Effects of cotransplanted fetal liver on fetal pancreas isografts.

Ricordi et al. described a hepatotrophic effect mediated by pancreatic islets on cotransplanted hepatocytes. We found a reciprocal salutary effect of fetal liver (FL) on fetal pancreas (FP) in the intramural small bowel (ISB) site. To further investigate this intriguing finding, composite FP/FL isografts were transplanted to the conventional renal subcapsular (RSC) site and the accessible but historically inhospitable intramuscular site in streptozotocin-diabetic Lewis rats. A comparison of recipients of FP/FL and FP alone found the proportion rendered normoglycemic was site dependent. All recipients of either composite FP/FL grafts or FP alone transplanted in the ISB site became normoglycemic. The proportion of normoglycemic recipients was lower in the RSC site (71% FP and 40% FP/FL) and the i.m. site (14% FP and 67% FP/FL). Importantly, regardless of site, normoglycemia was established with an accelerated time course in recipients of FP/FL versus FP alone (24 +/- 8 vs. 67 +/- 43 days; P = 0.001). Normal (or more rapid) glucose clearance after challenge was achieved in all normoglycemic recipients except those transplanted in the RSC site. On histological examination of excised FP/FL grafts, hepatocytes were present in association with islets. Cyclosporine-induced islet toxicity could not be overcome in 6 recipients of FP alone, but 6 of 8 recipients of FP/FL became normoglycemic (P less than 0.01). To assess the effect of FP on hepatocytes, allografts (Wistar donors) of FP or FP/FL were cotransplanted in the ISB of enzyme-deficient jaundiced Gunn rats. Immunosuppression consisted of rapamycin (0.8 mg/kg/day) infused intravenously for 4 weeks. In the FP/FL group (n = 4), the mean serum bilirubin level decreased from 8.6 to 4.9 mg/dl at 6 weeks after transplantation. This was a significant difference as compared with the increased mean serum bilirubin from 6.9 to 7.8 mg/dl (P less than 0.05; paired Student's t test) in recipients of FL alone (n = 4). In conclusion, we found a mutual paracrine effect on islets and hepatocytes transplanted as a composite FP/FL graft. FL hastened the establishment of normoglycemia following transplantation of FP in diabetic rats, and FP enhanced FL transplant function in Gunn rats.

Beneficial effects of fetal liver tissue on fetal pancreatic transplantation.

Recently, composite grafts of hepatocytes and islets have been shown to improve the survival of hepatocytes. The possibility of a reciprocal effect of hepatocytes on islet function was investigated. Diabetic Lewis rats were isografted with (1) fetal pancreas and fetal liver (FP/FL), (2) fetal pancreas alone (FP), and (3) fetal pancreas and fetal spleen (FP/FS). Grafts were transplanted to the small bowel subserosa. All (6/6) FP/FL recipients were cured (glucose less than 250 mg/dl for greater than 30 days), whereas only 72% (13/18) of FP alone and 60% (3/5) of FP/FS recipients were cured. The amount of time to normoglycemia for FP/FS recipients was less (26 +/- 15 days) compared with FP (50 +/- 29 days) or FP/FS recipients (71 +/- 40 days). Mean glucose levels at 6 weeks were 166 +/- 78 mg/dl, 237 +/- 97 mg/dl, and 355 +/- 81 mg/dl in cured FP/FL, FP, and FP/FS recipients, respectively. Glucose tolerance test results were not significantly different from those of nondiabetic control rats. In contrast to FP alone, FP/FL recipients had well-granulated hyperplastic islets and hepatocytes on histologic examination. When new isograft recipients were treated with cyclosporine, all FP recipients remained hyperglycemic; however, 75% (6/8) of FP/FL recipients were cured. In conclusion, FL in a composite graft with FP resulted in better engraftment, earlier isograft function, and protection from cyclosporine islet toxicity.

Studies of composite grafts of fetal pancreas (FP) and fetal liver (FL) in the streptozotocin-induced diabetic rat.

A hepatotrophic effect of pancreatic islets on co-transplanted hepatocytes has been described recently by Ricordi et al. We investigated a possible reciprocal effect of co-transplanted fetal liver (FL) on fetal pancreas (FP) isografted into streptozotocin diabetic rats. FL was co-transplanted with FP in three sites: the new intramural small bowel (ISB) site, the conventional renal subcapsular (RSC) site, and the historically inhospitable intramuscular (IM) site. Overall, as compared to grafts of FP alone, composite FP/FL grafts consistently provided earlier restoration of normoglycemia in streptozotocin diabetic recipients (24 +/- 8 vs. 67 +/- 43 days P = 0.001). The proportion of recipients rendered normoglycemic and the clearance of glucose was site-dependent. For FP and FP/FL recipients respectively, the ISB site resulted in 100% normoglycemia in both groups (19/19 and 6/6), the RSC site resulted in 71% (5/7) and 40% (2/5) and the IM site resulted in 14% (1/7) and 67% (6/9). In normoglycemic recipients, glucose clearance was normal or supraphysiologic except for the RSC site. Composite isografts brought about normoglycemia in 75% (6/8) of recipients treated with beta-cell toxic doses of cyclosporine that prevented reversal of diabetes in recipients of FP alone. Co-transplantation of FL benefits FP through paracrine mechanisms mediated by unknown factor(s). Thus, as compared to grafts of FP alone, composite FP/FL grafts established normoglycemia more rapidly, mitigated cyclosporine toxicity and corrected diabetes when transplanted in the small bowel site. There are several mediators that may be responsible for these paracrine effects between the liver cells and the pancreas. IGF-1 elaborated by FL is the most likely trophic factor.(ABSTRACT TRUNCATED AT 250 WORDS)

New model for microsurgical training and skills maintenance.

PracticeRat (Sharpoint, Reading PA) is a system containing a simulation vein, artery and nerve, designed as an alternative to live animal use in microsurgical training. We find PracticeRat to be more expensive than living models. However, it does decrease animal usage and provides a very convenient opportunity to practice microsurgical techniques and procedures in a fairly realistic manner. Trainees can practice anytime, for any length of time, wherever microscopes are available. In this regard we find PracticeRat+ to be a useful addition to microsurgical training programs and an excellent tool for skills maintenance.