Recent advances on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology

Annals of Translational Medicine

Volumn 1, Issue 3, 2013, Pages

  Franchitto, Antonio ^a,b   Onori, Paolo ^c   Renzi, Anastasia ^a   Carpino, Guido ^d   Mancinelli, Romina ^a   Alvaro, Domenico ^a   Gaudio, Eugenio ^a  

^a SAPIENZA UNIVERSITY OF ROME   (Italy)

^b Eleonora Lorillard Spencer Cenci Foundation   (Italy)

^c UNIVERSITY OF L'AQUILA   (Italy)

^d UNIVERSITY OF ROME FORO ITALICO   (Italy)

Author keywords

Biliary tree; Cholangiocytes; Liver; Neuroendocrine regulation; Proliferation

Indexed keywords

EID: 85015489635     PISSN: 23055839     EISSN: 23055847     Source Type: Journal    
DOI: 10.3978/j.issn.2305-5839.2012.10.03     Document Type: Article

References (109)

1. Munshi MK, Priester S, Gaudio E, et al. Regulation of biliary proliferation by neuroendocrine factors: implications for the pathogenesis of cholestatic liver diseases. Am J Pathol 2011;178:472-84.
2. 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:G767-75.
3. LeSagE G, Alvaro D, Benedetti A, et al. Cholinergic system modulates growth, apoptosis, and secretion of cholangiocytes from bile duct-ligated rats. Gastroenterology 1999;117:191-9.
4. Alpini G, Lenzi R, Sarkozi L, et al. Biliary physiology in rats with bile ductular cell hyperplasia. Evidence for a secretory function of proliferated bile ductules. J Clin Invest 1988;81:569-78.
5. 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:G1064-74.
6. Alpini G, Prall RT, LaRusso NF. The pathobiology of biliary epithelia. In: Arias IM, Boyer JL, Chisari FV, et al. eds. The Liver; Biology & Pathobiology, 4th Ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2001:421-35.
7. Alpini G, Roberts S, Kuntz SM, et al. Morphological, molecular, and functional heterogeneity of cholangiocytes from normal rat liver. Gastroenterology 1996;110:1636-43.
8. Kanno N, LeSage G, Glaser S, et al. Regulation of cholangiocyte bicarbonate secretion. Am J Physiol Gastrointest Liver Physiol 2001;281:G612-25.
9. Nathanson MH, Boyer JL. Mechanisms and regulation of bile secretion. Hepatology 1991;14:551-66.
10. Benedetti A, Bassotti C, Rapino K, et al. A morphometric study of the epithelium lining the rat intrahepatic biliary tree. J Hepatol 1996;24:335-42.
11. Carpino F, Gaudio E, Marinozzi G, et al. A scanning and transmission electron microscopic study of experimental extrahepatic cholestasis in the rat. J Submicrosc Cytol 1981;13:581-98.
12. 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;59:247-57.
13. 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;39:1739-45.
14. Gaudio E, Carpino G, Cardinale V, et al. New insights into liver stem cells. Dig Liver Dis 2009;41:455-62.
15. Turner R, Lozoya O, Wang Y, et al. Human hepatic stem cell and maturational liver lineage biology. Hepatology 2011;53:1035-45.
16. Carruthers JS, Steiner JW. Studies on the fine structure of proliferated bile ductules. I. Changes of cytoarchitecture of biliary epithelial cells. Can Med Assoc J 1961;85:1223-36.
17. Gaudio E, Franchitto A, Pannarale L, et al. Cholangiocytes and blood supply. World J Gastroenterol 2006;12:3546-52.
18. Kanno N, LeSage G, Glaser S, et al. Functional heterogeneity of the intrahepatic biliary epithelium. Hepatology 2000;31:555-61.
19. Glaser S, Alvaro D, Francis H, et al. Adrenergic receptor agonists prevent bile duct injury induced by adrenergic denervation by increased cAMP levels and activation of Akt. Am J Physiol Gastrointest Liver Physiol 2006;290:G813-26.
20. Gaudio E, Pannarale L, Franchitto A, et al. Hepatic microcirculation as a morpho-functional basis for the metabolic zonation in normal and pathological rat liver. Ital J Anat Embryol 1995;100:419-28.
21. Gaudio E, Pannarale L, Onori P, et al. A scanning electron microscopic study of liver microcirculation disarrangement in experimental rat cirrhosis. Hepatology 1993;17:477-85.
