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因子。一些研究人员最近发现，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。本研究采用大鼠肝部分切除(2-AAF/PH)模型，观察HGF对肝干细胞候选之一--肝卵圆细胞增殖和分化的影响。用重组人肝细胞生长因子(RhHGF)刺激2-AAF/PH模型大鼠肝脏卵圆细胞的增殖。经重组人肝细胞生长因子处理后第8天，肝卵圆细胞群内由卵圆细胞和增殖细胞核抗原阳性细胞组成的门静脉周围嗜碱性粒细胞面积较未用重组人肝细胞生长因子处理的卵圆细胞群显著增加。肝卵圆细胞上c-Kit和α-胎儿蛋白的表达在第4天高于对照组，第12天低于对照组。第4天给予重组人肝细胞生长因子可刺激肝组织白蛋白、肝细胞核因子-1α和-4α的表达。提示重组人肝细胞生长因子可通过上调肝组织中肝细胞核因子-1α和-4α的表达来促进卵圆细胞的增殖和分化。这些结果表明，重组人肝细胞生长因子可促进肝祖细胞的分化和增殖，应用重组人肝细胞生长因子可能成为诱导肝功能衰竭患者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.