Hepatic Progenitor Cells Contribute to the Progression of 2-Acetylaminofluorene/Carbon Tetrachloride-Induced Cirrhosis via the Non-Canonical Wnt Pathway.
Hepatic Progenitor Cells Contribute to the Progression of 2-Acetylaminofluorene/Carbon Tetrachloride-Induced Cirrhosis via the Non-Canonical Wnt Pathway.
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DOI：
10.1371/journal.pone.0130310
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Liu P
中科院分区：
文献类型：
--
作者：
Chen J;Zhang X;Xu Y;Li X;Ren S;Zhou Y;Duan Y;Zern M;Zhang H;Chen G;Liu C;Mu Y;Liu P
肝前体细胞（HPCs）在慢性肝损伤中起重要作用。在这项研究中，通过每周两次皮下注射50%四氯化碳（CCl 4），连续8周，在F-344大鼠（n = 32）中诱导肝硬化。然后，30%CCl4与2-乙酰氨基氟（2-AAF）联合灌胃4周以诱导HPC活化。WB-F344细胞用于提供HPC向肌成纤维细胞分化的直接证据。结果显示，2-AAF可显著增加大鼠心肌羟脯氨酸含量，增加α-SMA、Col I、Col IV、TGF-β1、CD 68、TNF-α、CK 19和OV 6的表达。纤维间隔中大量共表达OV 6和α-SMA，Wnt 5 b、frizzled 2、frizzled 3和frizzled 6的表达明显增加，而β-catenin的表达在不同组间无统计学差异。与上述结果一致，TGF-β1体外诱导WB-F344细胞向肌成纤维细胞分化，α-SMA、Col I、Col IV、Wnt 5 b和frizzled 2表达显著增加，β-catenin表达降低。经WIF-1阻断Wnt信号通路后，Wnt 5 b水平下调，α-SMA和F-actin表达显著降低。总之，这些结果表明，HPC似乎分化成肌成纤维细胞，并通过激活非经典Wnt途径在进行性肝硬化中表现出促纤维化作用。阻断非经典Wnt通路可以抑制HPC分化为肌成纤维细胞，这表明阻断该通路并改变分化的HPC的命运可能是肝硬化的潜在治疗方法。
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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