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Semin Liver Dis 2022; 42(03): 271-282
DOI: 10.1055/a-1869-7714
Review Article

Cellular Homeostasis and Repair in the Biliary Tree

Wei Wang
1   Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
,
Dongfeng Chen
1   Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
,
Jun Wang
1   Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
,
Liangzhi Wen
1   Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
› Author Affiliations Funding W.W. is supported by grants from the Natural Science Foundation Project of Chongqing (cstc2020jcyj-msxmX0145). L.W. is supported by grants from the National Natural Science Foundation of China (NCFS:81802459) and Chongqing Natural Science Foundation (cstc2018jcyjAX0603). D.C. is supported by grants from Youth Development Project of Army Medical University (2017XQN14).
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Abstract

During biliary tree homeostasis, BECs are largely in a quiescent state and their turnover is slow for maintaining normal tissue homeostasis. BTSCs continually replenish new BECs in the luminal surface of EHBDs. In response to various types of biliary injuries, distinct cellular sources, including HPCs, BTSCs, hepatocytes, and BECs, repair or regenerate the injured bile duct. BEC, biliary epithelial cell; BTSC, biliary tree stem/progenitor cell; EHBD, extrahepatic bile ducts; HPC, hepatic progenitor cell.

The biliary tree comprises intrahepatic bile ducts and extrahepatic bile ducts lined with epithelial cells known as biliary epithelial cells (BECs). BECs are a common target of various cholangiopathies for which there is an unmet therapeutic need in clinical hepatology. The repair and regeneration of biliary tissue may potentially restore the normal architecture and function of the biliary tree. Hence, the repair and regeneration process in detail, including the replication of existing BECs, expansion and differentiation of the hepatic progenitor cells and biliary tree stem/progenitor cells, and transdifferentiation of the hepatocytes, should be understood. In this paper, we review biliary tree homeostasis, repair, and regeneration and discuss the feasibility of regenerative therapy strategies for cholangiopathy treatment.

Keywords

biliary epithelial cells - homeostasis - injury - biliary regeneration

Abbreviations

BECs, biliary epithelial cells; BTSCs, biliary tree stem/progenitor cells; CFTR, cystic fibrosis transmembrane conductance regulator; EHBDs, extrahepatic bile ducts; HPCs, hepatic progenitor cells; Ig, immunoglobulin; IHBDs, intrahepatic bile ducts; PBC, primary biliary cholangitis; PD-1, programmed death-1; PSC, primary sclerosing cholangitis; scRNA-seq, single-cell RNA sequencing; TJs, tight junctions.




Publication History

Accepted Manuscript online:
07 June 2022

Article published online:
24 August 2022

© 2022. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
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  • References

  • 1 Lazaridis KN, LaRusso NF. The cholangiopathies. Mayo Clin Proc 2015; 90 (06) 791-800
    CrossrefPubMedSearch in Google Scholar
  • 2 Banales JM, Huebert RC, Karlsen T, Strazzabosco M, LaRusso NF, Gores GJ. Cholangiocyte pathobiology. Nat Rev Gastroenterol Hepatol 2019; 16 (05) 269-281
    CrossrefPubMedSearch in Google Scholar
  • 3 Dickson I. De novo hepatocyte-derived biliary system. Nat Rev Gastroenterol Hepatol 2018; 15 (07) 390
    CrossrefPubMedSearch in Google Scholar
  • 4 Kurial SNT, Willenbring H. Emerging cell therapy for biliary diseases. Science 2021; 371 (6531): 786-787
    CrossrefPubMedSearch in Google Scholar
  • 5 Gouw AS, Clouston AD, Theise ND. Ductular reactions in human liver: diversity at the interface. Hepatology 2011; 54 (05) 1853-1863
    CrossrefPubMedSearch in Google Scholar
  • 6 Sato K, Marzioni M, Meng F, Francis H, Glaser S, Alpini G. Ductular reaction in liver diseases: pathological mechanisms and translational significances. Hepatology 2019; 69 (01) 420-430
    CrossrefPubMedSearch in Google Scholar
  • 7 Overi D, Carpino G, Cardinale V. et al. Contribution of resident stem cells to liver and biliary tree regeneration in human diseases. Int J Mol Sci 2018; 19 (10) 2917
    CrossrefPubMedSearch in Google Scholar
  • 8 de Jong IEM, van Leeuwen OB, Lisman T, Gouw ASH, Porte RJ. Repopulating the biliary tree from the peribiliary glands. Biochim Biophys Acta Mol Basis Dis 2018; 1864 (4 Pt B): 1524-1531
    CrossrefPubMedSearch in Google Scholar
  • 9 Schaub JR, Huppert KA, Kurial SNT. et al. De novo formation of the biliary system by TGFβ-mediated hepatocyte transdifferentiation. Nature 2018; 557 (7704): 247-251
    CrossrefPubMedSearch in Google Scholar
  • 10 Lesage G, Glaser SS, Gubba S. et al. Regrowth of the rat biliary tree after 70% partial hepatectomy is coupled to increased secretin-induced ductal secretion. Gastroenterology 1996; 111 (06) 1633-1644
    CrossrefPubMedSearch in Google Scholar