22. Gaudio E, Barbaro B, Alvaro D, et al. Vascular endothelial growth factor stimulates rat cholangiocyte proliferation via an autocrine mechanism. Gastroenterology 2006;130:1270-82.
23. Gaudio E, Onori P, Pannarale L, et al. Hepatic microcirculation and peribiliary plexus in experimental biliary cirrhosis: a morphological study. Gastroenterology 1996;111:1118-24.
24. Reilly FD, McCuskey PA, McCuskey RS. Intrahepatic distribution of nerves in the rat. Anat Rec 1978;191:55-67.
25. Glaser S, Francis H, Demorrow S, et al. Heterogeneity of the intrahepatic biliary epithelium. World J Gastroenterol 2006;12:3523-36.
26. Glaser SS, Gaudio E, Miller T, et al. Cholangiocyte proliferation and liver fibrosis. Expert Rev Mol Med 2009;11:e7.
27. Alvaro D, Mancino MG, Glaser S, et al. Proliferating cholangiocytes: a neuroendocrine compartment in the diseased liver. Gastroenterology 2007;132:415-31.
28. Glaser SS, Gaudio E, Rao A, et al. Morphological and functional heterogeneity of the mouse intrahepatic biliary epithelium. Lab Invest 2009;89:456-69.
29. Glaser S, Lam IP, Franchitto A, et al. Knockout of secretin receptor reduces large cholangiocyte hyperplasia in mice with extrahepatic cholestasis induced by bile duct ligation. Hepatology 2010;52:204-14.
30. Alpini G, Ulrich C, Roberts S, et al. Molecular and functional heterogeneity of cholangiocytes from rat liver after bile duct ligation. Am J Physiol 1997;272:G289-97.
31. Alpini G, Ulrich CD 2nd, Phillips JO, et al. Upregulation of secretin receptor gene expression in rat cholangiocytes after bile duct ligation. Am J Physiol 1994;266:G922-8.
32. 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;111:1633-44.
33. Vacanti JP, Folkman J. Bile duct enlargement by infusion of L-proline: potential significance in biliary atresia. J Pediatr Surg 1979;14:814-8.
34. 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;29:307-19.
35. Lesage G, Glaser S, Ueno Y, et al. Regression of cholangiocyte proliferation after cessation of ANIT feeding is coupled with increased apoptosis. Am J Physiol Gastrointest Liver Physiol 2001;281:G182-90.
36. Alpini G, Glaser SS, Rodgers R, et al. Functional expression of the apical Na+-dependent bile acid transporter in large but not small rat cholangiocytes. Gastroenterology 1997;113:1734-40.
37. Alpini G, Glaser SS, Ueno Y, et al. Bile acid feeding induces cholangiocyte proliferation and secretion: evidence for bile acid-regulated ductal secretion. Gastroenterology 1999;116:179-86.
38. Slott PA, Liu MH, Tavoloni N. Origin, pattern, and mechanism of bile duct proliferation following biliary obstruction in the rat. Gastroenterology 1990;99:466-77.
39. 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:G1289-301.
40. Desmet VJ. Current problems in diagnosis of biliary disease and cholestasis. Semin Liver Dis 1986;6:233-45.
41. Lowes KN, Brennan BA, Yeoh GC, et al. Oval cell numbers in human chronic liver diseases are directly related to disease severity. Am J Pathol 1999;154:537-41.
42. Ren P, Silberg DG, Sirica AE. Expression of an intestinespecific transcription factor (CDX1) in intestinal metaplasia and in subsequently developed intestinal type of cholangiocarcinoma in rat liver. Am J Pathol 2000;156:621-7.
43. Farber E. Similarities in the sequence of early histological changes induced in the liver of the rat by ethionine, 2-acetylamino-fluorene, and 3'-methyl-4-dimethylaminoazobenzene. Cancer Res 1956;16:142-8.
44. Roskams T, Cassiman D, De Vos R, et al. Neuroregulation of the neuroendocrine compartment of the liver. Anat Rec A Discov Mol Cell Evol Biol 2004;280:910-23.
45. Alvaro D, Alpini G, Onori P, et al. Estrogens stimulate proliferation of intrahepatic biliary epithelium in rats. Gastroenterology 2000;119:1681-91.
