Skip to main content

Advertisement

SpringerLink
Log in

Fn14 hepatic progenitor cells are associated with liver fibrosis in biliary atresia

  • Original Article
  • Published:
Pediatric Surgery International Aims and scope Submit manuscript

Abstract

Purpose

The liver in biliary atresia (BA) is characterized by progressing fibrosis which is promoted by unclear reasons. We aimed to understand the factors influencing liver fibrosis. This study hypothesized that HPCs (hepatic progenitor cells) are activated and associated with liver fibrosis in biliary atresia.

Methods

Liver samples from biliary atresia patients are as BA group, and the normal liver derived from hepatoblastoma infants during operation are control group. The extent of fibrosis in liver samples was blindly evaluated by two experienced pathologists depending on Ishak system. The BA liver samples were divided into mild liver fibrosis group (grade I–IV, BAa) and severe liver fibrosis group (grade V–VI, BAb) to detect Fn14 protein expression.

Results

In mRNA level, Fn14 expression was 21.23 ± 8.3 vs. 1.00 ± 0.17, p = 0.023 < 0.05 and CD133 expression was 6.02 ± 2.16 vs. 1.14 ± 0.75, p = 0.008 < 0.01 between BA group and control group. Fn14 cells co-expressed the progenitor marker CD133 in liver, and activated in BA. Fn14 andα-SMA were co-location in fibrous area in liver. Compared to the control group, Fn14, CD133, and α-SMA protein expression were 2.10 ± 0.53 vs. 0.97 ± 0.2, p = 0.001, 2.23 ± 0.57 vs. 1.00 ± 0.03, p = 0.000, 4.96 ± 2.4 vs. 1.00 ± 0.22, p = 0.001. The Fn14 protein expression was 2.60 ± 0.35 vs. 1.86 ± 0.42, p = 0.012, between BAb and BAa group.

Conclusion

Fn14 cells, which co-express the progenitor marker CD133 in liver, are HPCs and activated in BA. Fn14 + HPCs are associated with liver fibrosis in BA.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. McKiernan PJ, Baker AJ, Kelly DA (2000) The frequency and outcome of biliary atresia in the UK and Ireland. Lancet 355:25–29. doi:10.1016/s0140-6736(99)03492-3

    Article  CAS  PubMed  Google Scholar 

  2. de Vries W, Homan-Van der Veen J, Hulscher JB, Hoekstra-Weebers JE, Houwen RH, Verkade HJ (2011) Twenty-year transplant-free survival rate among patients with biliary atresia. Clin Gastroenterol Hepatol 9:1086–1091. doi:10.1016/j.cgh.2011.07.024

    Article  PubMed  Google Scholar 

  3. Karrer FM, Price MR, Bensard DD, Sokol RJ, Narkewicz MR, Smith DJ, Lilly JR (1996) Long-term results with the Kasai operation for biliary atresia. Arch Surg 131:493–496

    Article  CAS  PubMed  Google Scholar 

  4. Carceller A, Blanchard H, Alvarez F, St-Vil D, Bensoussan AL, Di Lorenzo M (2000) Past and future of biliary atresia. J Pediatr Surg 35:717–720. doi:10.1053/jpsu.2000.6034

    Article  CAS  PubMed  Google Scholar 

  5. Pakarinen MP, Rintala RJ (2011) Surgery of biliary atresia. Scand J Surg 100:49–53

    Article  CAS  PubMed  Google Scholar 

  6. Mack CL, Feldman AG, Sokol RJ (2012) Clues to the etiology of bile duct injury in biliary atresia. Semin Liver Dis 32:307–316. doi:10.1055/s-0032-1329899

    Article  CAS  PubMed  Google Scholar 

  7. Paku S, Schnur J, Nagy P, Thorgeirsson SS (2001) Origin and structural evolution of the early proliferating oval cells in rat liver. Am J Pathol 158:1313–1323. doi:10.1016/s0002-9440(10)64082-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Petersen BE, Zajac VF, Michalopoulos GK (1998) Hepatic oval cell activation in response to injury following chemically induced periportal or pericentral damage in rats. Hepatology 27:1030–1038. doi:10.1002/hep.510270419

    Article  CAS  PubMed  Google Scholar 

  9. Sell S (2001) Heterogeneity and plasticity of hepatocyte lineage cells. Hepatology 33:738–750. doi:10.1053/jhep.2001.21900

    Article  CAS  PubMed  Google Scholar 

  10. Newsome PN, Hussain MA, Theise ND (2004) Hepatic oval cells: helping redefine a paradigm in stem cell biology. Curr Top Dev Biol 61:1–28. doi:10.1016/s0070-2153(04)61001-5

