Hepatic progenitor cells contribute to the progression of 2-acetylaminofluorene/carbon tetrachloride-induced cirrhosis via the non-canonical Wnt pathway

Jiamei Chen, Xiao Zhang, Ying Xu, Xuewei Li, Shuang Ren, Yaning Zhou, YuYou Duan, Mark A Zern, Hua Zhang, Gaofeng Chen, Chenghai Liu, Yongping Mu, Ping Liu

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Hepatic progenitor cells (HPCs) appear to play an important role in chronic liver injury. In this study, cirrhosis was induced in F-344 rats (n = 32) via subcutaneous injection of 50% carbon tetrachloride (CCl<inf>4</inf>) twice a week for 8 weeks. Then, 30% CCl<inf>4</inf> was administered in conjunction with intragastric 2-acetylaminofluorine (2-AAF) for 4 weeks to induce activation of HPCs. WB-F344 cells were used to provide direct evidence for differentiation of HPCs to myofibroblasts. The results showed that after administration of 2-AAF, the hydroxyproline content and the expressions of α-SMA, Col I, Col IV, TGF-β1, CD68, TNF-α, CK19 and OV6 were significantly increased. OV6 and α-SMA were largely co-expressed in fibrous septum and the expressions of Wnt5b, frizzled2, frizzled3 and frizzled6 were markedly increased, while β-catenin expression was not statistically different among the different groups. Consistent with the above results, WB-F344 cells, treated with TGF-β1 in vitro, differentiated into myofibroblasts and α-SMA, Col I, Col IV, Wnt5b and frizzled2 expressions were significantly increased, while β-catenin expression was decreased. After blocking the non-canonical Wnt pathway via WIF-1, the Wnt5b level was down regulated, and α-SMA and F-actin expressions were significantly decreased in the WIF-1-treated cells. In conclusion, these results indicate that HPCs appear to differentiate into myofibroblasts and exhibit a profibrotic effect in progressive cirrhosis via activation of the non-canonical Wnt pathway. Blocking the non-canonical Wnt pathway can inhibit the differentiation of HPCs into myofibroblasts, suggesting that blocking this pathway and changing the fate of differentiated HPCs may be a potential treatment for cirrhosis.

Original languageEnglish (US)
Article numbere0130310
JournalPLoS One
Volume10
Issue number6
DOIs
StatePublished - Jun 18 2015

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Chen, J., Zhang, X., Xu, Y., Li, X., Ren, S., Zhou, Y., Duan, Y., Zern, M. A., Zhang, H., Chen, G., Liu, C., Mu, Y., & Liu, P. (2015). Hepatic progenitor cells contribute to the progression of 2-acetylaminofluorene/carbon tetrachloride-induced cirrhosis via the non-canonical Wnt pathway. PLoS One, 10(6), [e0130310]. https://doi.org/10.1371/journal.pone.0130310