  • 11 De Assuncao TM, Jalan-Sakrikar N, Huebert RC. Regenerative medicine and the biliary Tree. Semin Liver Dis 2017; 37 (01) 17-27
    Thieme ConnectPubMedSearch in Google Scholar
  • 12 Lazaridis KN, Strazzabosco M, Larusso NF. The cholangiopathies: disorders of biliary epithelia. Gastroenterology 2004; 127 (05) 1565-1577
    CrossrefPubMedSearch in Google Scholar
  • 13 Cardinale V, Wang Y, Carpino G. et al. The biliary tree—a reservoir of multipotent stem cells. Nat Rev Gastroenterol Hepatol 2012; 9 (04) 231-240
    CrossrefPubMedSearch in Google Scholar
  • 14 Tanimizu N. The neonatal liver: normal development and response to injury and disease. Semin Fetal Neonatal Med 2022; 27 (01) 101229
    CrossrefPubMedSearch in Google Scholar
  • 15 Watanabe N, Tsukada N, Smith CR, Phillips MJ. Motility of bile canaliculi in the living animal: implications for bile flow. J Cell Biol 1991; 113 (05) 1069-1080
    CrossrefPubMedSearch in Google Scholar
  • 16 Sarnova L, Gregor M. Biliary system architecture: experimental models and visualization techniques. Physiol Res 2017; 66 (03) 383-390
    CrossrefPubMedSearch in Google Scholar
  • 17 Roskams TA, Theise ND, Balabaud C. et al. Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers. Hepatology 2004; 39 (06) 1739-1745
    CrossrefPubMedSearch in Google Scholar
  • 18 Alpini G, Glaser S, Robertson W. et al. Large but not small intrahepatic bile ducts are involved in secretin-regulated ductal bile secretion. Am J Physiol 1997; 272 (5 Pt 1): G1064-G1074
    PubMedSearch in Google Scholar
  • 19 Castaing D. Surgical anatomy of the biliary tract. HPB (Oxford) 2008; 10 (02) 72-76
    CrossrefPubMedSearch in Google Scholar
  • 20 Glaser SS, Gaudio E, Rao A. et al. Morphological and functional heterogeneity of the mouse intrahepatic biliary epithelium. Lab Invest 2009; 89 (04) 456-469
    CrossrefPubMedSearch in Google Scholar
  • 21 Alpini G, Roberts S, Kuntz SM. et al. Morphological, molecular, and functional heterogeneity of cholangiocytes from normal rat liver. Gastroenterology 1996; 110 (05) 1636-1643
    CrossrefPubMedSearch in Google Scholar
  • 22 Pepe-Mooney BJ, Dill MT, Alemany A. 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 2019; 25 (01) 23-38 .e8
    CrossrefPubMedSearch in Google Scholar
  • 23 Körner M, Hayes GM, Rehmann R. et al. Secretin receptors in the human liver: expression in biliary tract and cholangiocarcinoma, but not in hepatocytes or hepatocellular carcinoma. J Hepatol 2006; 45 (06) 825-835
    CrossrefPubMedSearch in Google Scholar
  • 24 Woo K, Sathe M, Kresge C. et al. Adenosine triphosphate release and purinergic (P2) receptor-mediated secretion in small and large mouse cholangiocytes. Hepatology 2010; 52 (05) 1819-1828
    CrossrefPubMedSearch in Google Scholar
  • 25 Dutta AK, Khimji AK, Kresge C. et al. Identification and functional characterization of TMEM16A, a Ca2+-activated Cl- channel activated by extracellular nucleotides, in biliary epithelium. J Biol Chem 2011; 286 (01) 766-776
    CrossrefPubMedSearch in Google Scholar
  • 26 Celli A, Que FG, Gores GJ, LaRusso NF. Glutathione depletion is associated with decreased Bcl-2 expression and increased apoptosis in cholangiocytes. Am J Physiol 1998; 275 (04) G749-G757
    PubMedSearch in Google Scholar
  • 27 Charlotte F, L'Herminé A, Martin N. et al. Immunohistochemical detection of bcl-2 protein in normal and pathological human liver. Am J Pathol 1994; 1994: 460-465
    PubMedSearch in Google Scholar
  • 28 Katayanagi K, Van de Water J, Kenny T. et al. Generation of monoclonal antibodies to murine bile duct epithelial cells: identification of annexin V as a new marker of small intrahepatic bile ducts. Hepatology 1999; 29 (04) 1019-1025
    CrossrefPubMedSearch in Google Scholar
  • 29 Mancinelli R, Franchitto A, Gaudio E. et al. After damage of large bile ducts by gamma-aminobutyric acid, small ducts replenish the biliary tree by amplification of calcium-dependent signaling and de novo acquisition of large cholangiocyte phenotypes. Am J Pathol 2010; 176 (04) 1790-1800
    CrossrefPubMedSearch in Google Scholar
  • 30 Mancinelli R, Franchitto A, Glaser S. et al. GABA induces the differentiation of small into large cholangiocytes by activation of Ca(2+)/CaMK I-dependent adenylyl cyclase 8. Hepatology 2013; 58 (01) 251-263
    CrossrefPubMedSearch in Google Scholar
  • 31 Tulasi DY, Castaneda DM, Wager K. et al. Sox9EGFP defines biliary epithelial heterogeneity downstream of Yap activity. Cell Mol Gastroenterol Hepatol 2021; 11 (05) 1437-1462
    CrossrefPubMedSearch in Google Scholar
  • 32 Sampaziotis F, Muraro D, Tysoe OC. et al. Cholangiocyte organoids can repair bile ducts after transplantation in the human liver. Science 2021; 371 (6531): 839-846
    CrossrefPubMedSearch in Google Scholar
  • 33 Rimland CA, Tilson SG, Morell CM. et al. Regional differences in human biliary tissues and corresponding in vitro-derived organoids. Hepatology 2021; 73 (01) 247-267