    Article  CAS  PubMed  Google Scholar 

  11. Lu WY, Bird TG, Boulter L, Tsuchiya A, Cole AM, Hay T, Guest RV, Wojtacha D, Man TY, Mackinnon A, Ridgway RA, Kendall T, Williams MJ, Jamieson T, Raven A, Hay DC, Iredale JP, Clarke AR, Sansom OJ, Forbes SJ (2015) Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat Cell Biol 17:971–983. doi:10.1038/ncb3203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lorenzini S, Bird TG, Boulter L, Bellamy C, Samuel K, Aucott R, Clayton E, Andreone P, Bernardi M, Golding M, Alison MR, Iredale JP, Forbes SJ (2010) Characterisation of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver. Gut 59:645–654. doi:10.1136/gut.2009.182345

    Article  PubMed  PubMed Central  Google Scholar 

  13. Bird TG, Lu WY, Boulter L, Gordon-Keylock S, Ridgway RA, Williams MJ, Taube J, Thomas JA, Wojtacha D, Gambardella A, Sansom OJ, Iredale JP, Forbes SJ (2013) Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling. Proc Natl Acad Sci USA 110:6542–6547. doi:10.1073/pnas.1302168110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tirnitz-Parker JE, Viebahn CS, Jakubowski A, Klopcic BR, Olynyk JK, Yeoh GC, Knight B (2010) Tumor necrosis factor-like weak inducer of apoptosis is a mitogen for liver progenitor cells. Hepatology 52:291–302. doi:10.1002/hep.23663

    Article  CAS  PubMed  Google Scholar 

  15. Jakubowski A, Ambrose C, Parr M, Lincecum JM, Wang MZ, Zheng TS, Browning B, Michaelson JS, Baetscher M, Wang B, Bissell DM, Burkly LC (2005) TWEAK induces liver progenitor cell proliferation. J Clin Invest 115:2330–2340. doi:10.1172/jci23486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Meighan-Mantha RL, Hsu DK, Guo Y, Brown SA, Feng SL, Peifley KA, Alberts GF, Copeland NG, Gilbert DJ, Jenkins NA, Richards CM, Winkles JA (1999) The mitogen-inducible Fn14 gene encodes a type I transmembrane protein that modulates fibroblast adhesion and migration. J Biol Chem 274:33166–33176

    Article  CAS  PubMed  Google Scholar 

  17. Feng SL, Guo Y, Factor VM, Thorgeirsson SS, Bell DW, Testa JR, Peifley KA, Winkles JA (2000) The Fn14 immediate-early response gene is induced during liver regeneration and highly expressed in both human and murine hepatocellular carcinomas. Am J Pathol 156:1253–1261. doi:10.1016/s0002-9440(10)64996-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ho DH, Vu H, Brown SA, Donohue PJ, Hanscom HN, Winkles JA (2004) Soluble tumor necrosis factor-like weak inducer of apoptosis overexpression in HEK293 cells promotes tumor growth and angiogenesis in athymic nude mice. Cancer Res 64:8968–8972. doi:10.1158/0008-5472.can-04-1879

    Article  CAS  PubMed  Google Scholar 

  19. Kawakita T, Shiraki K, Yamanaka Y, Yamaguchi Y, Saitou Y, Enokimura N, Yamamoto N, Okano H, Sugimoto K, Murata K, Nakano T (2004) Functional expression of TWEAK in human hepatocellular carcinoma: possible implication in cell proliferation and tumor angiogenesis. Biochem Biophys Res Commun 318:726–733. doi:10.1016/j.bbrc.2004.04.084

    Article  CAS  PubMed  Google Scholar 

  20. Chicheportiche Y, Bourdon PR, Xu H, Hsu YM, Scott H, Hession C, Garcia I, Browning JL (1997) TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis. J Biol Chem 272:32401–32410

    Article  CAS  PubMed  Google Scholar 

  21. Brown SA, Ghosh A, Winkles JA (2010) Full-length, membrane-anchored TWEAK can function as a juxtacrine signaling molecule and activate the NF-kappaB pathway. J Biol Chem 285:17432–17441. doi:10.1074/jbc.M110.131979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Karaca G, Swiderska-Syn M, Xie G, Syn WK, Kruger L, Machado MV, Garman K, Choi SS, Michelotti GA, Burkly LC, Ochoa B, Diehl AM (2014) TWEAK/Fn14 signaling is required for liver regeneration after partial hepatectomy in mice. PLoS One 9:e83987. doi:10.1371/journal.pone.0083987

