, M. et al. Proteoglycan gene expression in rat liver after partial hepatectomy. Biochem. Biophys. Res. Commun. 228, 690–694 (1996).

    CAS 
    PubMed 

    Google Scholar
     

  • 30.

    Weymann, A. et al. p21 is required for dextrose-mediated inhibition of mouse liver regeneration. Hepatology 50, 207–215 (2009).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 31.

    Moolten, F. L. & Bucher, N. L. Regeneration of rat liver: transfer of humoral agent by cross circulation. Science 158, 272–274 (1967).

    CAS 
    PubMed 

    Google Scholar
     

  • 32.

    Jirtle, R. L. & Michalopoulos, G. Effects of partial hepatectomy on transplanted hepatocytes. Cancer Res. 42, 3000–3004 (1982).

    CAS 
    PubMed 

    Google Scholar
     

  • 33.

    Kohler, C. et al. Expression of Notch-1 and its ligand Jagged-1 in rat liver during liver regeneration. Hepatology 39, 1056–1065 (2004).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 34.

    Monga, S. P., Pediaditakis, P., Mule, K., Stolz, D. B. & Michalopoulos, G. K. Changes in WNT/β-catenin pathway during regulated growth in rat liver regeneration. Hepatology 33, 1098–1109 (2001).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 35.

    Stolz, D. B., Mars, W. M., Petersen, B. E., Kim, T. H. & Michalopoulos, G. K. Growth factor signal transduction immediately after two-thirds partial hepatectomy in the rat. Cancer Res. 59, 3954–3960 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • 36.

    Taub, R. Liver regeneration 4: transcriptional control of liver regeneration. FASEB J. 10, 413–427 (1996).

    CAS 
    PubMed 

    Google Scholar
     

  • 37.

    Apte, U. et al. Enhanced liver regeneration following changes induced by hepatocyte-specific genetic ablation of integrin-linked kinase. Hepatology 50, 844–851 (2009).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 38.

    Desbarats, J. & Newell, M. K. Fas engagement accelerates liver regeneration after partial hepatectomy. Nat. Med. 6, 920–923 (2000).

    CAS 
    PubMed 

    Google Scholar
     

  • 39.

    Albrecht, J. H. et al. Involvement of p21 and p27 in the regulation of CDK activity and cell cycle progression in the regenerating liver. Oncogene 16, 2141–2150 (1998).

    CAS 
    PubMed 

    Google Scholar
     

  • 40.

    Bhave, V. S. et al. Genes inducing iPS phenotype play a role in hepatocyte survival and proliferation in vitro and liver regeneration in vivo. Hepatology 54, 1360–1370 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 41.

    Mullany, L. K. et al. Distinct proliferative and transcriptional effects of the D-type cyclins in vivo. Cell Cycle 7, 2215–2224 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 42.

    Russell, W. E., Kaufmann, W. K., Sitaric, S., Luetteke, N. C. & Lee, D. C. Liver regeneration and hepatocarcinogenesis in transforming growth factor-alpha-targeted mice. Mol. Carcinog. 15, 183–189 (1996).

    CAS 
    PubMed 

    Google Scholar
     

  • 43.

    Taub, R. Liver regeneration: from myth to mechanism. Nat. Rev. Mol. Cell Biol. 5, 836–847 (2004).

    CAS 
    PubMed 

    Google Scholar
     

  • 44.

    Paranjpe, S. et al. Combined systemic elimination of MET and epidermal growth factor receptor signaling completely abolishes liver regeneration and leads to liver decompensation. Hepatology 64, 1711–1724 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 45.

    Greenbaum, L. E., Cressman, D. E., Haber, B. A. & Taub, R. Coexistence of C/EBP alpha, beta, growth-induced proteins and DNA synthesis in hepatocytes during liver regeneration. Implications for maintenance of the differentiated state during liver growth. J. Clin. Invest. 96, 1351–1365 (1995).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 46.

    Wang, X. et al. Rapid hepatocyte nuclear translocation of the Forkhead Box M1B (FoxM1B) transcription factor caused a transient increase in size of regenerating transgenic hepatocytes. Gene Expr. 11, 149–162 (2003).

    CAS 
    PubMed 

    Google Scholar
     

  • 47.

    Klochendler, A. et al. A transgenic mouse marking live replicating cells reveals in vivo transcriptional program of proliferation. Dev. Cell 23, 681–690 (2012).

    CAS 
    PubMed 

    Google Scholar
     

  • 48.

    Rabes, H. M. Kinetics of hepatocellular proliferation as a function of the microvascular structure and functional state of the liver. Ciba Found. Symp. https://doi.org/10.1002/9780470720363.ch3 (1977).

  • 49.

    Volk, A., Michalopoulos, G., Weidner, M. & Gebhardt, R. Different proliferative responses of periportal and pericentral rat hepatocytes to hepatocyte growth factor. Biochem. Biophys. Res. Commun. 207, 578–584 (1995).

    CAS 
    PubMed 

    Google Scholar
     

  • 50.

    Stocker, E. & Heine, W. D. Regeneration of liver parenchyma under normal and pathological conditions. Beitr. Pathol. 144, 400–408 (1971).

    CAS 
    PubMed 

    Google Scholar
     

  • 51.