    CrossrefPubMedSearch in Google Scholar
  • 34 Dyson JK, Beuers U, Jones DEJ, Lohse AW, Hudson M. Primary sclerosing cholangitis. Lancet 2018; 391 (10139): 2547-2559
    CrossrefPubMedSearch in Google Scholar
  • 35 Carpino G, Cardinale V, Renzi A. et al. Activation of biliary tree stem cells within peribiliary glands in primary sclerosing cholangitis. J Hepatol 2015; 63 (05) 1220-1228
    CrossrefPubMedSearch in Google Scholar
  • 36 Lleo A, Wang G-Q, Gershwin ME, Hirschfield GM. Primary biliary cholangitis. Lancet 2020; 396 (10266): 1915-1926
    CrossrefPubMedSearch in Google Scholar
  • 37 Carpino G, Cardinale V, Folseraas T. et al. Hepatic stem/progenitor cell activation differs between primary sclerosing and primary biliary cholangitis. Am J Pathol 2018; 188 (03) 627-639
    CrossrefPubMedSearch in Google Scholar
  • 38 Spee B, Carpino G, Schotanus BA. et al. Characterisation of the liver progenitor cell niche in liver diseases: potential involvement of Wnt and Notch signalling. Gut 2010; 59 (02) 247-257
    CrossrefPubMedSearch in Google Scholar
  • 39 Masyuk TV, Ritman EL, LaRusso NF. Quantitative assessment of the rat intrahepatic biliary system by three-dimensional reconstruction. Am J Pathol 2001; 158 (06) 2079-2088
    CrossrefPubMedSearch in Google Scholar
  • 40 Nakanuma Y, Sasaki M, Harada K. Autophagy and senescence in fibrosing cholangiopathies. J Hepatol 2015; 62 (04) 934-945
    CrossrefPubMedSearch in Google Scholar
  • 41 Nakanuma Y, Tsuneyama K, Harada K. Pathology and pathogenesis of intrahepatic bile duct loss. J Hepatobiliary Pancreat Surg 2001; 8 (04) 303-315
    CrossrefPubMedSearch in Google Scholar
  • 42 Yang L, Faris RA, Hixson DC. Long-term culture and characteristics of normal rat liver bile duct epithelial cells. Gastroenterology 1993; 104 (03) 840-852
    CrossrefPubMedSearch in Google Scholar
  • 43 LeSage GD, Benedetti A, Glaser S. et al. Acute carbon tetrachloride feeding selectively damages large, but not small, cholangiocytes from normal rat liver. Hepatology 1999; 29 (02) 307-319
    CrossrefPubMedSearch in Google Scholar
  • 44 Hayata Y, Nakagawa H, Kurosaki S. et al. Axin2+ peribiliary glands in the periampullary region generate biliary epithelial stem cells that give rise to ampullary carcinoma. Gastroenterology 2021; 160 (06) 2133-2148 .e6
    CrossrefPubMedSearch in Google Scholar
  • 45 Arber N, Zajicek G. Streaming liver. VI: streaming intra-hepatic bile ducts. Liver 1990; 10 (04) 205-208
    CrossrefPubMedSearch in Google Scholar
  • 46 Iwata M, Harada K, Kono N, Kaneko S, Kobayashi K, Nakanuma Y. Expression of Bcl-2 familial proteins is reduced in small bile duct lesions of primary biliary cirrhosis. Hum Pathol 2000; 31 (02) 179-184
    CrossrefPubMedSearch in Google Scholar
  • 47 Stähelin BJ, Marti U, Zimmermann H, Reichen J. The interaction of Bcl-2 and Bax regulates apoptosis in biliary epithelial cells of rats with obstructive jaundice. Virchows Arch 1999; 434 (04) 333-339
    CrossrefPubMedSearch in Google Scholar
  • 48 Pham DH, Kudira R, Xu L. et al. Deleterious variants in ABCC12 are detected in idiopathic chronic cholestasis and cause intrahepatic bile duct loss in model organisms. Gastroenterology 2021; 161 (01) 287-300 .e16
    CrossrefPubMedSearch in Google Scholar
  • 49 Koppe C, Verheugd P, Gautheron J. et al. IκB kinaseα/β control biliary homeostasis and hepatocarcinogenesis in mice by phosphorylating the cell-death mediator receptor-interacting protein kinase 1. Hepatology 2016; 64 (04) 1217-1231
    CrossrefPubMedSearch in Google Scholar
  • 50 Koppe C, Reisinger F, Wehr K. et al. An NF-kappaB- and IKK-independent function of NEMO prevents hepatocarcinogenesis by suppressing compensatory liver regeneration. Cancers (Basel) 2019; 11 (07) 999
    CrossrefPubMedSearch in Google Scholar
  • 51 Sticova E, Jirsa M. ABCB4 disease: many faces of one gene deficiency. Ann Hepatol 2020; 19 (02) 126-133
    CrossrefPubMedSearch in Google Scholar
  • 52 Rosmorduc O, Poupon R. Low phospholipid associated cholelithiasis: association with mutation in the MDR3/ABCB4 gene. Orphanet J Rare Dis 2007; 2: 29
    CrossrefPubMedSearch in Google Scholar
  • 53 Masyuk AI, Huang BQ, Ward CJ. et al. Biliary exosomes influence cholangiocyte regulatory mechanisms and proliferation through interaction with primary cilia. Am J Physiol Gastrointest Liver Physiol 2010; 299 (04) G990 –G999
    CrossrefPubMedSearch in Google Scholar
  • 54 Boyer JL, Soroka CJ. Bile formation and secretion: an update. J Hepatol 2021; 75 (01) 190-201
    CrossrefPubMedSearch in Google Scholar
  • 55 Karlsen TH, Lammert F, Thompson RJ. Genetics of liver disease: from pathophysiology to clinical practice. J Hepatol 2015; 62 (1, Suppl) S6-S14
    CrossrefPubMedSearch in Google Scholar
  • 56 Fabris L, Fiorotto R, Spirli C. et al. Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases. Nat Rev Gastroenterol Hepatol 2019; 16 (08) 497-511
    CrossrefPubMedSearch in Google Scholar
