Hepatocyte growth factor accelerates proliferation and differentiation of hepatic oval cells in a 2-acetylaminofluorene/partial hepatectomy model in rat

肝细胞生长因子（HGF）是促进成熟肝细胞增殖的主要因子。最近几个研究者已经表明，HGF是肝祖细胞分化和增殖以及胚胎干细胞分化为肝细胞的重要因素。但目前尚不清楚HGF是否能促进这些细胞在体内的分化。本研究采用2-乙酰氨基芴/部分肝切除（2-AAF/PH）大鼠模型，观察HGF对肝卵圆细胞增殖和分化的影响。在2-AAF/PH模型中，腹腔注射重组人肝细胞生长因子（rhHGF）刺激大鼠肝卵圆细胞增殖。门静脉周围嗜碱性区域组成的卵圆细胞和增殖细胞核抗原阳性细胞在卵圆细胞簇在大鼠肝脏与rhHGF处理相比，没有rhHGF的卵圆细胞簇在第8天显着增加。与对照组相比，rhHGF组卵圆细胞c-Kit和甲胎蛋白的表达在第4天升高，第12天降低。CK 19的表达模式在两组中的所有时相都是相同的。此外，给予rhHGF刺激第4天白蛋白、肝细胞核因子-1 α和-4α的mRNA表达。rhHGF可能通过上调2-AAF/PHx模型大鼠肝组织中肝细胞核因子-1 α和-4α的表达，促进卵圆细胞的增殖和分化。这些结果表明，rhHGF促进肝祖细胞的分化和增殖，rhHGF的管理可能成为一个新的治疗模式诱导肝再生的肝衰竭患者。

Hepatocyte growth factor (HGF) is known as a major agent promoting the proliferation of mature hepatocytes. Several investigators have recently shown that HGF is an important factor in differentiation and proliferation of hepatic progenitor cells, and in the differentiation of embryonic stem cells into hepatocytes. But it is unclear whether HGF could accelerate the differentiation of these cells in vivo. In this study, we investigated the effect of HGF on proliferation and differentiation of hepatic oval cells, one of hepatic stem cell candidates, using a 2-acetylaminofluorene/partial hepatectomy (2-AAF/PH) model in rat. The proliferation of oval cells in rat livers in a 2-AAF/PH model was stimulated by intraperitoneal administration of recombinant human HGF (rhHGF). Periportal basophiic areas consisting of oval cells and proliferating cell nuclear antigen-positive cells in oval cell clusters in rat livers treated with rhHGF were significantly increased in comparison with oval cell clusters without rhHGF on day 8. The expression of c-Kit and α-fetoprotein on oval cell with rhHGF were higher than control at day 4 and lower at day 12. The pattern of CK 19 expression was the same in both groups in all phases. Furthermore, administration of rhHGF stimulated mRNA expression of albumin, hepatocyte nuclear factor-1 α and -4α on Day 4. It is suggested that treatment with rhHGF induced proliferation and differentiation of oval cells through up-regulation of hepatocyte nuclear factor-1 α and -4α in liver tissue of 2-AAF/PHx model rats. These results indicate that rhHGF promotes differentiation and proliferation of hepatic progenitor cells, and the administration of rhHGF could become a new treatment modality inducing liver regeneration in patients with liver failure.