    Biondo-Simoes Mde, L. et al. Effect of aging on liver regeneration in rats. Acta Cir. Bras. 21, 197–202 (2006).

    PubMed 

    Google Scholar
     

  • 52.

    Matsumoto, T., Wakefield, L., Tarlow, B. D. & Grompe, M. In vivo lineage tracing of polyploid hepatocytes reveals extensive proliferation during liver regeneration. Cell Stem Cell 26, 34–47.e3 (2020).

    CAS 
    PubMed 

    Google Scholar
     

  • 53.

    Trusolino, L., Bertotti, A. & Comoglio, P. M. MET signalling: principles and functions in development, organ regeneration and cancer. Nat. Rev. Mol. Cell Biol. 11, 834–848 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 54.

    Gentile, A., Trusolino, L. & Comoglio, P. M. The Met tyrosine kinase receptor in development and cancer. Cancer Metastasis Rev. 27, 85–94 (2008).

    CAS 
    PubMed 

    Google Scholar
     

  • 55.

    Liu, M. L., Mars, W. M., Zarnegar, R. & Michalopoulos, G. K. Uptake and distribution of hepatocyte growth factor in normal and regenerating adult rat liver. Am. J. Pathol. 144, 129–140 (1994).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 56.

    Bard-Chapeau, E. A. et al. Concerted functions of Gab1 and Shp2 in liver regeneration and hepatoprotection. Mol. Cell Biol. 26, 4664–4674 (2006).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 57.

    Zarnegar, R., DeFrances, M. C., Kost, D. P., Lindroos, P. & Michalopoulos, G. K. Expression of hepatocyte growth factor mRNA in regenerating rat liver after partial hepatectomy. Biochem. Biophys. Res. Commun. 177, 559–565 (1991).

    CAS 
    PubMed 

    Google Scholar
     

  • 58.

    Kono, S., Nagaike, M., Matsumoto, K. & Nakamura, T. Marked induction of hepatocyte growth factor mRNA in intact kidney and spleen in response to injury of distant organs. Biochem. Biophys. Res. Commun. 186, 991–998 (1992).

    CAS 
    PubMed 

    Google Scholar
     

  • 59.

    Yanagita, K. et al. Lung may have an endocrine function producing hepatocyte growth factor in response to injury of distal organs. Biochem. Biophys. Res. Commun. 182, 802–809 (1992).

    CAS 
    PubMed 

    Google Scholar
     

  • 60.

    Broten, J., Michalopoulos, G., Petersen, B. & Cruise, J. Adrenergic stimulation of hepatocyte growth factor expression. Biochem. Biophys. Res. Commun. 262, 76–79 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • 61.

    Passino, M. A., Adams, R. A., Sikorski, S. L. & Akassoglou, K. Regulation of hepatic stellate cell differentiation by the neurotrophin receptor p75NTR. Science 315, 1853–1856 (2007).

    CAS 
    PubMed 

    Google Scholar
     

  • 62.

    Carver, R. S., Stevenson, M. C., Scheving, L. A. & Russell, W. E. Diverse expression of ErbB receptor proteins during rat liver development and regeneration. Gastroenterology 123, 2017–2027 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • 63.

    Paranjpe, S. et al. RNA interference against hepatic epidermal growth factor receptor has suppressive effects on liver regeneration in rats. Am. J. Pathol. 176, 2669–2681 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 64.

    Odegard, J. et al. Differential effects of epidermal growth factor (EGF) receptor ligands on receptor binding, downstream signalling pathways and DNA synthesis in hepatocytes. Growth Factors 35, 239–248 (2017).

    CAS 
    PubMed 

    Google Scholar
     

  • 65.

    Olsen, P. S., Poulsen, S. S. & Kirkegaard, P. Adrenergic effects on secretion of epidermal growth factor from Brunner’s glands. Gut 26, 920–927 (1985).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 66.

    Skov Olsen, P. et al. Influence of epidermal growth factor on liver regeneration after partial hepatectomy in rats. Hepatology 8, 992–996 (1988).

    CAS 
    PubMed 

    Google Scholar
     

  • 67.

    Dao, D. T., Anez-Bustillos, L., Adam, R. M., Puder, M. & Bielenberg, D. R. Heparin-binding epidermal growth factor-like growth factor as a critical mediator of tissue repair and regeneration. Am. J. Pathol. 188, 2446–2456 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 68.

    Webber, E. M., FitzGerald, M. J., Brown, P. I., Bartlett, M. H. & Fausto, N. Transforming growth factor-alpha expression during liver regeneration after partial hepatectomy and toxic injury, and potential interactions between transforming growth factor-alpha and hepatocyte growth factor. Hepatology 18, 1422–1431 (1993).

    CAS 
    PubMed 

    Google Scholar
     

  • 69.

    Lee, D. C. et al. TACE/ADAM17 processing of EGFR ligands indicates a role as a physiological convertase. Ann. NY Acad. Sci. 995, 22–38 (2003).

    CAS 
    PubMed 

    Google Scholar
     

  • 70.

    Berasain, C. et al. Amphiregulin: an early trigger of liver regeneration in mice. Gastroenterology 128, 424–432 (2005).

    CAS 
    PubMed 

    Google Scholar
     

  • 71.