  • 57 Hohenester S, Maillette de Buy Wenniger L, Jefferson DM, Oude Elferink RP, Beuers U. Biliary bicarbonate secretion constitutes a protective mechanism against bile acid-induced injury in man. Dig Dis 2011; 29 (01) 62-65
    CrossrefPubMedSearch in Google Scholar
  • 58 Beuers U, Hohenester S, de Buy Wenniger LJ, Kremer AE, Jansen PL, Elferink RP. The biliary HCO(3)(-) umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology 2010; 52 (04) 1489-1496
    CrossrefPubMedSearch in Google Scholar
  • 59 Andrianifahanana M, Moniaux N, Batra SK. Regulation of mucin expression: mechanistic aspects and implications for cancer and inflammatory diseases. Biochim Biophys Acta 2006; 1765 (02) 189-222
    PubMedSearch in Google Scholar
  • 60 Medina JF, Martínez-Ansó, Vazquez JJ, Prieto J. Decreased anion exchanger 2 immunoreactivity in the liver of patients with primary biliary cirrhosis. Hepatology 1997; 25 (01) 12-17
    CrossrefPubMedSearch in Google Scholar
  • 61 Poupon R, Ping C, Chrétien Y. et al. Genetic factors of susceptibility and of severity in primary biliary cirrhosis. J Hepatol 2008; 49 (06) 1038-1045
    CrossrefPubMedSearch in Google Scholar
  • 62 Hov JR, Keitel V, Laerdahl JK. et al; IBSEN Study Group. Mutational characterization of the bile acid receptor TGR5 in primary sclerosing cholangitis. PLoS One 2010; 5 (08) e12403
    CrossrefPubMedSearch in Google Scholar
  • 63 Colombo C, Battezzati PM, Strazzabosco M, Podda M. Liver and biliary problems in cystic fibrosis. Semin Liver Dis 1998; 18 (03) 227-235
    Thieme ConnectPubMedSearch in Google Scholar
  • 64 Herrmann U, Dockter G, Lammert F. Cystic fibrosis-associated liver disease. Best Pract Res Clin Gastroenterol 2010; 24 (05) 585-592
    CrossrefPubMedSearch in Google Scholar
  • 65 Riordan JR, Rommens JM, Kerem B. et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989; 245 (4922): 1066-1073
    CrossrefPubMedSearch in Google Scholar
  • 66 Rao RK, Samak G. Bile duct epithelial tight junctions and barrier function. Tissue Barriers 2013; 1 (04) e25718
    CrossrefPubMedSearch in Google Scholar
  • 67 Sambrotta M, Strautnieks S, Papouli E. et al; University of Washington Center for Mendelian Genomics. Mutations in TJP2 cause progressive cholestatic liver disease. Nat Genet 2014; 46 (04) 326-328
    CrossrefPubMedSearch in Google Scholar
  • 68 Baala L, Hadj-Rabia S, Hamel-Teillac D. et al. Homozygosity mapping of a locus for a novel syndromic ichthyosis to chromosome 3q27-q28. J Invest Dermatol 2002; 119 (01) 70-76
    CrossrefPubMedSearch in Google Scholar
  • 69 Roehlen N, Roca Suarez AA, El Saghire H. et al. Tight junction proteins and the biology of hepatobiliary disease. Int J Mol Sci 2020; 21 (03) 825
    CrossrefPubMedSearch in Google Scholar
  • 70 Fava G, Glaser S, Francis H, Alpini G. The immunophysiology of biliary epithelium. Semin Liver Dis 2005; 25 (03) 251-264
    Thieme ConnectPubMedSearch in Google Scholar
  • 71 Manning RJ, Walker PG, Carter L, Barrington PJ, Jackson GD. Studies on the origins of biliary immunoglobulins in rats. Gastroenterology 1984; 87 (01) 173-179
    CrossrefPubMedSearch in Google Scholar
  • 72 Jackson GD, Walker PG. The transient appearance of IgM antibodies in the bile of rats injected with Salmonella enteritidis. Immunol Lett 1983; 7 (01) 41-45
    CrossrefPubMedSearch in Google Scholar
  • 73 Saito K, Nakanuma Y. Lactoferrin and lysozyme in the intrahepatic bile duct of normal livers and hepatolithiasis. An immunohistochemical study. J Hepatol 1992; 15 (1-2): 147-153
    CrossrefPubMedSearch in Google Scholar
  • 74 Chen XM, O'Hara SP, Nelson JB. et al. Multiple TLRs are expressed in human cholangiocytes and mediate host epithelial defense responses to Cryptosporidium parvum via activation of NF-kappaB. J Immunol 2005; 175 (11) 7447-7456
    CrossrefPubMedSearch in Google Scholar
  • 75 Harada K, Isse K, Nakanuma Y. Interferon gamma accelerates NF-kappaB activation of biliary epithelial cells induced by toll-like receptor and ligand interaction. J Clin Pathol 2006; 59 (02) 184-190
    CrossrefPubMedSearch in Google Scholar
  • 76 Zhang H, Leung PSC, Gershwin ME, Ma X. How the biliary tree maintains immune tolerance?. Biochim Biophys Acta Mol Basis Dis 2018; 1864 (4 Pt B): 1367-1373
    CrossrefPubMedSearch in Google Scholar
  • 77 Markus BH, Duquesnoy RJ, Blaheta RA, Scholz M, Encke A. Role of HLA antigens in liver transplantation with special reference to cellular immune reactions. Langenbecks Arch Surg 1998; 383 (01) 87-94
    CrossrefPubMedSearch in Google Scholar
  • 78 Dong H, Zhu G, Tamada K, Flies DB, van Deursen JM, Chen L. B7-H1 determines accumulation and deletion of intrahepatic CD8(+) T lymphocytes. Immunity 2004; 20 (03) 327-336
    CrossrefPubMedSearch in Google Scholar
  • 79 Concepcion AR, Salas JT, Sáez E. et al. CD8+ T cells undergo activation and programmed death-1 repression in the liver of aged Ae2a,b-/- mice favoring autoimmune cholangitis. Oncotarget 2015; 6 (30) 28588-28606
