Long-term effects of intrasplenically transplanted adult hepatocytes and fetal liver in hyperbilirubinemic Gunn rats

Kokudo, Norihiro; Otsu, Ichiro; Okazaki, Tadaharu; Takahashi, Shigeki; Sanjo, Kensho; Adachi, Yukihiko; Makino, Susumu; Nozawa, Masumi

doi:10.1111/j.1432-2277.1995.tb01519.x

Cited by 26 publications

(5 citation statements)

References 23 publications

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“…Coincident to the results obtained by Kokudo et al (1995b) the improvement in serum hyperbilirubinaemia was not statistically different between foetal and adult hepatocyte transplantation. Furthermore, after FHT the decrease in TSB is more remarkable from 3 months on after transplantation (Kokudo et al 1995a). However, when liver cell transplantation in the Gunn rat is carried out in conjunction with the preconditioning of the host with RS and the stimulation of transplanted cells with T 3 , both foetal and adult hepatocytes show a similar short-and long-term functionality as we have proved in this report.…”

Section: Discussionmentioning

confidence: 98%

“…When, T 3 was administered in RS-pre-treated animals both foetal and adult cells transplantation resulted in an improvement of TSB at all times of the study. There have been several reports on the functionality of hepatocytes after transplantation in Gunn rats (Kokudo et al 1995a;Cubero et al 2001). Coincident to the results obtained by Kokudo et al (1995b) the improvement in serum hyperbilirubinaemia was not statistically different between foetal and adult hepatocyte transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we compare adult and foetal cells repopulation in the RS/T 3 model. Combining this model with the use of foetal liver cells, highly regenerative and known to grow and function for a long period after intrasplenic transplantation (Kokudo et al . 1995a;Cubero et al .…”

Section: Introductionmentioning

confidence: 99%

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Hepatic proliferation in Gunn rats transplanted with hepatocytes: effect of retrorsine and tri‐iodothyronine

et al. 2005

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Hepatocyte transplantation would offer an attractive alternative to liver transplantation in the treatment of inborn errors of liver metabolism. However, a major problem in most transplantation studies to date has been the limited growth of transplanted cells in the recipient organ. We performed a strategy for selective proliferation of transplanted cells by interfering with the proliferative capacity of resident hepatocytes, using the pyrrolizidine alkaloid retrorsine and then transplanting liver cells in conjunction with repeated administration of triiodothyronine, an inducer of hepatocyte proliferation in rats. In the present study, foetal and adult syngeneic hepatocyte transplantation into spleen was performed in retrorsine-treated hyperbilirubinemic Gunn rats. In parallel, repeated injections of triiodothyronine were given to recipients. Rats were sacrificed at 1, 7, 30 and 90 days after transplantation and blood and bile samples were taken to assess the functionality of transplanted cells. The proliferative activity of transplanted hepatocytes was evaluated using proliferating cell nuclear antigen labelling index. In summary, both adult and foetal hepatocyte transplantation were effective in correcting a metabolic abnormality in Gunn rats for as long as 3 months. The RS/T3 model, as a measure to increase graft function, could represent an important advance to future clinical application of hepatocyte transplantation.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Hepatic proliferation in Gunn rats transplanted with hepatocytes: effect of retrorsine and tri‐iodothyronine

et al. 2005

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“…Monitoring serum total bilirubin levels as an indicator of graft function, this model has widely been used for the experiments of liver transplantation 6 or adult or fetal hepatocyte transplantation. 7,8 Other than the liver, several organs, including small bowel 9 and kidneys, 10 are known to have B-UDP-GT activity in normal rats. We hypothesized that small-bowel transplantation or kidney transplantation from normal rats can also correct metabolic disorders in Gunn rats.…”