    Khai, N. C. et al. In vivo hepatic HB-EGF gene transduction inhibits Fas-induced liver injury and induces liver regeneration in mice: a comparative study to HGF. J. Hepatol. 44, 1046–1054 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • 72.

    Mitchell, C. et al. Heparin-binding epidermal growth factor-like growth factor links hepatocyte priming with cell cycle progression during liver regeneration. J. Biol. Chem. 280, 2562–2568 (2005).

    CAS 
    PubMed 

    Google Scholar
     

  • 73.

    Maretti-Mira, A. C., Wang, X., Wang, L. & DeLeve, L. D. Incomplete differentiation of engrafted bone marrow endothelial progenitor cells initiates hepatic fibrosis in the rat. Hepatology 69, 1259–1272 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 74.

    Natarajan, A., Wagner, B. & Sibilia, M. The EGF receptor is required for efficient liver regeneration. Proc. Natl Acad. Sci. USA 104, 17081–17086 (2007).

    CAS 
    PubMed 

    Google Scholar
     

  • 75.

    Scheving, L. A., Zhang, X., Stevenson, M. C., Threadgill, D. W. & Russell, W. E. Loss of hepatocyte EGFR has no effect alone but exacerbates carbon tetrachloride-induced liver injury and impairs regeneration in hepatocyte Met-deficient mice. Am. J. Physiol. Gastrointest. Liver Physiol. 308, G364–G377 (2015).

    CAS 
    PubMed 

    Google Scholar
     

  • 76.

    Normanno, N. et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 366, 2–16 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • 77.

    Jo, M. et al. Cross-talk between epidermal growth factor receptor and c-Met signal pathways in transformed cells. J. Biol. Chem. 275, 8806–8811 (2000).

    CAS 
    PubMed 

    Google Scholar
     

  • 78.

    Tsagianni, A. et al. Combined systemic disruption of MET and epidermal growth factor receptor signaling causes liver failure in normal mice. Am. J. Pathol. 88, 2223–2235 (2018).


    Google Scholar
     

  • 79.

    Limaye, P. B. et al. Mechanisms of hepatocyte growth factor-mediated and epidermal growth factor-mediated signaling in transdifferentiation of rat hepatocytes to biliary epithelium. Hepatology 47, 1702–1713 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 80.

    Bhushan, B. et al. TCPOBOP-induced hepatomegaly and hepatocyte proliferation are attenuated by combined disruption of MET and EGFR signaling. Hepatology 69, 1702–1718 (2019).

    CAS 
    PubMed 

    Google Scholar
     

  • 81.

    Houck, K. A., Zarnegar, R., Muga, S. J. & Michalopoulos, G. K. Acidic fibroblast growth factor (HBGF-1) stimulates DNA synthesis in primary rat hepatocyte cultures. J. Cell Physiol. 143, 129–132 (1990).

    CAS 
    PubMed 

    Google Scholar
     

  • 82.

    Kan, M. et al. Heparin-binding growth factor type 1 (acidic fibroblast growth factor): a potential biphasic autocrine and paracrine regulator of hepatocyte regeneration. Proc. Natl Acad. Sci. USA 86, 7432–7436 (1989).

    CAS 
    PubMed 

    Google Scholar
     

  • 83.

    Huang, X. et al. Ectopic activity of fibroblast growth factor receptor 1 in hepatocytes accelerates hepatocarcinogenesis by driving proliferation and vascular endothelial growth factor-induced angiogenesis. Cancer Res. 66, 1481–1490 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • 84.

    Luo, Y. et al. Metabolic regulator βKlotho interacts with fibroblast growth factor receptor 4 (FGFR4) to induce apoptosis and inhibit tumor cell proliferation. J. Biol. Chem. 285, 30069–30078 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 85.

    Padrissa-Altes, S. et al. Control of hepatocyte proliferation and survival by Fgf receptors is essential for liver regeneration in mice. Gut 64, 1444–1453 (2015).

    CAS 
    PubMed 

    Google Scholar
     

  • 86.

    Cicione, C., Degirolamo, C. & Moschetta, A. Emerging role of fibroblast growth factors 15/19 and 21 as metabolic integrators in the liver. Hepatology 56, 2404–2411 (2012).

    CAS 
    PubMed 

    Google Scholar
     

  • 87.

    Kong, B. et al. Fibroblast growth factor 15 deficiency impairs liver regeneration in mice. Am. J. Physiol. Gastrointest. Liver Physiol 306, G893–G902 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 88.

    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 28, 959–970 (1998).

    CAS 
    PubMed 

    Google Scholar
     

  • 89.

    Kirillova, I., Chaisson, M. & Fausto, N. Tumor necrosis factor induces DNA replication in hepatic cells through nuclear factor κB activation. Cell Growth Differ. 10, 819–828 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • 90.

    Cressman, D. E. et al. Liver failure and defective hepatocyte regeneration in interleukin-6- deficient mice. Science 274, 1379–1383 (1996).

    CAS 
    PubMed 

    Google Scholar
     

  • 91.

    Norris, C. A. et al. Synthesis of IL-6 by hepatocytes is a normal response to common hepatic stimuli. PLoS ONE 9, e96053 (2014).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 92.

    Fausto, N. Liver regeneration. J. Hepatol. 32, 19–31 (2000).

    CAS 
    PubMed 

    Google Scholar
     

  • 93.

