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Response of Cultured Hepatocytes to a Hepatomitogen after Initiation by Conditioned Medium or Other Factors¹

Departments of Neurobiology, Anatomy, and Cell Science [P. O., M. L. C.] and of Surgery [L. M., T. E. S.], University of Pittsburgh, Pittsburgh, Pennsylvania 15261, and Department of Gastroenterology, University of Bari [A. F.], Bari, Italy

Injection of a substantially purified hepatomitogen into recipient rats that had 40% of their liver removed resulted in a significant stimulation of hepatic DNA synthesis as determined by the labeling index and the mitotic index. Normal or sham-operated rats did not respond to the injection of the mitogen. The extraction and partial purification of this hepatomitogen have previously been reported (A. Francavilla et al., Cancer Res., 47:5600–5605, 1987). Addition of the factor to an epithelial-like liver-derived cell line in culture (clone 9) or to a hepatoma cell line (HTC-SR) resulted in a dose-dependent stimulation of DNA synthesis. Hepatocytes in primary culture, on the other hand, were not stimulated by the addition of the factor. However, when the mitogen was added to hepatocytes in primary culture, together with conditioned medium, obtained from the responsive cell lines, a significant stimulation of DNA synthesis could be demonstrated in hepatocytes in culture. The stimulation was dose dependent with respect to the mitogen, was abolished by 10 mM hydroxyurea, and was independent of epidermal growth factor. The conditioned medium could be replaced by a protein factor extracted from the two cell lines as previously reported (P. Ove et al., J. Cell. Physiol., 131: 165–174, 1987). It appears that a cofactor is provided by the conditioned medium or by the cell extract, enabling the hepatomitogen to act on hepatocytes in primary culture.

¹ This study was supported by a research project grant from the Veterans Administration; by Project Grant AM-29961 from the NIH, Bethesda, MD; by Grant 885/0216544 from Consiglio Nazionale delle Ricerche, Italy; and by Central Research Development Fund, Category 1, University of Pittsburgh, Pittsburgh, PA 15260.

² Present address: American Cancer Society, 3340 Peachtree Road, N.E., Atlanta, GA 30326.

³ To whom requests for reprints should be addressed, at Department of Neurobiology, Anatomy, and Cell Science, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261.

Received 3/10/88. Revised 7/18/88. Revised 9/26/88. Accepted 10/ 4/88.