    CrossrefPubMedSearch in Google Scholar
  • 80 Imoto K, Kohjima M, Hioki T. et al. Clinical features of liver injury induced by immune checkpoint inhibitors in Japanese patients. Can J Gastroenterol Hepatol 2019; 2019: 6391712
    CrossrefPubMedSearch in Google Scholar
  • 81 Stanger BZ. Cellular homeostasis and repair in the mammalian liver. Annu Rev Physiol 2015; 77: 179-200
    CrossrefPubMedSearch in Google Scholar
  • 82 Sutton ME, op den Dries S, Koster MH, Lisman T, Gouw AS, Porte RJ. Regeneration of human extrahepatic biliary epithelium: the peribiliary glands as progenitor cell compartment. Liver Int 2012; 32 (04) 554-559
    CrossrefPubMedSearch in Google Scholar
  • 83 Wells JM, Watt FM. Diverse mechanisms for endogenous regeneration and repair in mammalian organs. Nature 2018; 557 (7705): 322-328
    CrossrefPubMedSearch in Google Scholar
  • 84 Kamimoto K, Kaneko K, Kok CY, Okada H, Miyajima A, Itoh T. Heterogeneity and stochastic growth regulation of biliary epithelial cells dictate dynamic epithelial tissue remodeling. eLife 2016; 5: e15034
    CrossrefPubMedSearch in Google Scholar
  • 85 Greenbaum LE, Wells RG. The role of stem cells in liver repair and fibrosis. Int J Biochem Cell Biol 2011; 43 (02) 222-229
    CrossrefPubMedSearch in Google Scholar
  • 86 LaRusso NF. Morphology, physiology, and biochemistry of biliary epithelia. Toxicol Pathol 1996; 24 (01) 84-89
    CrossrefPubMedSearch in Google Scholar
  • 87 Franchitto A, Onori P, Renzi A. et al. Recent advances on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology. Ann Transl Med 2013; 1 (03) 27
    PubMedSearch in Google Scholar
  • 88 Alvaro D, Gigliozzi A, Attili AF. Regulation and deregulation of cholangiocyte proliferation. J Hepatol 2000; 33 (02) 333-340
    CrossrefPubMedSearch in Google Scholar
  • 89 Okada H, Yamada M, Kamimoto K. et al. The transcription factor Klf5 is essential for intrahepatic biliary epithelial tissue remodeling after cholestatic liver injury. J Biol Chem 2018; 293 (17) 6214-6229
    CrossrefPubMedSearch in Google Scholar
  • 90 Kosar K, Cornuet P, Singh S. et al. WNT7B regulates cholangiocyte proliferation and function during murine cholestasis. Hepatol Commun 2021; 5 (12) 2019-2034
    CrossrefPubMedSearch in Google Scholar
  • 91 Jhandier MN, Kruglov EA, Lavoie EG, Sévigny J, Dranoff JA. Portal fibroblasts regulate the proliferation of bile duct epithelia via expression of NTPDase2. J Biol Chem 2005; 280 (24) 22986-22992
    CrossrefPubMedSearch in Google Scholar
  • 92 Guillot A, Guerri L, Feng D. et al. Bile acid-activated macrophages promote biliary epithelial cell proliferation through integrin αvβ6 upregulation following liver injury. J Clin Invest 2021; 131 (09) e132305
    CrossrefPubMedSearch in Google Scholar
  • 93 Gaudio E, Barbaro B, Alvaro D. et al. Administration of r-VEGF-A prevents hepatic artery ligation-induced bile duct damage in bile duct ligated rats. Am J Physiol Gastrointest Liver Physiol 2006; 291 (02) G307 –G317
    CrossrefPubMedSearch in Google Scholar
  • 94 Glaser SS, Gaudio E, Alpini G. Vascular factors, angiogenesis and biliary tract disease. Curr Opin Gastroenterol 2010; 26 (03) 246-250
    CrossrefPubMedSearch in Google Scholar
  • 95 Cordero-Espinoza L, Dowbaj AM, Kohler TN. et al. Dynamic cell contacts between periportal mesenchyme and ductal epithelium act as a rheostat for liver cell proliferation. Cell Stem Cell 2021; 28 (11) 1907-1921 .e8
    CrossrefPubMedSearch in Google Scholar
  • 96 Rodrigo-Torres D, Affò S, Coll M. et al. The biliary epithelium gives rise to liver progenitor cells. Hepatology 2014; 60 (04) 1367-1377
    CrossrefPubMedSearch in Google Scholar
  • 97 Michalopoulos GK, DeFrances MC. Liver regeneration. Science 1997; 276 (5309): 60-66
    CrossrefPubMedSearch in Google Scholar
  • 98 Alpini G, Glaser SS, Ueno Y. et al. Heterogeneity of the proliferative capacity of rat cholangiocytes after bile duct ligation. Am J Physiol 1998; 274 (04) G767-G775
    PubMedSearch in Google Scholar
  • 99 LeSage GD, Glaser SS, Marucci L. et al. Acute carbon tetrachloride feeding induces damage of large but not small cholangiocytes from BDL rat liver. Am J Physiol 1999; 276 (05) G1289-G1301
    PubMedSearch in Google Scholar
  • 100 Pinto C, Giordano DM, Maroni L, Marzioni M. Role of inflammation and proinflammatory cytokines in cholangiocyte pathophysiology. Biochim Biophys Acta Mol Basis Dis 2018; 1864 (4 Pt B): 1270-1278
    CrossrefPubMedSearch in Google Scholar
  • 101 Strazzabosco M, Fiorotto R, Cadamuro M. et al. Pathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium. Biochim Biophys Acta Mol Basis Dis 2018; 1864 (4 Pt B): 1374-1379
    CrossrefPubMedSearch in Google Scholar
  • 102 Wilson DH, Jarman EJ, Mellin RP. et al. Non-canonical Wnt signalling regulates scarring in biliary disease via the planar cell polarity receptors. Nat Commun 2020; 11 (01) 445
    CrossrefPubMedSearch in Google Scholar