    Runge, D. M., Runge, D., Foth, H., Strom, S. C. & Michalopoulos, G. K. STAT 1alpha/1beta, STAT 3 and STAT 5: expression and association with c- MET and EGF-receptor in long-term cultures of human hepatocytes. Biochem. Biophys. Res. Commun. 265, 376–381 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • 94.

    Cruise, J. L., Knechtle, S. J., Bollinger, R. R., Kuhn, C. & Michalopoulos, G. Alpha 1-adrenergic effects and liver regeneration. Hepatology 7, 1189–1194 (1987).

    CAS 
    PubMed 

    Google Scholar
     

  • 95.

    Cruise, J. L., Houck, K. A. & Michalopoulos, G. K. Induction of DNA synthesis in cultured rat hepatocytes through stimulation of alpha 1 adrenoreceptor by norepinephrine. Science 227, 749–751 (1985).

    CAS 
    PubMed 

    Google Scholar
     

  • 96.

    Han, C., Bowen, W. C., Michalopoulos, G. K. & Wu, T. Alpha-1 adrenergic receptor transactivates signal transducer and activator of transcription-3 (Stat3) through activation of Src and epidermal growth factor receptor (EGFR) in hepatocytes. J. Cell Physiol. 216, 486–497 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 97.

    Houck, K. A., Cruise, J. L. & Michalopoulos, G. Norepinephrine modulates the growth-inhibitory effect of transforming growth factor-beta in primary rat hepatocyte cultures. J. Cell Physiol. 135, 551–555 (1988).

    CAS 
    PubMed 

    Google Scholar
     

  • 98.

    Huang, W. et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312, 233–236 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • 99.

    Borude, P. et al. Hepatocyte-specific deletion of farnesoid X receptor delays but does not inhibit liver regeneration after partial hepatectomy in mice. Hepatology 56, 2344–2352 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 100.

    Block, G. D. et al. Population expansion, clonal growth, and specific differentiation patterns in primary cultures of hepatocytes induced by HGF/SF, EGF and TGF alpha in a chemically defined (HGM) medium. J. Cell Biol. 132, 1133–1149 (1996).

    CAS 
    PubMed 

    Google Scholar
     

  • 101.

    Francavilla, A. et al. Screening for candidate hepatic growth factors by selective portal infusion after canine Eck’s fistula. Hepatology 14, 665–670 (1991).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 102.

    Fafalios, A. et al. A hepatocyte growth factor receptor (Met)-insulin receptor hybrid governs hepatic glucose metabolism. Nat. Med. 17, 1577–1584 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 103.

    Planas-Paz, L. et al. The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size. Nat. Cell Biol. 18, 467–479 (2016).

    CAS 
    PubMed 

    Google Scholar
     

  • 104.

    Capurro, M., Martin, T., Shi, W. & Filmus, J. Glypican-3 binds to Frizzled and plays a direct role in the stimulation of canonical Wnt signaling. J. Cell Sci. 127, 1565–1575 (2014).

    CAS 
    PubMed 

    Google Scholar
     

  • 105.

    Li, N. et al. A frizzled-like cysteine-rich domain in glypican-3 mediates wnt binding and regulates hepatocellular carcinoma tumor growth in mice. Hepatology 70, 1231–1245 (2019).

    CAS 
    PubMed 

    Google Scholar
     

  • 106.

    Monga, S. P. et al. Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes. Cancer Res. 62, 2064–2071 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • 107.

    Tetsu, O. & McCormick, F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398, 422–426 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • 108.

    Yang, J. et al. β-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation! Hepatology 60, 964–976 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 109.

    Ochoa, B. et al. Hedgehog signaling is critical for normal liver regeneration after partial hepatectomy in mice. Hepatology 51, 1712–1723 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 110.

    Swiderska-Syn, M. et al. Hedgehog regulates yes-associated protein 1 in regenerating mouse liver. Hepatology 64, 232–244 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 111.

    Liu, B. et al. Suppression of liver regeneration and hepatocyte proliferation in hepatocyte-targeted glypican 3 transgenic mice. Hepatology 52, 1060–1067 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 112.

    Bhave, V. S. et al. Regulation of liver growth by glypican 3, CD81, hedgehog, and Hhex. Am. J. Pathol. 183, 153–159 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 113.

    Machado, M. V. & Diehl, A. M. Hedgehog signalling in liver pathophysiology. J. Hepatol. 68, 550–562 (2018).

    CAS 
    PubMed 

    Google Scholar
     

  • 114.

    Li, W. et al. A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling. Cell Stem Cell 25, 54–68 (2019).

    CAS 
    PubMed 

    Google Scholar
     

  • 115.

    Septer, S. et al. Yes-associated protein is involved in proliferation and differentiation during postnatal liver development. Am. J. Physiol. Gastrointest. Liver Physiol 302, G493–G503 (2012).

    CAS 
    PubMed 

    Google Scholar
     

  • 116.

    Halder, G. & Johnson, R. L. Hippo signaling: growth control and beyond. Development 138, 9–22 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 117.

    Patel, S. H., Camargo, F. D. & Yimlamai, D. Hippo signaling in the liver regulates organ size, cell fate, and carcinogenesis. Gastroenterology 152, 533–545 (2017).

    CAS 
    PubMed 

    Google Scholar
     

  • 118.