46. Pannarale L, Onori P, Ripani M, et al. Precapillary patterns and perivascular cells in the retinal microvasculature. A scanning electron microscope study. J Anat 1996;188:693-703.
47. Glaser S, Benedetti A, Marucci L, et al. Gastrin inhibits cholangiocyte growth in bile duct-ligated rats by interaction with cholecystokinin-B/Gastrin receptors via D-myo-inositol 1,4,5-triphosphate-, Ca(2+)-, and protein kinase C alpha-dependent mechanisms. Hepatology 2000;32:17-25.
48. Francis H, Glaser S, Ueno Y, et al. cAMP stimulates the secretory and proliferative capacity of the rat intrahepatic biliary epithelium through changes in the PKA/Src/MEK/ERK1/2 pathway. J Hepatol 2004;41:528-37.
49. Alvaro D, Onori P, Metalli VD, et al. Intracellular pathways mediating estrogen-induced cholangiocyte proliferation in the rat. Hepatology 2002;36:297-304.
50. Gigliozzi A, Alpini G, Baroni GS, et al. Nerve growth factor modulates the proliferative capacity of the intrahepatic biliary epithelium in experimental cholestasis. Gastroenterology 2004;127:1198-209.
51. Alvaro D, Metalli VD, Alpini G, et al. The intrahepatic biliary epithelium is a target of the growth hormone/insulinlike growth factor 1 axis. J Hepatol 2005;43:875-83.
52. Marzioni M, Glaser S, Francis H, et al. Autocrine/paracrine regulation of the growth of the biliary tree by the neuroendocrine hormone serotonin. Gastroenterology 2005;128:121-37.
53. Francis H, Glaser S, Demorrow S, et al. Small mouse cholangiocytes proliferate in response to H1 histamine receptor stimulation by activation of the IP3/CaMK I/CREB pathway. Am J Physiol Cell Physiol 2008;295:C499-513.
54. Alpini G, Franchitto A, Demorrow S, et al. Activation of alpha(1) -adrenergic receptors stimulate the growth of small mouse cholangiocytes via calcium-dependent activation of nuclear factor of activated T cells 2 and specificity protein 1. Hepatology 2011;53:628-39.
55. 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;52:1819-28.
56. Francis HL, Demorrow S, Franchitto A, et al. Histamine stimulates the proliferation of small and large cholangiocytes by activation of both IP3/Ca2+ and cAMP-dependent signaling mechanisms. Lab Invest 2012;92:282-94.
57. 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 calciumdependent signaling and de novo acquisition of large cholangiocyte phenotypes. Am J Pathol 2010;176:1790-800.
58. Desmet VJ, van Eyken P, Roskams T. Histopathology of vanishing bile duct diseases. Adv Clin Path 1998;2:87-99.
59. Desmet VJ. Histopathology of chronic cholestasis and adult ductopenic syndrome. Clin Liver Dis 1998;2:249-64, viii.
60. Harnois DM, Que FG, Celli A, et al. Bcl-2 is overexpressed and alters the threshold for apoptosis in a cholangiocarcinoma cell line. Hepatology 1997;26:884-90.
61. Gatto M, Bragazzi MC, Semeraro R, et al. Cholangiocarcinoma: update and future perspectives. Dig Liver Dis 2010;42:253-60.
62. Onori P, DeMorrow S, Gaudio E, et al. Caffeic acid phenethyl ester decreases cholangiocarcinoma growth by inhibition of NF-kappaB and induction of apoptosis. Int J Cancer 2009;125:565-76.
63. DeMorrow S, Francis H, Gaudio E, et al. The endocannabinoid anandamide inhibits cholangiocarcinoma growth via activation of the noncanonical Wnt signaling pathway. Am J Physiol Gastrointest Liver Physiol 2008;295:G1150-8.
64. Alvaro D, Gigliozzi A, Attili AF. Regulation and deregulation of cholangiocyte proliferation. J Hepatol 2000;33:333-40.
65. Alvaro D, Onori P, Alpini G, et al. Morphological and functional features of hepatic cyst epithelium in autosomal dominant polycystic kidney disease. Am J Pathol 2008;172:321-32.
66. Sirica AE, Cihla HP. Isolation and partial characterizations of oval and hyperplastic bile ductular cell-enriched populations from the livers of carcinogen and noncarcinogen-treated rats. Cancer Res 1984;44:3454-66.
