Effect of the transdifferentiation of BECs into myofibroblasts on the pathogenesis of secondary cholestatic hepatic fibrosis

Qiu,Bing‑Feng; Zhang,Guo‑Qiang; Xu,Fang‑Ming; Xu,Qi; Xu,Tang

doi:10.3892/etm.2019.7234

Effect of the transdifferentiation of BECs into myofibroblasts on the pathogenesis of secondary cholestatic hepatic fibrosis

Authors:
- Bing‑Feng Qiu
- Guo‑Qiang Zhang
- Fang‑Ming Xu
- Qi Xu
- Tang Xu
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Affiliations: Department of Gastrointestinal Surgery, Zhoushan Hospital, Zhoushan, Zhejiang 316000, P.R. China
Published online on: February 4, 2019 https://doi.org/10.3892/etm.2019.7234
Pages: 2769-2776

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Abstract

The present study investigated the effect of the transdifferentiation of bile duct epithelial cells (BECs) into myofibroblasts on the pathogenesis of secondary cholestatic hepatic fibrosis and examined the underlying mechanisms. A total of 60 male rats with hepatic fibrosis were randomly divided into two groups: A secondary cholestatic hepatic fibrosis model group induced by ligation of the bile duct (BDL) and a sham group, which only underwent segregation of the choledochus. Rats in the BDL group were dynamically observed after week 1, 2, 3 and 4 post‑BDL, and the remaining rats were sacrificed after week 5 to determine histological changes and hydroxyproline content. The cellular co‑localization of cytokeratin (CK)7/α‑smooth muscle actin (SMA) or α‑SMA/desmin was detected by immunofluorescence staining and laser confocal microscopy, while the protein expression levels of CK7, α‑SMA and desmin were determined by western blot analysis. Sirius red staining was also performed and quantified. The results revealed a significant correlation between the protein expression of CK7 and α‑SMA (r=0.9692, P<0.01). Furthermore, a predominant correlation between the number of cells stained for CK7/α‑SMA and collagen deposition in liver tissues was identified, while the correlation of cells with co‑localized α‑SMA and desmin was less pronounced. The transdifferentiation of BECs into myofibroblasts may be a key pathological factor in secondary cholestatic hepatic fibrosis formation.

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1	Westbrook RH, Dusheiko G and Williamson C: Pregnancy and liver disease. J Hepatol. 64:933–945. 2016. View Article : Google Scholar : PubMed/NCBI
2	Wells RG: The portal fibroblast: Not just a poor man's stellate cell. Gastroenterology. 147:41–47. 2014. View Article : Google Scholar : PubMed/NCBI
3	Glaser S, Han Y, Francis H and Alpini G: Melatonin regulation of biliary functions. Hepatobiliary Surg Nutr. 3:35–43. 2014.PubMed/NCBI
4	Lazaridis KN and LaRusso NF: The cholangiopathies. Mayo Clin Proc. 90:791–800. 2015. View Article : Google Scholar : PubMed/NCBI
5	Beuers U, Trauner M, Jansen P and Poupon R: New paradigms in the treatment of hepatic cholestasis: From UDCA to FXR, PXR and beyond. J Hepatol. 62 (1 Suppl):S25–S37. 2015. View Article : Google Scholar : PubMed/NCBI
6	Xia JL, Dai C, Michalopoulos GK and Liu Y: Hepatocyte growth factor attenuates liver fibrosis induced by bile duct ligation. Am J Pathol. 168:1500–1512. 2006. View Article : Google Scholar : PubMed/NCBI
7	Ezure T, Sakamoto T, Tsuji H, Lunz JG III, Murase N, Fung JJ and Demetris AJ: The development and compensation of biliary cirrhosis in interleukin-6-deficient mice. Am J Pathol. 156:1627–1639. 2000. View Article : Google Scholar : PubMed/NCBI
8	Jamall IS, Finelli VN and Que Hee SS: A simple method to determine nanogram levels of 4-hydroxyproline in biological tissues. Anal Biochem. 112:70–75. 1981. View Article : Google Scholar : PubMed/NCBI
9	Nieto MA, Huang RY, Jackson RA and Thiery JP: EMT: 2016. Cell. 166:21–45. 2016. View Article : Google Scholar : PubMed/NCBI
10	Anders HJ and Schaefer L: Beyond tissue injury-damage-associated molecular patterns, toll-like receptors, and inflammasomes also drive regeneration and fibrosis. J Am Soc Nephrol. 25:1387–1400. 2014. View Article : Google Scholar : PubMed/NCBI
11	Benali SL, Lees GE, Castagnaro M and Aresu L: Epithelial mesenchymal transition in the progression of renal disease in dogs. Histol Histopathol. 29:1409–1414. 2014.PubMed/NCBI
12	Della Latta V, Cecchettini A, Del Ry S and Morales MA: Bleomycin in the setting of lung fibrosis induction: From biological mechanisms to counteractions. Pharmacol Res. 97:122–130. 2015. View Article : Google Scholar : PubMed/NCBI
13	Lee SJ, Kim KH and Park KK: Mechanisms of fibrogenesis in liver cirrhosis: The molecular aspects of epithelial-mesenchymal transition. World J Hepatol. 6:207–216. 2014. View Article : Google Scholar : PubMed/NCBI
14	Robertson H, Kirby JA, Yip WW, Jones DE and Burt AD: Biliary epithelial-mesenchymal transition in posttransplantation recurrence of primary biliary cirrhosis. Hepatology. 45:977–981. 2007. View Article : Google Scholar : PubMed/NCBI
15	Omenetti A, Porrello A, Jung Y, Yang L, Popov Y, Choi SS, Witek RP, Alpini G, Venter J, Vandongen HM, et al: Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest. 118:3331–3342. 2008.PubMed/NCBI
16	Schulze F, Schardt K, Wedemeyer I, Konze E, Wendland K, Dirsch O, Töx U, Dienes HP and Odenthal M: Epithelial-mesenchymal transition of biliary epithelial cells in advanced liver fibrosis. Verh Dtsch Ges Pathol. 91:250–256. 2007.(In German). PubMed/NCBI
17	Park SM: The crucial role of cholangiocytes in cholangiopathies. Gut Liver. 6:295–304. 2012. View Article : Google Scholar : PubMed/NCBI
18	Lee SJ, Park JB, Kim KH, Lee WR, Kim JY, An HJ and Park KK: Immunohistochemical study for the origin of ductular reaction in chronic liver disease. Int J Clin Exp Pathol. 7:4076–4085. 2014.PubMed/NCBI
19	Sato Y, Harada K, Ozaki S, Furubo S, Kizawa K, Sanzen T, Yasoshima M, Ikeda H, Sasaki M and Nakanuma Y: Cholangiocytes with mesenchymal features contribute to progressive hepatic fibrosis of the polycystic kidney rat. Am J Pathol. 171:1859–1871. 2007. View Article : Google Scholar : PubMed/NCBI
20	Weiss MC and Strick-Marchand H: Isolation and characterization of mouse hepatic stem cells in vitro. Semin Liver Dis. 23:313–324. 2003. View Article : Google Scholar : PubMed/NCBI
21	Tsukada S, Parsons CJ and Rippe RA: Mechanisms of liver fibrosis. Clin Chim Acta. 364:33–60. 2006. View Article : Google Scholar : PubMed/NCBI
22	Tsutsumi M, Takada A and Takase S: Characterization of desmin-pvsitive rat liver sinusoidal cells. Hepatology. 7:277–228. 1987. View Article : Google Scholar : PubMed/NCBI