  • 103 Ferreira-Gonzalez S, Lu WY, Raven A. et al. Paracrine cellular senescence exacerbates biliary injury and impairs regeneration. Nat Commun 2018; 9 (01) 1020
    CrossrefPubMedSearch in Google Scholar
  • 104 Miyajima A, Tanaka M, Itoh T. Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming. Cell Stem Cell 2014; 14 (05) 561-574
    CrossrefPubMedSearch in Google Scholar
  • 105 Huch M, Gehart H, van Boxtel R. et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 2015; 160 (1-2): 299-312
    CrossrefPubMedSearch in Google Scholar
  • 106 Morrison SJ, Spradling AC. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 2008; 132 (04) 598-611
    CrossrefPubMedSearch in Google Scholar
  • 107 Theise ND. Gastrointestinal stem cells. III. Emergent themes of liver stem cell biology: niche, quiescence, self-renewal, and plasticity. Am J Physiol Gastrointest Liver Physiol 2006; 290 (02) G189-G193
    CrossrefPubMedSearch in Google Scholar
  • 108 Sancho-Bru P, Altamirano J, Rodrigo-Torres D. et al. Liver progenitor cell markers correlate with liver damage and predict short-term mortality in patients with alcoholic hepatitis. Hepatology 2012; 55 (06) 1931-1941
    CrossrefPubMedSearch in Google Scholar
  • 109 Williams MJ, Clouston AD, Forbes SJ. Links between hepatic fibrosis, ductular reaction, and progenitor cell expansion. Gastroenterology 2014; 146 (02) 349-356
    CrossrefPubMedSearch in Google Scholar
  • 110 Tabibian JH, O'Hara SP, Splinter PL, Trussoni CE, LaRusso NF. Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis. Hepatology 2014; 59 (06) 2263-2275
    CrossrefPubMedSearch in Google Scholar
  • 111 Alvaro D, Mancino MG, Glaser S. et al. Proliferating cholangiocytes: a neuroendocrine compartment in the diseased liver. Gastroenterology 2007; 132 (01) 415-431
    CrossrefPubMedSearch in Google Scholar
  • 112 Lanzoni G, Cardinale V, Carpino G. The hepatic, biliary, and pancreatic network of stem/progenitor cell niches in humans: a new reference frame for disease and regeneration. Hepatology 2016; 64 (01) 277-286
    CrossrefPubMedSearch in Google Scholar
  • 113 Lu WY, Bird TG, Boulter L. et al. Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat Cell Biol 2015; 17 (08) 971-983
    CrossrefPubMedSearch in Google Scholar
  • 114 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 (04) 572-579
    CrossrefPubMedSearch in Google Scholar
  • 115 Sparks EE, Huppert KA, Brown MA, Washington MK, Huppert SS. Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice. Hepatology 2010; 51 (04) 1391-1400
    CrossrefPubMedSearch in Google Scholar
  • 116 Fiorotto R, Raizner A, Morell CMT. et al. Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice. J Hepatol 2013; 59 (01) 124-130
    CrossrefPubMedSearch in Google Scholar
  • 117 Geisler F, Strazzabosco M. Emerging roles of Notch signaling in liver disease. Hepatology 2015; 61 (01) 382-392
    CrossrefPubMedSearch in Google Scholar
  • 118 Kitade M, Factor VM, Andersen JB. et al. Specific fate decisions in adult hepatic progenitor cells driven by MET and EGFR signaling. Genes Dev 2013; 27 (15) 1706-1717
    CrossrefPubMedSearch in Google Scholar
  • 119 Omenetti A, Yang L, Li YX. et al. Hedgehog-mediated mesenchymal-epithelial interactions modulate hepatic response to bile duct ligation. Lab Invest 2007; 87 (05) 499-514
    CrossrefPubMedSearch in Google Scholar
  • 120 Hu M, Kurobe M, Jeong YJ. et al. Wnt/beta-catenin signaling in murine hepatic transit amplifying progenitor cells. Gastroenterology 2007; 133 (05) 1579-1591
    CrossrefPubMedSearch in Google Scholar
  • 121 Jakubowski A, Ambrose C, Parr M. et al. TWEAK induces liver progenitor cell proliferation. J Clin Invest 2005; 115 (09) 2330-2340
    CrossrefPubMedSearch in Google Scholar
  • 122 Tirnitz-Parker JE, Viebahn CS, Jakubowski A. et al. Tumor necrosis factor-like weak inducer of apoptosis is a mitogen for liver progenitor cells. Hepatology 2010; 52 (01) 291-302
    CrossrefPubMedSearch in Google Scholar
  • 123 Alvarez-Dominguez JR, Melton DA. Cell maturation: Hallmarks, triggers, and manipulation. Cell 2022; 185 (02) 235-249
    CrossrefPubMedSearch in Google Scholar
  • 124 Carpino G, Cardinale V, Onori P. et al. Biliary tree stem/progenitor cells in glands of extrahepatic and intraheptic bile ducts: an anatomical in situ study yielding evidence of maturational lineages. J Anat 2012; 220 (02) 186-199
    CrossrefPubMedSearch in Google Scholar
  • 125 Cardinale V, Wang Y, Carpino G. et al. Multipotent stem/progenitor cells in human biliary tree give rise to hepatocytes, cholangiocytes, and pancreatic islets. Hepatology 2011; 54 (06) 2159-2172
    CrossrefPubMedSearch in Google Scholar
  • 126 Ridola L, Bragazzi MC, Cardinale V, Carpino G, Gaudio E, Alvaro D. Cholangiocytes: cell transplantation. Biochim Biophys Acta Mol Basis Dis 2018; 1864 (4 Pt B): 1516-1523
    CrossrefPubMedSearch in Google Scholar