    Grijalva, J. L. et al. Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration. Am. J. Physiol. Gastrointest. Liver Physiol 307, G196–G204 (2014).

    CAS 
    PubMed 

    Google Scholar
     

  • 119.

    Oh, S. H., Swiderska-Syn, M., Jewell, M. L., Premont, R. T. & Diehl, A. M. Liver regeneration requires Yap1-TGFbeta-dependent epithelial-mesenchymal transition in hepatocytes. J. Hepatol. 69, 359–367 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 120.

    Xue, Y. et al. Hepatitis C virus mimics effects of glypican-3 on CD81 and promotes development of hepatocellular carcinomas via activation of hippo pathway in hepatocytes. Am. J. Pathol. 188, 1469–1477 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 121.

    Ferdous, Z., Wei, V. M., Iozzo, R., Hook, M. & Grande-Allen, K. J. Decorin-transforming growth factor- interaction regulates matrix organization and mechanical characteristics of three-dimensional collagen matrices. J. Biol. Chem. 282, 35887–35898 (2007).

    CAS 
    PubMed 

    Google Scholar
     

  • 122.

    Jirtle, R. L., Carr, B. I. & Scott, C. D. Modulation of insulin-like growth factor-II/mannose 6-phosphate receptors and transforming growth factor-beta 1 during liver regeneration. J. Biol. Chem. 266, 22444–22450 (1991).

    CAS 
    PubMed 

    Google Scholar
     

  • 123.

    Jakowlew, S. B. et al. Transforming growth factor-beta (TGF-beta) isoforms in rat liver regeneration: messenger RNA expression and activation of latent TGF- beta. Cell Regul. 2, 535–548 (1991).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 124.

    Chari, R. S., Price, D. T., Sue, S. R., Meyers, W. C. & Jirtle, R. L. Down-regulation of transforming growth factor beta receptor type I, II, and III during liver regeneration. Am. J. Surg. 169, 126–131 (1995).

    CAS 
    PubMed 

    Google Scholar
     

  • 125.

    Thenappan, A. et al. Loss of transforming growth factor beta adaptor protein β-2 spectrin leads to delayed liver regeneration in mice. Hepatology 53, 1641–1650 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 126.

    Pepper, M. S., Vassalli, J. D., Orci, L. & Montesano, R. Biphasic effect of transforming growth factor-beta 1 on in vitro angiogenesis. Exp. Cell Res. 204, 356–363 (1993).

    CAS 
    PubMed 

    Google Scholar
     

  • 127.

    Hu, J. et al. Endothelial cell-derived angiopoietin-2 controls liver regeneration as a spatiotemporal rheostat. Science 343, 416–419 (2014).

    CAS 
    PubMed 

    Google Scholar
     

  • 128.

    Ichikawa, T. et al. Transforming growth factor beta and activin tonically inhibit DNA synthesis in the rat liver. Hepatology 34, 918–925 (2001).

    CAS 
    PubMed 

    Google Scholar
     

  • 129.

    Carpentier, R. et al. Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells. Gastroenterology 141, 1432–1438 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 130.

    Clotman, F. et al. Control of liver cell fate decision by a gradient of TGF beta signaling modulated by Onecut transcription factors. Genes. Dev. 19, 1849–1854 (2005).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 131.

    Clotman, F. et al. The onecut transcription factor HNF6 is required for normal development of the biliary tract. Development 129, 1819–1828 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • 132.

    Grisham, J. A morphologic study of deoxyribonucleic acid synthesis and cell proliferation in regenerating liver; autoradiography with thymidine-H3. Cancer Res. 22, 842–849 (1962).

    CAS 
    PubMed 

    Google Scholar
     

  • 133.

    Matsumoto, K., Fujii, H., Michalopoulos, G., Fung, J. J. & Demetris, A. J. Human biliary epithelial cells secrete and respond to cytokines and hepatocyte growth factors in vitro: interleukin-6, hepatocyte growth factor and epidermal growth factor promote DNA synthesis in vitro. Hepatology 20, 376–382 (1994).

    CAS 
    PubMed 

    Google Scholar
     

  • 134.

    Keitel, V. & Haussinger, D. TGR5 in the biliary tree. Dig. Dis. 29, 45–47 (2011).

    PubMed 

    Google Scholar
     

  • 135.

    Pean, N. et al. The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice. Hepatology 58, 1451–1460 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • 136.

    Glaser, S., Han, Y., Francis, H. & Alpini, G. Melatonin regulation of biliary functions. Hepatobiliary Surg. Nutr. 3, 35–43 (2014).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 137.

    Johnson, C. et al. Histamine restores biliary mass following carbon tetrachloride-induced damage in a cholestatic rat model. Dig. Liver Dis. 47, 211–217 (2015).

    CAS 
    PubMed 

    Google Scholar
     

  • 138.

    Michalopoulos, G. K., Barua, L. & Bowen, W. C. Transdifferentiation of rat hepatocytes into biliary cells after bile duct ligation and toxic biliary injury. Hepatology 41, 535–544 (2005).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 139.

    Pepe-Mooney, B. J. et al. Single-cell analysis of the liver epithelium reveals dynamic heterogeneity and an essential role for YAP in homeostasis and regeneration. Cell Stem Cell 25, 23–38.e8 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 140.

