Xenogeneic milieu markedly remodels endocrine cell populations after transplantation of fish islets into streptozotocin-diabetic nude mice
Introduction It is unknown whether irrelevant foreign endocrine products secreted by xenografts would be biologically active; 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. Endocrine cell populations in teleost fish and mammalian islets differ markedly; teleost islets have two populations of somatostatin (SST)-producing delta cells - one making SST-14, a 14 amino acid SST identical to mammalian SST, and the other a "large" (i.e. 22-28 aa) SST derived from a preproSST-II gene not found in mammals.
Materials and methods Tilapia islets were enzymically harvested, cultured overnight, and then transplanted under the kidney capsules of streptozotocin-diabetic nude mice. Mice with functioning grafts were killed at 7-8, 35-42 and 66-78 days (n = 3/group). Serial sections of graft bearing kidneys were immunostained for insulin (Ins+), SST-14+, SST-25+ and glucagon (Gluc+) cells. At least four graft sites from each kidney were scanned into a Compix system using Simple PCI software. Four scans from each site (one for each immunostain) were superimposed using Photoshop software so that the same region was measured for each hormone. The area of each cell type in each graft site was measured. Sections of untransplanted tilapia islets (both in situ and after harvest/culture) were analyzed as controls.
Results The mean proportions of Ins+:SST-14+:SST-25+:Gluc+ cells in untransplanted tilapia islets were 31:24:26:19 (in situ) and 34:21:24:21 (cultured). The mean proportions were 40:30:16:14 in the 7-8-day-old-transplants, 46:26:12:16 at 35-42 days, and 54:21:3:22 at 66-78 days. Striking degenerative changes specific to SST-25+ cells were clearly apparent in all 7-8 day grafts.
Conclusions Xenotransplantation of tilapia islets into diabetic nude mice resulted in the proportions of cell types in the grafts gradually changing from a piscine pattern to that of mammalian islets (i.e. 68:10:0:20). In the absence of appropriate stimulation or feedback from the recipient, islet xenograft SST-25+ cells were rapidly lost. Harvesting/culture without xenotransplantation had no apparent effect on cell populations, as both controls were nearly identical.