    Article  PubMed  PubMed Central  Google Scholar 

  23. Affo S, Dominguez M, Lozano JJ, Sancho-Bru P, Rodrigo-Torres D, Morales-Ibanez O, Moreno M, Millan C, Loaeza-del-Castillo A, Altamirano J, Garcia-Pagan JC, Arroyo V, Gines P, Caballeria J, Schwabe RF, Bataller R (2013) Transcriptome analysis identifies TNF superfamily receptors as potential therapeutic targets in alcoholic hepatitis. Gut 62:452–460. doi:10.1136/gutjnl-2011-301146

    Article  CAS  PubMed  Google Scholar 

  24. Mavila N, James D, Shivakumar P, Nguyen MV, Utley S, Mak K, Wu A, Zhou S, Wang L, Vendyres C, Groff M, Asahina K, Wang KS (2014) Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia. Hepatology 60:941–953. doi:10.1002/hep.27203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kuramitsu K, Sverdlov DY, Liu SB, Csizmadia E, Burkly L, Schuppan D, Hanto DW, Otterbein LE, Popov Y (2013) Failure of fibrotic liver regeneration in mice is linked to a severe fibrogenic response driven by hepatic progenitor cell activation. Am J Pathol 183:182–194. doi:10.1016/j.ajpath.2013.03.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Friedman SL (2004) Mechanisms of disease: Mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol 1:98–105. doi:10.1038/ncpgasthep0055

    Article  PubMed  Google Scholar 

  27. Ruddell RG, Knight B, Tirnitz-Parker JE, Akhurst B, Summerville L, Subramaniam VN, Olynyk JK, Ramm GA (2009) Lymphotoxin-beta receptor signaling regulates hepatic stellate cell function and wound healing in a murine model of chronic liver injury. Hepatology 49:227–239. doi:10.1002/hep.22597

    Article  CAS  PubMed  Google Scholar 

  28. Clouston AD, Powell EE, Walsh MJ, Richardson MM, Demetris AJ, Jonsson JR (2005) Fibrosis correlates with a ductular reaction in hepatitis C: roles of impaired replication, progenitor cells and steatosis. Hepatology 41:809–818. doi:10.1002/hep.20650

    Article  CAS  PubMed  Google Scholar 

  29. Knight B, Akhurst B, Matthews VB, Ruddell RG, Ramm GA, Abraham LJ, Olynyk JK, Yeoh GC (2007) Attenuated liver progenitor (oval) cell and fibrogenic responses to the choline deficient, ethionine supplemented diet in the BALB/c inbred strain of mice. J Hepatol 46:134–141. doi:10.1016/j.jhep.2006.08.015

    Article  CAS  PubMed  Google Scholar 

  30. Knight B, Lim R, Yeoh GC, Olynyk JK (2007) Interferon-gamma exacerbates liver damage, the hepatic progenitor cell response and fibrosis in a mouse model of chronic liver injury. J Hepatol 47:826–833. doi:10.1016/j.jhep.2007.06.022

    Article  CAS  PubMed  Google Scholar 

  31. Dwyer BJ, Olynyk JK, Ramm GA, Tirnitz-Parker JE (2014) TWEAK and LTbeta signaling during chronic liver disease. Front Immunol 5:39. doi:10.3389/fimmu.2014.00039

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by the frontier technology research project of Shanghai Shenkang Hospital Development Center (SHDC12013124).

Author information

Authors and Affiliations

  1. Department of Pediatric Surgery, Shanghai Children’s Hospital, Shanghai Jiao Tong University, No. 355 Luding Road, Shanghai, 200062, China

    Lulu Zheng, Zhibao Lv, Zhenhua Gong, Qingfeng Sheng, Yuting Zhang, Shenghua Yu & Junmei Zhou

  2. Department of Center Laboratory, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, 200062, China

    Zhimei Gao

  3. Department of Pathology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, 200062, China

    Zhengjun Xi & Xueli Wang

Authors
  1. Lulu Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhibao Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhenhua Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qingfeng Sheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhimei Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuting Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shenghua Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Junmei Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhengjun Xi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xueli Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhibao Lv.

Ethics declarations

Funding

This study was funded the frontier technology research project of Shanghai Shenkang Hospital Development Center (grant number SHDC12013124).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zheng, L., Lv, Z., Gong, Z. et al. Fn14 hepatic progenitor cells are associated with liver fibrosis in biliary atresia. Pediatr Surg Int 33, 593–599 (2017). https://doi.org/10.1007/s00383-017-4068-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00383-017-4068-5

Keywords

Search

Navigation