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

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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

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2-Acetylaminofluorene
carbon tetrachloride
Wnt Signaling Pathway
Carbon Tetrachloride
hepatocytes
stem cells
Hepatocytes
Fibrosis
Stem Cells
Myofibroblasts
Catenins
Chemical activation
hydroxyproline
Hydroxyproline
subcutaneous injection
cells
Subcutaneous Injections
Liver
actin
Rats

ASJC Scopus subject areas

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

Cite this

Hepatic progenitor cells contribute to the progression of 2-acetylaminofluorene/carbon tetrachloride-induced cirrhosis via the non-canonical Wnt pathway. / Chen, Jiamei; Zhang, Xiao; Xu, Ying; Li, Xuewei; Ren, Shuang; Zhou, Yaning; Duan, YuYou; Zern, Mark A; Zhang, Hua; Chen, Gaofeng; Liu, Chenghai; Mu, Yongping; Liu, Ping.

In: PLoS One, Vol. 10, No. 6, e0130310, 18.06.2015.

Research output: Contribution to journalArticle

Chen, Jiamei ; Zhang, Xiao ; Xu, Ying ; Li, Xuewei ; Ren, Shuang ; Zhou, Yaning ; Duan, YuYou ; Zern, Mark A ; Zhang, Hua ; Chen, Gaofeng ; Liu, Chenghai ; Mu, Yongping ; Liu, Ping. / Hepatic progenitor cells contribute to the progression of 2-acetylaminofluorene/carbon tetrachloride-induced cirrhosis via the non-canonical Wnt pathway. In: PLoS One. 2015 ; Vol. 10, No. 6.
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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 (CCl4) twice a week for 8 weeks. Then, 30{\%} CCl4 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.",
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AU - Zhang, Xiao

AU - Xu, Ying

AU - Li, Xuewei

AU - Ren, Shuang

AU - Zhou, Yaning

AU - Duan, YuYou

AU - Zern, Mark A

AU - Zhang, Hua

AU - Chen, Gaofeng

AU - Liu, Chenghai

AU - Mu, Yongping

AU - Liu, Ping

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