Xenogeneic milieu markedly remodels endocrine cell populations after transplantation of fish islets into streptozotocin-diabetic nude mice

Abstract

It is unknown whether irrelevant foreign endocrine products secreted by xenografts would be biologically active and potentially harmful to recipients; even if entirely inert, continuous production might result in harmful circulating antigen-antibody complexes. We examined the fate of such a product using a fish (tilapia)-to-mouse islet xenograft model. Teleost fish islets, like mammalian islets, are composed primarily of cells producing insulin, glucagon or somatostatin; however, teleost fish have two different populations of somatostatin (SST) producing delta cells, one producing SST-14, a 14 amino acid SST identical to mammalian SST, which is derived from the pre-proSST-I gene which is present in all vertebrates, and the other a "large" (i.e. 22 to 28 amino acid) SST derived from a pre-proSST-II gene, which is not found in mammals. In contrast to 'large' SST, which has no mammalian homolog, teleost fish insulins, glucagons and SST-14 exhibit significant biological activity in mammals. Tilapia islets were transplanted under the kidney capsules of streptozotocin-diabetic nude mice, and mice with functioning grafts were killed at various times after transplantation. Serial sections of graft-bearing kidneys were stained by immunoperoxidase for insulin, SST-14, SST-25 and glucagon positive cells, and the areas of each cell type in the graft were measured using image analysis. Sections of untransplanted tilapia islets (both in situ and after harvest/culture) were also immunostained and measured as controls. Xenotransplantation of fish islets into diabetic nude mice resulted in the rapid degeneration and near total loss of SST-25+ cells, as well as a marked redistribution of the proportions of the remaining endocrine cell types. The proportions of cell types in the grafts gradually changed from a piscine pattern to that of mammalian islets.