ACTIVATION OF HEPATIC STEM-CELL COMPARTMENT IN THE RAT - ROLE OF TRANSFORMING GROWTH-FACTOR-ALPHA, HEPATOCYTE GROWTH-FACTOR, AND ACIDIC FIBROBLAST GROWTH-FACTOR IN EARLY PROLIFERATION

We have demonstrated previously a pronounced increase in the expressio n of hepatocyte growth factor (HGF) (Z. Hu, R. P. Evarts, K. Fujio, E. R. Marsden, and S. S. Thorgeirsson, Am. J. Pathol., 142: 1823-1830, 1 993), transforming growth factor alpha (TGF-alpha) (R. P. Evarts, H. N akatsukasa, E. R. Marsden, Z. Hu, and S. S. Thorgeirsson, Mol. Carcino g., 5. 25-31, 1992), and acidic fibroblast growth factor (aFGF) (E. R. Marsden, Z. Hu, K. Fujio, H. Nakatsukasa, S. S. Thorgeirsson, and R. P. Evarts, Lab. Invest., 67. 427-433, 1992) that coincided with the pr oliferation and differentiation of putative hepatic stem cells and per isinusoidal stellate (Ito) cells. Here, we examine the earliest stages of stem cell activation in rat liver using an experimental model invo lving treatment with acetylaminofluorene and partial hepatectomy (R. P . Evarts, P. Nagy, E. Marsden, and S. S. Thorgeirsson, Carcinogenesis (Lond.), 8: 1737-1740, 1987). Histochemical identification of stem cel l progeny and Ito cells was accomplished by OV6 and desmin antibodies, respectively. Expression of the 2.1-kilobase a-fetoprotein transcript s and the concomitant DNA synthesis ([H-3]thymidine label) were used a s indicators for the activation of the stem cell compartment. Expressi on of HGF, TGF-alpha, and aFGF was analyzed at the time of partial hep atectomy and 4, 12, 24, 48, 72, and 92 h after the operation. [H-3]-Th ymidine-labeled OV6- and desmin-positive cells were present in the por tal space and in the Glisson capsule 4 h after partial hepatectomy. Th e appearance of these [H-3]thymidine-labeled cells coincided with the increase in the expression of AFP, HGF, and TGF-alpha, whereas the inc rease in the expression of aFGF was first observed 24 h after the oper ation. By 72 h, a large number of the cells in the periportal space we re in DNA synthesis, and about one-half of them were OV6 positive. The desmin-positive cells infiltrated the liver parenchyma and seemed to move ahead of the OV6-positive oval cells. The early expression of TGF -alpha and HGF suggests an immediate involvement of these growth facto rs in proliferation and the characteristic 'infiltration' of liver ste m cells into the liver acinus. Since HGF has a powerful motogenic effe ct upon numerous cell types including hepatocyte, we suggest that TGF- alpha may be the primary mitogen, whereas the primary action of HGF ma y be as a motogen in hepatic stem cell activation. The delayed express ion of aFGF may indicate a function for this cytokine in the expanding progeny of the hepatic stem cells that is different from those of TGF -alpha and HGF.