    Fouassier, L. & Fiorotto, R. Ezrin finds its groove in cholangiocytes. Hepatology 61, 1467–1470 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 141.

    Ross, M. A., Sander, C. M., Kleeb, T. B., Watkins, S. C. & Stolz, D. B. Spatiotemporal expression of angiogenesis growth factor receptors during the revascularization of regenerating rat liver. Hepatology 34, 1135–1148 (2001).

    CAS 
    PubMed 

    Google Scholar
     

  • 142.

    LeCouter, J. et al. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 299, 890–893 (2003).

    CAS 
    PubMed 

    Google Scholar
     

  • 143.

    Ding, B. S. et al. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature 468, 310–315 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 144.

    Rocha, A. S. et al. The angiocrine factor rspondin3 is a key determinant of liver zonation. Cell Rep. 13, 1757–1764 (2015).

    CAS 
    PubMed 

    Google Scholar
     

  • 145.

    Wang, L. et al. Liver sinusoidal endothelial cell progenitor cells promote liver regeneration in rats. J. Clin. Invest. 122, 1567–1573 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 146.

    Ikarashi, M. et al. Distinct development and functions of resident and recruited liver Kupffer cells/macrophages. J. Leukoc. Biol. 94, 1325–1336 (2013).

    PubMed 

    Google Scholar
     

  • 147.

    Nishiyama, K. et al. Mouse CD11b+ Kupffer cells recruited from bone marrow accelerate liver regeneration after partial hepatectomy. PLoS ONE 10, e0136774 (2015).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 148.

    Li, N. & Hua, J. Immune cells in liver regeneration. Oncotarget 8, 3628–3639 (2017).

    PubMed 

    Google Scholar
     

  • 149.

    Oben, J. A. et al. Hepatic fibrogenesis requires sympathetic neurotransmitters. Gut 53, 438–445 (2004).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 150.

    Tsuchida, T. & Friedman, S. L. Mechanisms of hepatic stellate cell activation. Nat. Rev. Gastroenterol. Hepatol. 14, 397–411 (2017).

    CAS 
    PubMed 

    Google Scholar
     

  • 151.

    Gkretsi, V. et al. Liver-specific ablation of integrin-linked kinase in mice results in abnormal histology, enhanced cell proliferation, and hepatomegaly. Hepatology 48, 1932–1941 (2008).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 152.

    Gkretsi, V., Bowen, W. C., Yang, Y., Wu, C. & Michalopoulos, G. K. Integrin-linked kinase is involved in matrix-induced hepatocyte differentiation. Biochem. Biophys. Res. Commun. 353, 638–643 (2007).

    CAS 
    PubMed 

    Google Scholar
     

  • 153.

    Donthamsetty, S. et al. Role of PINCH and its partner tumor suppressor Rsu-1 in regulating liver size and tumorigenesis. PLoS ONE 8, e74625 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 154.

    Oe, S. et al. Intact signaling by transforming growth factor beta is not required for termination of liver regeneration in mice. Hepatology 40, 1098–1105 (2004).

    CAS 
    PubMed 

    Google Scholar
     

  • 155.

    Yang, J. et al. WNT5A inhibits hepatocyte proliferation and concludes beta-catenin signaling in liver regeneration. Am. J. Pathol. 185, 2194–2205 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 156.

    Huck, I., Gunewardena, S., Espanol-Suner, R., Willenbring, H. & Apte, U. Hepatocyte nuclear factor 4 alpha activation is essential for termination of liver regeneration in mice. Hepatology 70, 666–681 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 157.

    Jin, J. et al. Cooperation of C/EBP family proteins and chromatin remodeling proteins is essential for termination of liver regeneration. Hepatology 61, 315–325 (2015).

    CAS 
    PubMed 

    Google Scholar
     

  • 158.

    Michalopoulos, G. K. & Khan, Z. Liver stem cells: experimental findings and implications for human liver disease. Gastroenterology 149, 876–882 (2015).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 159.

    Trautwein, C. et al. 2-acetaminofluorene blocks cell cycle progression after hepatectomy by p21 induction and lack of cyclin E expression. Oncogene 18, 6443–6453 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • 160.

    Evarts, R. P. et al. Precursor-product relationship between oval cells and hepatocytes: comparison between tritiated thymidine and bromodeoxyuridine as tracers. Carcinogenesis 17, 2143–2151 (1996).

    CAS 
    PubMed 

    Google Scholar
     

  • 161.

    Lu, W. Y. et al. Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat. Cell Biol. 17, 971–983 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 162.

    Raven, A. et al. Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration. Nature 547, 350–354 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 163.

    Deng, X. et al. Chronic liver injury induces conversion of biliary epithelial cells into hepatocytes. Cell Stem Cell 23, 114–122.e3 (2018).

    CAS 
    PubMed 

    Google Scholar
     

  • 164.

    Russell, J. O. et al. Hepatocyte-specific beta-catenin deletion during severe liver injury provokes cholangiocytes to differentiate into hepatocytes. Hepatology 69, 742–759 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 165.

    Dorrell, C. et al. Prospective isolation of a bipotential clonogenic liver progenitor cell in adult mice. Genes. Dev. 25, 1193–1203 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 166.

