ENHANCEMENT OF PROLIFERATION OF INTRASPLENICALLY TRANSPLANTED HEPATOCYTES IN CIRRHOTIC RATS BY HEPATIC STIMULATORY SUBSTANCE

This study aimed at investigating the efficacy of hepatic stimulatory substance (HSS) on the proliferation of transplanted hepatocytes in th e spleen of rats with carbon tetrachloride (CCl4)-induced liver cirrho sis, After hepatocyte transplantation (HTx; 1x10(7) cells/ rat), the r ecipients received intravenous administration of HSS (3ml) of 2, 4, or 7 times/week to investigate the effect of the frequency of HSS treatm ent on the proliferation of intrasplenically transplanted hepatocytes, Next, to investigate the effect of the severity of liver cirrhosis on HSS-stimulated proliferation of transplanted hepatocytes, different d oses (0.00, 0.08, 0.12, and 0.16 ml/week) of CCl4 were given to rats a fter HTx. The recipients were killed and the spleens were removed at 2 and 4 weeks after HTx and stained with bromodeoxyuridine (BrdU) and h ematoxylin and eosin for determining the BrdU labeling index (L.I.) an d the hepatocyte-occupied area ratio in the longitudinal cut surface o f the spleen (H:S ratio), respectively, The H:S ratio was measured in the hematoxylin and eosin-stained splenic sections under a light micro scope connected to an image processor. HSS-treated rats showed signifi cantly higher BrdU L.I. and H:S ratios than the untreated control rats at 2 and 4 weeks after HTx. However, the difference in the BrdU L.I. and H:S ratio was not statistically significant among the HSS-treated rats, Without HSS treatment, the severity of liver cirrhosis did not a ffect the proliferation of intrasplenically transplanted hepatocytes, On the other hand, HSS-induced proliferation of transplanted hepatocyt es was further enhanced in proportion to the severity of liver cirrhos is, The H:S ratio of the rats treated with 0.04, 0.08, and 0.16 ml/wee k of CCl4 after HTx was 1.27+/-0.5%, 4.32+/-0.65%, and 6.25+/-0.70%, r espectively, at week 4. During the longterm observation of up to 12 we eks, a marked decrease in the H:S ratio was observed in HSS-untreated control rats at weeks 4-12 compared with week 2. While HSS-treated rat s revealed gradual proliferation of intrasplenically transplanted hepa tocytes, the difference in the H:S ratio between HSS-treated and -untr eated rats became larger, These results indicate that HSS treatment of recipient rats stimulated the proliferation of intrasplenically trans planted hepatocytes in cirrhotic rats and that the severity of liver c irrhosis enhanced the stimulative effect of HSS on the proliferation o f transplanted hepatocytes.