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）被认为是促进成熟肝细胞增殖的主要药物。最近几位研究者发现HGF是肝祖细胞分化和增殖以及胚胎干细胞向肝细胞分化的重要因素。但目前尚不清楚HGF是否能在体内加速这些细胞的分化。本研究采用2-乙酰氨基荧光素/肝部分切除（2-AAF/PH）大鼠模型，研究了HGF对肝干细胞候选细胞之一肝卵圆细胞增殖和分化的影响。通过腹腔注射重组人HGF （rhHGF）刺激2-AAF/PH模型大鼠肝脏卵圆细胞的增殖。第8天，经rhHGF处理的大鼠肝脏门静脉周围嗜碱性细胞区由卵形细胞和卵形细胞簇中的增殖细胞核抗原阳性细胞组成，与未经rhHGF处理的卵形细胞簇相比显著增加。c-Kit和α-胎蛋白在rhHGF作用下卵形细胞的表达在第4天高于对照组，在第12天低于对照组。两组在各时期CK 19的表达模式相同。此外，rhHGF在第4天刺激白蛋白、肝细胞核因子-1 α和-4α mRNA的表达。提示rhHGF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，诱导卵圆细胞增殖分化。上述结果表明，rhHGF可促进肝祖细胞的分化和增殖，可能成为肝衰竭患者诱导肝再生的一种新的治疗方式。

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.