    Li, B. et al. Adult mouse liver contains two distinct populations of cholangiocytes. Stem Cell Rep. 9, 478–489 (2017).

    CAS 

    Google Scholar
     

  • 167.

    Isse, K. et al. Preexisting epithelial diversity in normal human livers: a tissue-tethered cytometric analysis in portal/periportal epithelial cells. Hepatology 57, 1632–1643 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 168.

    Aizarani, N. et al. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature 572, 199–204 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 169.

    Petersen, B. E., Zajac, V. F. & Michalopoulos, G. K. Hepatic oval cell activation in response to injury following chemically induced periportal or pericentral damage in rats. Hepatology 27, 1030–1038 (1998).

    CAS 
    PubMed 

    Google Scholar
     

  • 170.

    Kasprzak, A. et al. p21/Wafl/Cipl cellular expression in chronic long-lasting hepatitis C: correlation with HCV proteins (C, NS3, NS5A), other cell-cycle related proteins and selected clinical data. Folia Histochem. Cytobiol. 47, 385–394 (2009).

    PubMed 

    Google Scholar
     

  • 171.

    Sclair, S. N. et al. Increased hepatic progenitor cell response and ductular reaction in patients with severe recurrent HCV post-liver transplantation. Clin. Transpl. 30, 722–730 (2016).


    Google Scholar
     

  • 172.

    Khaliq, M. et al. Stat3 regulates liver progenitor cell-driven liver regeneration in zebrafish. Gene Expr. 18, 157–170 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 173.

    Limaye, P. B., Bowen, W. C., Orr, A., Apte, U. M. & Michalopoulos, G. K. Expression of hepatocytic- and biliary-specific transcription factors in regenerating bile ducts during hepatocyte-to-biliary epithelial cell transdifferentiation. Comp. Hepatol. 9, 9 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 174.

    Font-Burgada, J. et al. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer. Cell 162, 766–779 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 175.

    Michalopoulos, G. K., Bowen, W. C., Mule, K. & Luo, J. HGF-, EGF-, and dexamethasone-induced gene expression patterns during formation of tissue in hepatic organoid cultures. Gene Expr. 11, 55–75 (2003).

    CAS 
    PubMed 

    Google Scholar
     

  • 176.

    Michalopoulos, G. K., Bowen, W. C., Mule, K. & Stolz, D. B. Histological organization in hepatocyte organoid cultures. Am. J. Pathol. 159, 1877–1887 (2001).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 177.

    Schaub, J. R. et al. De novo formation of the biliary system by TGFβ-mediated hepatocyte transdifferentiation. Nature 557, 247–251 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 178.

    Yovchev, M. I., Lee, E. J., Rodriguez-Silva, W., Locker, J. & Oertel, M. Biliary obstruction promotes multilineage differentiation of hepatic stem cells. Hepatol. Commun. 3, 1137–1150 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 179.

    Limaye, P. B. et al. Expression of specific hepatocyte and cholangiocyte transcription factors in human liver disease and embryonic development. Lab. Invest. 88, 865–872 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 180.

    Hattoum, A., Rubin, E., Orr, A. & Michalopoulos, G. K. Expression of hepatocyte epidermal growth factor receptor, FAS and glypican 3 in EpCAM-positive regenerative clusters of hepatocytes, cholangiocytes, and progenitor cells in human liver failure. Hum. Pathol. 44, 743–749 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • 181.

    Stueck, A. E. & Wanless, I. R. Hepatocyte buds derived from progenitor cells repopulate regions of parenchymal extinction in human cirrhosis. Hepatology 61, 1696–1707 (2015).

    CAS 
    PubMed 

    Google Scholar
     

  • 182.

    Bhushan, B. & Apte, U. Liver regeneration after acetaminophen hepatotoxicity: mechanisms and therapeutic opportunities. Am. J. Pathol. 189, 719–729 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 183.

    Bhushan, B. et al. Pro-regenerative signaling after acetaminophen-induced acute liver injury in mice identified using a novel incremental dose model. Am. J. Pathol. 184, 3013–3025 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 184.

    Bhushan, B. et al. Dual role of epidermal growth factor receptor in liver injury and regeneration after acetaminophen overdose in mice. Toxicol. Sci. 155, 363–378 (2017).

    CAS 
    PubMed 

    Google Scholar
     

  • 185.

    Hughes, R. D., Zhang, L., Tsubouchi, H., Daikuhara, Y. & Williams, R. Plasma hepatocyte growth factor and biliprotein levels and outcome in fulminant hepatic failure. J. Hepatol. 20, 106–111 (1994).

    CAS 
    PubMed 

    Google Scholar
     

  • 186.

    James, L. P., Kurten, R. C., Lamps, L. W., McCullough, S. & Hinson, J. A. Tumour necrosis factor receptor 1 and hepatocyte regeneration in acetaminophen toxicity: a kinetic study of proliferating cell nuclear antigen and cytokine expression. Basic Clin. Pharmacol. Toxicol. 97, 8–14 (2005).

    CAS 
    PubMed 

    Google Scholar
     

  • 187.

    James, L. P., Lamps, L. W., McCullough, S. & Hinson, J. A. Interleukin 6 and hepatocyte regeneration in acetaminophen toxicity in the mouse. Biochem. Biophys. Res. Commun. 309, 857–863 (2003).