67. Yang S, Koteish A, Lin H, et al. Oval cells compensate for damage and replicative senescence of mature hepatocytes in mice with fatty liver disease. Hepatology 2004;39:403-11.
68. Xiao JC, Ruck P, Adam A, et al. Small epithelial cells in human liver cirrhosis exhibit features of hepatic stem-like cells: immunohistochemical, electron microscopic and immunoelectron microscopic findings. Histopathology 2003;42:141-9.
69. Roskams T, De Vos R, Van Eyken P, et al. Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man. J Hepatol 1998;29:455-63.
70. Eagon PK, Porter LE, Francavilla A, et al. Estrogen and androgen receptors in liver: their role in liver disease and regeneration. Semin Liver Dis 1985;5:59-69.
71. Alvaro D, Angelico M, Cantafora A, et al. Improvement of estradiol 17 beta-D-glucuronide cholestasis by intravenous administration of dimethylethanolamine in the rat. Hepatology 1991;13:1158-72.
72. Alvaro D, Alpini G, Onori P, et al. Effect of ovariectomy on the proliferative capacity of intrahepatic rat cholangiocytes. Gastroenterology 2002;123:336-44.
73. Alvaro D, Invernizzi P, Onori P, et al. Estrogen receptors in cholangiocytes and the progression of primary biliary cirrhosis. J Hepatol 2004;41:905-12.
74. Beckmann MW, Jap D, Djahansouzi S, et al. Hormone replacement therapy after treatment of breast cancer: effects on postmenopausal symptoms, bone mineral density and recurrence rates. Oncology 2001;60:199-206.
75. Reddy A, Prince M, James OF, et al. Tamoxifen: a novel treatment for primary biliary cirrhosis? Liver Int 2004;24:194-7.
76. Alvaro D, Barbaro B, Franchitto A, et al. Estrogens and insulin-like growth factor 1 modulate neoplastic cell growth in human cholangiocarcinoma. Am J Pathol 2006;169:877-88.
77. Bardin A, Hoffmann P, Boulle N, et al. Involvement of estrogen receptor beta in ovarian carcinogenesis. Cancer Res 2004;64:5861-9.
78. Lau KM, LaSpina M, Long J, et al. Expression of estrogen receptor (ER)-alpha and ER-beta in normal and malignant prostatic epithelial cells: regulation by methylation and involvement in growth regulation. Cancer Res 2000;60:3175-82.
79. Marzioni M, Torrice A, Saccomanno S, et al. An oestrogen receptor ß-selective agonist exerts anti-neoplastic effects in experimental intrahepatic cholangiocarcinoma. Dig Liver Dis 2012;44:134-42.
80. Yang F, Priester S, Onori P, et al. Castration inhibits biliary proliferation induced by bile duct obstruction: novel role for the autocrine trophic effect of testosterone. Am J Physiol Gastrointest Liver Physiol 2011;301:G981-91.
81. Hinchliffe SA, Woods S, Gray S, et al. Cellular distribution of androgen receptors in the liver. J Clin Pathol 1996;49:418-20.
82. Glaser S, DeMorrow S, Francis H, et al. Progesterone stimulates the proliferation of female and male cholangiocytes via autocrine/paracrine mechanisms. Am J Physiol Gastrointest Liver Physiol 2008;295:G124-G136.
83. Taffetani S, Glaser S, Francis H, et al. Prolactin stimulates the proliferation of normal female cholangiocytes by differential regulation of Ca2+-dependent PKC isoforms. BMC Physiol 2007;7:6.
84. Ulloa-Aguirre A, Uribe A, Zariñán T, et al. Role of the intracellular domains of the human FSH receptor in G(alphaS) protein coupling and receptor expression. Mol Cell Endocrinol 2007;260-262:153-62.
85. Gonzales PH, Rhoden CR, Luz C, et al. Male gonadal function, prolactin secretion and lactotroph population in an experimental model of cirrhosis. Braz J Med Biol Res 2007;40:1383-8.
86. Diamond T, Stiel D, Posen S. Osteoporosis in hemochromatosis: iron excess, gonadal deficiency, or other factors? Ann Intern Med 1989;110:430-6.
87. Mancinelli R, Onori P, Gaudio E, et al. Folliclestimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1. Am J Physiol Gastrointest Liver Physiol 2009;297:G11-26.
88. Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995;16:3-34.
