Influence of hepatocyte-rich liver cell mixture and liver fibroblasts on prolonging graft islet survival in rats without immunosuppressive drugs

Background: We noted that a liver cell suspension, made up of a mixture of several kinds of hepatic cells, affected allogenic islet survival when it was transplanted into the liver, mixed with the islets or separately. Aim: To study if this effect was related to a liver cell mixture rich in hepatocytes (hp) or to liver fibroblasts (fb). Methods: We studied 14 groups of rats: (A) a sham group with saline; (B) a group receiving transplantation with hepatic cells alone; (C) a control group, with islets alone via the portal vein, without hepatic cells (hp or fb). For the other groups, we used a different ratio of cells/islets (100:1,150: 1 and 200:1) and different co-transplantation techniques with both types of cells. For the D, E,J groups, a mixture of hepatocytes (hepatocyte-rich liver cell mixture) or fibroblasts with islets was injected into the portal vein. For the other groups, we used a sequential procedure with a 15 minute interval between a first injection of hp or fb into the portal vein or into the vena cava, and a second injection of islets always into the portal vein; thus, it was a sequential portal/portal procedure with hepatocyte-rich liver cell mixture (hp) (F, G) or fibroblasts (K, L) and a sequential cava/portal with hp (H, I) or fibroblasts (M, N). Results: Most of the co-transplantation groups showed functional islets (blood glucose < 250 mg/dl) on the first or second day of transplantation; after several days they once again had high glucose levels, though not as high as pre-transplantation. There was statistical significance (p < 0.001) between the presence or not of hepatic cells to obtain prolongation of graft survival (blood glucose <250mg/dl). Statistical significance (p<0.001) was found for several sequential groups with hp (F, I) and fb (K, L). It was also remarkable that 3 rats (37.5%) from the I group (sequential cava/portal with hp/islets 200:1) were euglycemic (blood glucose <150mg/dl) for more than 3 months. ANOVA showed a large interaction between the type of transplant performed and the cellular ratio used, with a significance of p <0.001. Histological studies in rats with prolonged euglycemia, showed insulin-producing cell aggregates in the liver, while there was a remarkable decrease in insulin-producing cells in the remaining islets of pancreatic tissue. Conclusion: The results showed a marginal prolongation of islet graft survival when they are co-transplanted with a hepatocyte-rich liver cell mixture or with liver fibroblasts. The mechanism does not seem to be a cellular interaction between different hepatic cells and islets, but some kind of cellular interaction or released factor from either two cell types on the immune system, blocking or modulating it, at least temporarily.