  • 127 op den DriesS, Westerkamp AC, Karimian N. et al. Injury to peribiliary glands and vascular plexus before liver transplantation predicts formation of non-anastomotic biliary strictures. J Hepatol 2014; 60: 1172-1179
    CrossrefPubMedSearch in Google Scholar
  • 128 de Jong IEM, Matton APM, van Praagh JB. et al. Peribiliary glands are key in regeneration of the human biliary epithelium after severe bile duct injury. Hepatology 2019; 69 (04) 1719-1734
    CrossrefPubMedSearch in Google Scholar
  • 129 Turner R, Lozoya O, Wang Y. et al. Human hepatic stem cell and maturational liver lineage biology. Hepatology 2011; 53 (03) 1035-1045
    CrossrefPubMedSearch in Google Scholar
  • 130 Schmelzer E, Zhang L, Bruce A. et al. Human hepatic stem cells from fetal and postnatal donors. J Exp Med 2007; 204 (08) 1973-1987
    CrossrefPubMedSearch in Google Scholar
  • 131 Carpino G, Nevi L, Overi D. et al. Peribiliary gland niche participates in biliary tree regeneration in mouse and in human primary sclerosing cholangitis. Hepatology 2020; 71 (03) 972-989
    CrossrefPubMedSearch in Google Scholar
  • 132 Merrell AJ, Stanger BZ. Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style. Nat Rev Mol Cell Biol 2016; 17 (07) 413-425
    CrossrefPubMedSearch in Google Scholar
  • 133 Sekiya S, Suzuki A. Hepatocytes, rather than cholangiocytes, can be the major source of primitive ductules in the chronically injured mouse liver. Am J Pathol 2014; 184 (05) 1468-1478
    CrossrefPubMedSearch in Google Scholar
  • 134 Russell JO, Lu WY, Okabe H. et al. Hepatocyte-specific β-catenin deletion during severe liver injury provokes cholangiocytes to differentiate into hepatocytes. Hepatology 2019; 69 (02) 742-759
    CrossrefPubMedSearch in Google Scholar
  • 135 He J, Lu H, Zou Q, Luo L. Regeneration of liver after extreme hepatocyte loss occurs mainly via biliary transdifferentiation in zebrafish. Gastroenterology 2014; 146 (03) 789-800 .e8
    CrossrefPubMedSearch in Google Scholar
  • 136 Yanger K, Zong Y, Maggs LR. et al. Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev 2013; 27 (07) 719-724
    CrossrefPubMedSearch in Google Scholar
  • 137 Jeliazkova P, Jörs S, Lee M. et al. Canonical Notch2 signaling determines biliary cell fates of embryonic hepatoblasts and adult hepatocytes independent of Hes1. Hepatology 2013; 57 (06) 2469-2479
    CrossrefPubMedSearch in Google Scholar
  • 138 Walter TJ, Vanderpool C, Cast AE, Huppert SS. Intrahepatic bile duct regeneration in mice does not require Hnf6 or Notch signaling through Rbpj. Am J Pathol 2014; 184 (05) 1479-1488
    CrossrefPubMedSearch in Google Scholar
  • 139 Molina LM, Zhu J, Li Q. et al. Compensatory hepatic adaptation accompanies permanent absence of intrahepatic biliary network due to YAP1 loss in liver progenitors. Cell Rep 2021; 36 (01) 109310
    CrossrefPubMedSearch in Google Scholar
  • 140 Yimlamai D, Christodoulou C, Galli GG. et al. Hippo pathway activity influences liver cell fate. Cell 2014; 157 (06) 1324-1338
    CrossrefPubMedSearch in Google Scholar
  • 141 Thompson MD, Awuah P, Singh S, Monga SP. Disparate cellular basis of improved liver repair in beta-catenin-overexpressing mice after long-term exposure to 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Am J Pathol 2010; 177 (04) 1812-1822
    CrossrefPubMedSearch in Google Scholar
  • 142 Okabe H, Yang J, Sylakowski K. et al. Wnt signaling regulates hepatobiliary repair following cholestatic liver injury in mice. Hepatology 2016; 64 (05) 1652-1666
    CrossrefPubMedSearch in Google Scholar
  • 143 Xu T, Lu Z, Xiao Z. et al. Myofibroblast induces hepatocyte-to-ductal metaplasia via laminin-ɑvβ6 integrin in liver fibrosis. Cell Death Dis 2020; 11 (03) 199
    CrossrefPubMedSearch in Google Scholar
  • 144 Fan B, Malato Y, Calvisi DF. et al. Cholangiocarcinomas can originate from hepatocytes in mice. J Clin Invest 2012; 122 (08) 2911-2915
    CrossrefPubMedSearch in Google Scholar
  • 145 Sekiya S, Suzuki A. Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes. J Clin Invest 2012; 122 (11) 3914-3918
    CrossrefPubMedSearch in Google Scholar
  • 146 Yu Y, Wang Q, Wang C, Shang L. Living materials for regenerative medicine. Eng Regen 2021; 2: 96-104
    PubMedSearch in Google Scholar
  • 147 Aikawa M, Miyazawa M, Okamoto K. et al. A novel treatment for bile duct injury with a tissue-engineered bioabsorbable polymer patch. Surgery 2010; 147 (04) 575-580
    CrossrefPubMedSearch in Google Scholar
  • 148 Tao L, Li Q, Ren H. et al. Repair of extrahepatic bile duct defect using a collagen patch in a swine model. Artif Organs 2015; 39 (04) 352-360
    CrossrefPubMedSearch in Google Scholar
  • 149 Liang YL, Yu YC, Liu K. et al. Repair of bile duct defect with degradable stent and autologous tissue in a porcine model. World J Gastroenterol 2012; 18 (37) 5205-5210
    PubMedSearch in Google Scholar
  • 150 Sampaziotis F, Justin AW, Tysoe OC. et al. Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids. Nat Med 2017; 23 (08) 954-963
    CrossrefPubMedSearch in Google Scholar
