In vitro stimulation of cell growth by hepatic stimulator substance

Abstract

An extract of normal weanling or adult regenerating rat liver called hepatic stimulator substance (HSS) stimulates incorporation of tritiated thymidine ([3H]dThd) into liver DNA. In vivo, it is organ specific, species nonspecific, displays diurnal rhythm, and has a molecular weight of approximately 10,000-20,000. It has now been further characterized in vitro. HSS retained organ specificity, stimulating normal adult hepatocytes in primary culture, the HTC, PLC, and MH1C1 hepatoma cell lines, and the PRC rat liver cell line. It did not stimulate human or mouse lymphocytes, 3T3 mouse fibroblasts, Y1BS1 mouse adrenal cells, Chinese hamster ovary cells, rat hypernephroma cells, C6 rat glial cells, or L1210 mouse leukemic cells. More detailed studies of the response of HTC cells to HSS revealed a dose-dependent increase in [3H]dThd incorporation (up to 30-fold) with a response to as little as 140-ng purified extract/ml culture medium. Autoradiography confirmed that the thymidine was taken up by nuclear DNA. This represented a true stimulation of growth as shown by an almost twofold increase in cell number after 6 days of exposure to low doses of HSS.

Partial purification of rat hepatic stimulator substance and characterization of its action on hepatoma cells and normal hepatocytes

“…Interestingly, normal hepatocytes only responded to HSS in t,he simultaneous presence of EGF, much like the MH,CI cell line. This observation is a t variance with the dat,a of LaBrecque (13,32) but, is supported by the findings of Francavilla et al (33). The question of whether EGF is required as a permissive agent to sensitize hepatocytes to HSS, possibly by the expression of a specific cell surface receptor, or whether an otherwise inact,ive HSS simply augments the hepatocellular response to EGF is the subject of further investigation.…”

Endogenous hepatic growth‐modulating factors and effects of a choline‐devoid diet and of phenobarbital on hepatocarcinogenesis in the rat

“…These results are consistent with previous findings that an inhibitor of liver cell proliferation, rather than a stimulator, is normally expressed in adult rat livers (31,40), whereas the opposite occurs after a PH in the same animals (31,33). Moreover, the results are in agreement with previous reports that while both nontumorigenic and neoplastic liver cells are sensitive to the action of the stimulator, only nontumorigenic cells are sensitive to the inhibitor (41,42). This equivalency of results, along with comparable isolation procedures, indicates that the growth-modulating factors we assayed are very similar to, if not the same as, those previously studied by other investigators.…”

Protection of regenerating liver after partial hepatectomy from carbon tetrachloride hepatotoxicity in rats: Role of hepatic stimulator substance

“… 14 It also enhances the epidermal growth factor (EGF)‐induced stimulatory effect on DNA synthesis in cultured hepatocytes. 15 Moreover, injection of HSS increased survival following administration of hepatotoxins, such as D ‐galactosamine to rats or CCl 4 to mice. 16–19 However, the role of HSS in protecting the regenerating liver from CCl 4 ‐induced hepatotoxicity is not clear.…”