Section: Microsurgery 19:103-107 1999mentioning

confidence: 99%

Supplement of liver enzyme by intestinal and kidney transplants in congenitally enzyme-deficient rat

et al. 1999

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Gunn rats have a congenital deficiency of bilirubin-uridine diphosphate glucuronyltransferase (B-UDP-GT) activity and are unable to glucuronidate bilirubin in the bile, resulting in unconjugated hyperbilirubinemia. Other than the liver, several organs, including small bowel and kidneys, are known to have B-UDP-GT activity in normal rats. We performed total- or partial-small-bowel transplantation as well as kidney transplantation for Gunn rats in congenic combination and compared the effects of these procedures. Serum total bilirubin (TBil) levels significantly decreased from 7.84 +/- 0.24 mg/dl to 2.19 +/- 0.43 mg/dl 2 weeks after total-small-bowel transplantation (n = 12). Correlation of hyperbilirubinemia was roughly proportional to the length of the transplanted small bowel. There were no difference in metabolic correction between jejunal and ileal transplantation. Serum TBil levels significantly decreased from 7.83 +/- 0.21 mg/dl to 2.24 +/- 0.98 mg/dl 2 weeks after kidney transplantation (n = 5). In conclusion, small-bowel and kidney transplantation were effective in correcting metabolic abnormality in Gunn rats for the period of 4-6 months. Estimated total B-UDP-GT activity supplemented by small-bowel or kidney transplantation was about 1/5-1/4 of the minimal requirement for the complete normalization of serum total bilirubin levels.

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“…In view of this cells, but also of cells with high histocompatibility, as clinical application, a lot of experiments on liver cell experimentally shown for syngenic transplants (15,25,34, survival and on clinical benefits have already been con -43). In this case, however, with time dedifferentiation or ducted with rats, rabbits, dogs, and pigs [see (2-4, 11, even malignant degeneration of the ectopically trans-14, 17,25,[31][32][33]41,42,50,57,68)]. Some preliminary replanted cells may be possible and has to be considered sults were also reported from human patients with sebefore applying this method for human treatment.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of 2-Year-Old Intrasplenic Fetal Liver Tissue Transplants in Rats

2003

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Liver cell transplantation into host organs like the spleen may possibly provide a temporary relief after extensive liver resection or severe liver disease or may enable treatment of an enzyme deficiency. With time, however, dedifferentiation or malignant transformation of the ectopically transplanted cells may be possible. Thus, in the present study syngenic fetal liver tissue suspensions were transplanted into the spleen of adult male rats and evaluated 2 years thereafter in comparison to orthotopic livers for histopathological changes and (as markers for preneoplastic transformation) for cytochrome P450 (P450) and glutathione S-transferase (GST) isoform expression. Because inducibility of P450 and GST isoforms may be changed in preneoplastic foci, prior to sacrifice animals were additionally treated either with beta-naphthoflavone, phenobarbital, dexamethasone, or the respective solvent. In the 2-year-old grafts more than 70% of the spleen mass was occupied by the transplant. The transplanted hepatocytes were arranged in cord-like structures. Also few bile ducts were present. Morphologically, no signs of malignancy were visible. With all rats, transplant recipients as well as controls, however, discrete nodular structures were seen in the livers. Due to age, both livers and transplants displayed only a low P450 2B1 and 3A2 and GST class alpha and mu isoform expression. No immunostaining for P450 1A1 was visible. At both sites, beta-naphthoflavone, phenobarbital, or dexamethasone treatment enhanced P450 1A1, P450 2B1 and 3A2, or P450 3A2 expression, respectively. No immunostaining for GST class pi isoforms was seen in the transplants. The livers of both transplant recipients and control rats, however, displayed GST pi-positive foci, corresponding to the nodular structures seen histomorphologically. Compared to the surrounding tissue, these foci also exhibited a more pronounced staining for GST class alpha and mu isoforms and a stronger inducibility of the P450 1A1 expression due to beta-naphthoflavone. In conclusion, in contrast to the livers, no preneoplastic foci seem to appear in the intrasplenic transplants even 2 years after transplantation. This may be due either to the protection of these transplants by the orthotopic livers or to the different humoral and nerval influences at the ectopic site.

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Long-term effects of intrasplenically transplanted adult hepatocytes and fetal liver in hyperbilirubinemic Gunn rats

Cited by 26 publications

References 23 publications

Hepatic proliferation in Gunn rats transplanted with hepatocytes: effect of retrorsine and tri‐iodothyronine

Hepatic proliferation in Gunn rats transplanted with hepatocytes: effect of retrorsine and tri‐iodothyronine

Supplement of liver enzyme by intestinal and kidney transplants in congenitally enzyme-deficient rat

Evaluation of 2-Year-Old Intrasplenic Fetal Liver Tissue Transplants in Rats

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