Studies on competence factors in hepatocyte proliferation

近年来，利用肝细胞原代培养对肝细胞增殖的研究取得了很大进展。预期几种生长因子通过对肝细胞的增殖活性在肝再生中发挥重要作用。然而，人们对肝脏再生的“触发”因素知之甚少。有报道称，两种生长因子在成纤维细胞增殖过程中依次起作用：能力因子和进程因子。虽然肝细胞的生理性再生因子从未报道过，但它可能是肝再生的触发因子，因为它可以作用于静止细胞，使其对进展因子敏感。在本研究中，我们发现原代培养的大鼠肝细胞上的前列腺素（PG） E_2受体密度在部分肝切除的大鼠肝细胞中降低。我们认为，这种减少是PGE_2受体的下调，反映了手术后肝细胞在体内直接暴露于PGE_2。此外，我们发现PGs通过增强其对胰岛素和表皮生长因子的敏感性，对无血清原代培养的肝细胞具有增殖活性。该活性在PGE_2中最为明显，其作用主要通过PGE_2立体特异性受体和百日咳毒素敏感g蛋白介导。高浓度的PGF_2 α可与PGE_2受体发生交叉反应。PG的作用至少部分是由细胞内Ca^<2+>浓度的升高介导的。PGE_2可能来源于窦壁内皮细胞，因为培养的细胞分泌PGE_2。由此可见，PGE_2可作为肝细胞增殖的能力因子，并可作为肝再生的触发因子。

The studies on hepatocyte proliferation has been made great advance in recent years using primary cultures of hepatocytes. Several growth factors were anticipated that they played important roles in liver regeneration through their proliferative activities on hepatocytes., However, little is known about the "trigger" factor (s) of liver regeneration. It was reported that two kinds of growth factors acted sequentially in fibroblast proliferation : competence f-actor and progression factor. Although physiological coinpe-tence factor of hepatocytes has never been reported, it would probably be a trigger factor of liver regeneration because it can act on quiescent cells and can make them sensitive to progression factors.In the present studies, we found that the density of prostaglandin (PG) E_2 receptors on the rat hepa-Locytes in primary culture was decreased when cells were prepared from the rats received partial hepatectomy. We concluded that this decrease was the down regulation of PGE_2 receptors reflecting the direct exposure of the hepatocytes to PGE_2 in vivo after the surgery.In addition, we revealed that PGs had proliferative activities on hepatocyte in serum-free primary culture by enhancing their sensitivity to insulin plus epidermal growth factor. This activity was most prominent in PGE_2, and the action was mediated through stereo-specific PGE_2 receptor and pertusis toxin sensitive G-protein. PGF_2 alpha in higher concentration could act by cross-reacting to PGE_2 receptor. PG actions were, at least in part, mediated by the increase in the intracellular Ca^<2+> concentration. PGE_2 might be derived from sinusoldal endotherial cells, because cultured cells secreated PGE_2.In conclusion, PGE_2 was suggested to be a competence factor in hepatocyte proliferation, and to act as a trigger factor for liver regeneration.