Hepatocyte growth factor accelerates the proliferation of hepatic oval cells and possibly promotes the differentiation in a 2‐acetylaminofluorene/partial hepatectomy model in rats

Abstract

Hepatocyte growth factor (HGF) is the primary agent promoting the proliferation of mature hepatocytes. The purpose of the present paper was to clarify the effects of HGF on the proliferation and differentiation of hepatic oval cells using a 2-acetylaminofluorene/partial hepatectomy (2-AAF/PH) model in rats. Recombinant human HGF (0.2 mg/day) was administered to 2-AAF/PH rats for 7 days using osmotic pumps intraperitoneally implanted in conjunction with hepatectomy (day zero). Periportal basophilic areas consisting of oval cells were significantly enlarged by treatment with HGF on day 8. In control animals, expression of alpha-fetoprotein (AFP) in the liver was gradually upregulated, leading a marked increase on day 12. In HGF-treated rats, AFP expression was stimulated at an earlier date and decreased to an undetectable level on day 12. Conversely, expression of albumin transcripts, which was stimulated by HGF-treatment at a later date, continued to increase even after HGF administration ceased, leading to an extremely high level on day 12. Moreover, treatment with HGF also stimulated the expression of hepatocyte nuclear factor-1alpha and -4alpha at an early date. These results indicate that, besides the proliferation of hepatic oval cells, HGF possibly promotes the differentiation to hepatocytes in vivo, suggesting that recombinant human HGF accelerates the regeneration of severely damaged livers, a situation in which the proliferation of mature hepatocytes is impaired.