We have demonstrated previously a pronounced increase in the expression of hepatocyte growth factor (HGF)(Z. Hu, RP Evarts, K. Fujio, ER Marsden, and SS Thorgeirsson, Am. J. Pathol., 142: 1823-1830, 1993), transforming growth factor alpha (TGF-alpha)(RP Evarts, H. Nakatsukasa, ER Marsden, Z. Hu, and SS Thorgeirsson, Mol. Carcinog., 5: 25-31, 1992), and acidic fibroblast growth factor (aFGF)(ER Marsden, Z. Hu, K. Fujio, H. Nakatsukasa, SS Thorgeirsson, and RP Evarts, Lab. Invest., 67: 427-433, 1992) that coincided with the proliferation and differentiation of putative hepatic stem cells and perisinusoidal stellate (Ito) cells. Here, we examine the earliest stages of stem cell activation in rat liver using an experimental model involving treatment with acetylaminofluorene and partial hepatectomy (RP Evarts, P. Nagy, E. Marsden, and SS Thorgeirsson, Carcinogenesis (Lond.), 8: 1737-1740, 1987). Histochemical identification of stem cell progeny and Ito cells was accomplished by OV6 and desmin antibodies, respectively. Expression of the 2.1-kilobase alpha-fetoprotein transcripts and the concomitant DNA synthesis ([3H] thymidine label) were used as indicators for the activation of the stem cell compartment. Expression of HGF, TGF-alpha, and aFGF was analyzed at the time of partial hepatectomy and 4, 12, 24, 48, 72, and 92 h after the operation.[3H]-Thymidine-labeled OV6-and desmin-positive cells were present in the portal space and in the Glisson capsule 4 h after partial hepatectomy.(ABSTRACT TRUNCATED AT 250 WORDS)