89. Alvaro D, Macarri G, Mancino MG, et al. Serum and biliary insulin-like growth factor I and vascular endothelial growth factor in determining the cause of obstructive cholestasis. Ann Intern Med 2007;147:451-9.
90. Zachary I, Gliki G. Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovasc Res 2001;49:568-81.
91. Onori P, Wise C, Gaudio E, et al. Secretin inhibits cholangiocarcinoma growth via dysregulation of the cAMP-dependent signaling mechanisms of secretin receptor. Int J Cancer 2010;127:43-54.
92. Glaser SS, Rodgers RE, Phinizy JL, et al. Gastrin inhibits secretin-induced ductal secretion by interaction with specific receptors on rat cholangiocytes. Am J Physiol 1997;273:G1061-70.
93. Kanno N, Glaser S, Chowdhury U, et al. Gastrin inhibits cholangiocarcinoma growth through increased apoptosis by activation of Ca2+-dependent protein kinase C-alpha. J Hepatol 2001;34:284-91.
94. Tietz PS, Alpini G, Pham LD, et al. Somatostatin inhibits secretin-induced ductal hypercholeresis and exocytosis by cholangiocytes. Am J Physiol 1995;269:G110-8.
95. Tan CK, Podila PV, Taylor JE, et al. Human cholangiocarcinomas express somatostatin receptors and respond to somatostatin with growth inhibition. Gastroenterology 1995;108:1908-16.
96. Francis H, Franchitto A, Ueno Y, et al. H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway. Lab Invest 2007;87:473-87.
97. Francis H, DeMorrow S, Venter J, et al. Inhibition of histidine decarboxylase ablates the autocrine tumorigenic effects of histamine in human cholangiocarcinoma. Gut 2012;61:753-64.
98. Renzi A, Glaser S, Demorrow S, et al. Melatonin inhibits cholangiocyte hyperplasia in cholestatic rats by interaction with MT1 but not MT2 melatonin receptors. Am J Physiol Gastrointest Liver Physiol 2011;301:G634-43.
99. Kirimlioglu H, Ecevit A, Yilmaz S, et al. Effect of resveratrol and melatonin on oxidative stress enzymes, regeneration, and hepatocyte ultrastructure in rats subjected to 70% partial hepatectomy. Transplant Proc 2008;40:285-9.
100. Tahan G, Akin H, Aydogan F, et al. Melatonin ameliorates liver fibrosis induced by bile-duct ligation in rats. Can J Surg 2010;53:313-8.
101. Esrefoglu M, Gül M, Emre MH, et al. Protective effect of low dose of melatonin against cholestatic oxidative stress after common bile duct ligation in rats. World J Gastroenterol 2005;11:1951-6.
102. Han Y, Demorrow S, Invernizzi P, et al. Melatonin exerts by an autocrine loop antiproliferative effects in cholangiocarcinoma: its synthesis is reduced favoring cholangiocarcinoma growth. Am J Physiol Gastrointest Liver Physiol 2011;301:G623-33.
103. Joplin R, Hishida T, Tsubouchi H, et al. Human intrahepatic biliary epithelial cells proliferate in vitro in response to human hepatocyte growth factor. J Clin Invest 1992;90:1284-9.
104. Alvaro D, Alpini G, Jezequel AM, et al. Role and mechanisms of action of acetylcholine in the regulation of rat cholangiocyte secretory functions. J Clin Invest 1997;100:1349-62.
105. Marzioni M, Ueno Y, Glaser S, et al. Cytoprotective effects of taurocholic acid feeding on the biliary tree after adrenergic denervation of the liver. Liver Int 2007;27:558-68.
106. Alpini G, Glaser S, Robertson W, et al. Bile acids stimulate proliferative and secretory events in large but not small cholangiocytes. Am J Physiol 1997;273:G518-29.
107. Glaser S, Alvaro D, Roskams T, et al. Dopaminergic inhibition of secretin-stimulated choleresis by increased PKC-gamma expression and decrease of PKA activity. Am J Physiol Gastrointest Liver Physiol 2003;284:G683-94.
108. Glaser SS, Ueno Y, DeMorrow S, et al. Knockout of alpha-calcitonin gene-related peptide reduces cholangiocyte proliferation in bile duct ligated mice. Lab Invest 2007;87:914-26.
109. Glaser S, Gaudio E, Renzi A, et al. Knockout of the neurokinin-1 receptor reduces cholangiocyte proliferation in bile duct-ligated mice. Am J Physiol Gastrointest Liver Physiol 2011;301:G297-305.