  • 151 Justin AW, Saeb-Parsy K, Markaki AE, Vallier L, Sampaziotis F. Advances in the generation of bioengineered bile ducts. Biochim Biophys Acta Mol Basis Dis 2018; 1864 (4 Pt B): 1532-1538
    CrossrefPubMedSearch in Google Scholar
  • 152 Sun Q, Shen Z, Liang X. et al. Progress and current limitations of materials for artificial bile duct engineering. Materials (Basel) 2021; 14 (23) 7468
    CrossrefPubMedSearch in Google Scholar
  • 153 Sampaziotis F, de Brito MC, Madrigal P. et al. Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation. Nat Biotechnol 2015; 33 (08) 845-852
    CrossrefPubMedSearch in Google Scholar
  • 154 Kotini AG, de Stanchina E, Themeli M, Sadelain M, Papapetrou EP. Escape mutations, ganciclovir resistance, and teratoma formation in human iPSCs expressing an HSVtk suicide gene. Mol Ther Nucleic Acids 2016; 5: e284
    CrossrefPubMedSearch in Google Scholar
  • 155 Tysoe OC, Justin AW, Brevini T. et al. Isolation and propagation of primary human cholangiocyte organoids for the generation of bioengineered biliary tissue. Nat Protoc 2019; 14 (06) 1884-1925
    CrossrefPubMedSearch in Google Scholar
  • 156 Chen C, Jochems PGM, Salz L. et al. Bioengineered bile ducts recapitulate key cholangiocyte functions. Biofabrication 2018; 10 (03) 034103
    CrossrefPubMedSearch in Google Scholar
  • 157 Sampaziotis F, de Brito MC, Geti I, Bertero A, Hannan NR, Vallier L. Directed differentiation of human induced pluripotent stem cells into functional cholangiocyte-like cells. Nat Protoc 2017; 12 (04) 814-827
    CrossrefPubMedSearch in Google Scholar
  • 158 McDaniel K, Meng F, Wu N. et al. Forkhead box A2 regulates biliary heterogeneity and senescence during cholestatic liver injury in mice‡. Hepatology 2017; 65 (02) 544-559
    CrossrefPubMedSearch in Google Scholar
  • 159 Khan AA, Parveen N, Mahaboob VS. et al. Management of hyperbilirubinemia in biliary atresia by hepatic progenitor cell transplantation through hepatic artery: a case report. Transplant Proc 2008; 40 (04) 1153-1155
    CrossrefPubMedSearch in Google Scholar
  • 160 Hallett JM, Ferreira-Gonzalez S, Man TY. et al. Human biliary epithelial cells from discarded donor livers rescue bile duct structure and function in a mouse model of biliary disease. Cell Stem Cell 2022; 29 (03) 355-371 .e10
    CrossrefPubMedSearch in Google Scholar
  • 161 Cao H, Yang L, Hou B. et al. Heme oxygenase-1-modified bone marrow mesenchymal stem cells combined with normothermic machine perfusion to protect donation after circulatory death liver grafts. Stem Cell Res Ther 2020; 11 (01) 218
    CrossrefPubMedSearch in Google Scholar
  • 162 Zhang YC, Liu W, Fu BS. et al. Therapeutic potentials of umbilical cord-derived mesenchymal stromal cells for ischemic-type biliary lesions following liver transplantation. Cytotherapy 2017; 19 (02) 194-199
    CrossrefPubMedSearch in Google Scholar
  • 163 Basu J, Ludlow JW. Exosomes for repair, regeneration and rejuvenation. Expert Opin Biol Ther 2016; 16 (04) 489-506
    CrossrefPubMedSearch in Google Scholar
  • 164 Jun JH, Kim JY, Choi JH, Lim JY, Kim K, Kim GJ. Exosomes from placenta-derived mesenchymal stem cells are involved in liver regeneration in hepatic failure induced by bile duct ligation. Stem Cells Int 2020; 2020: 5485738
    PubMedSearch in Google Scholar
  • 165 Hirsova P, Ibrahim SH, Verma VK. et al. Extracellular vesicles in liver pathobiology: small particles with big impact. Hepatology 2016; 64 (06) 2219-2233
    CrossrefPubMedSearch in Google Scholar
  • 166 Sato K, Meng F, Venter J, Giang T, Glaser S, Alpini G. The role of the secretin/secretin receptor axis in inflammatory cholangiocyte communication via extracellular vesicles. Sci Rep 2017; 7 (01) 11183
    CrossrefPubMedSearch in Google Scholar
  • 167 García-Manrique P, Gutiérrez G, Blanco-López MC. Fully artificial exosomes: towards new theranostic biomaterials. Trends Biotechnol 2018; 36 (01) 10-14
    CrossrefPubMedSearch in Google Scholar
  • 168 Kaneko K, Kamimoto K, Miyajima A, Itoh T. Adaptive remodeling of the biliary architecture underlies liver homeostasis. Hepatology 2015; 61 (06) 2056-2066
    CrossrefPubMedSearch in Google Scholar
  • 169 Cazzagon N, Sarcognato S, Floreani A. et al. Cholangiocyte senescence in primary sclerosing cholangitis is associated with disease severity and prognosis. JHEP Reports 2021; 3: 100286
    CrossrefPubMedSearch in Google Scholar
  • 170 Chiche A, Chen C, Li H. The crosstalk between cellular reprogramming and senescence in aging and regeneration. Exp Gerontol 2020; 138: 111005
    CrossrefPubMedSearch in Google Scholar
  • 171 Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y. Modulation of the microenvironment by senescent biliary epithelial cells may be involved in the pathogenesis of primary biliary cirrhosis. J Hepatol 2010; 53 (02) 318-325
    CrossrefPubMedSearch in Google Scholar
  • 172 Plackett B. Miniature organs to heal damaged livers. Nature 2021
    PubMedSearch in Google Scholar