    CAS 
    PubMed 

    Google Scholar
     

  • 188.

    Donahower, B. et al. Vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicity. Am. J. Physiol. Gastrointest. Liver Physiol. 291, G102–G109 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • 189.

    Kato, T. et al. Vascular endothelial growth factor receptor-1 signaling promotes liver repair through restoration of liver microvasculature after acetaminophen hepatotoxicity. Toxicol. Sci. 120, 218–229 (2011).

    CAS 
    PubMed 

    Google Scholar
     

  • 190.

    Bhushan, B. et al. Role of bile acids in liver injury and regeneration following acetaminophen overdose. Am. J. Pathol. 183, 1518–1526 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 191.

    Bhushan, B., Poudel, S., Manley, M. W. Jr. Roy, N. & Apte, U. Inhibition of glycogen synthase kinase 3 accelerated liver regeneration after acetaminophen-induced hepatotoxicity in mice. Am. J. Pathol. 187, 543–552 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 192.

    Alvarez-Sola, G. et al. Engineered fibroblast growth factor 19 protects from acetaminophen-induced liver injury and stimulates aged liver regeneration in mice. Cell Death Dis. 8, e3083 (2017).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 193.

    Bird, T. G. et al. TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Sci. Transl Med. 10, eaan1230 (2018).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 194.

    Borude, P., Bhushan, B. & Apte, U. DNA damage response regulates initiation of liver regeneration following acetaminophen overdose. Gene Expr. 18, 115–123 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 195.

    Borude, P. et al. Pleiotropic role of p53 in injury and liver regeneration after acetaminophen overdose. Am. J. Pathol. 188, 1406–1418 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 196.

    Overturf, K. et al. Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I. Nat. Genet. 12, 266–273 (1996).

    CAS 
    PubMed 

    Google Scholar
     

  • 197.

    Overturf, K., al-Dhalimy, M., Ou, C. N., Finegold, M. & Grompe, M. Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes. Am. J. Pathol. 151, 1273–1280 (1997).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 198.

    Monga, S. P. Updates on hepatic homeostasis and the many tiers of hepatobiliary repair. Nat. Rev. Gastroenterol. Hepatol. 16, 84–86 (2019).

    CAS 
    PubMed 

    Google Scholar
     

  • 199.

    Wang, B., Zhao, L., Fish, M., Logan, C. Y. & Nusse, R. Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver. Nature 524, 180–185 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 200.

    Kennedy, S., Rettinger, S., Flye, M. W. & Ponder, K. P. Experiments in transgenic mice show that hepatocytes are the source for postnatal liver growth and do not stream. Hepatology 22, 160–168 (1995).

    CAS 
    PubMed 

    Google Scholar
     

  • 201.

    Lin, S. et al. Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury. Nature 556, 244–248 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 202.

    Chen, F. et al. Broad distribution of hepatocyte proliferation in liver homeostasis and regeneration. Cell Stem Cell 26, 27–33.e4 (2020).

    CAS 
    PubMed 

    Google Scholar
     

  • 203.

    Sun, T. et al. AXIN2+ pericentral hepatocytes have limited contributions to liver homeostasis and regeneration. Cell Stem Cell 26, 97–107.e6 (2019).

    PubMed 

    Google Scholar
     

  • 204.

    Monga, S. P. No zones left behind: democratic hepatocytes contribute to liver homeostasis and repair. Cell Stem Cell 26, 2–3 (2020).

    CAS 
    PubMed 

    Google Scholar
     

  • 205.

    Michalopoulos, G. K. Hepatostat: liver regeneration and normal liver tissue maintenance. Hepatology 65, 1384–1392 (2017).

    PubMed 

    Google Scholar
     

  • 206.

    Klaas, M. et al. The alterations in the extracellular matrix composition guide the repair of damaged liver tissue. Sci. Rep. 6, 27398 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 207.

    Canbay, A. et al. Apoptotic body engulfment by a human stellate cell line is profibrogenic. Lab. Invest. 83, 655–663 (2003).

    CAS 
    PubMed 

    Google Scholar
     

  • 208.

    Duncan, A. W. et al. The ploidy conveyor of mature hepatocytes as a source of genetic variation. Nature 467, 707–710 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 209.

    Anti, M. et al. DNA ploidy pattern in human chronic liver diseases and hepatic nodular lesions. Flow cytometric analysis on echo-guided needle liver biopsy. Cancer 73, 281–288 (1994).

    CAS 
    PubMed 

    Google Scholar
     

  • 210.

    Duncan, A. W. et al. Frequent aneuploidy among normal human hepatocytes. Gastroenterology 142, 25–28 (2012).

    PubMed 

    Google Scholar
     

  • 211.

    Boege, Y. et al. A dual role of caspase-8 in triggering and sensing proliferation-associated DNA damage, a key determinant of liver cancer development. Cancer Cell 32, 342–359 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 212.

    Zhu, M. et al. Somatic mutations increase hepatic clonal fitness and regeneration in chronic liver disease. Cell 177, 608–621 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 213.

    Luo, J. H. et al. Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas. Hepatology 44, 1012–1024 (2006).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Source Link

    Related Articles

    Leave a Comment

    This website uses cookies to improve your experience. We will assume you are ok with this, but you can opt-out if you wish. Accept Read More

    %d bloggers like this: