Long-term function of fish islet xenografts in mice by alginate encapsulation

Abstract

Background. Large, anatomically discrete pancreatic islets, Brockmann bodies (BBs), exist in certain teleost fish. When transplanted under the renal capsules of streptozotocin-diabetic athymic nude mice, BB grafts produce uniform normoglycemia for 50 days and mammalian-like glucose tolerance profiles; however, these very discordant islets reject in 7-8 days when transplanted into euthymic BALB/c mice. Methods. In the present study, BBs were mass harvested, minced into <1-mm tissue fragments, and encapsulated in alginate-based macrospheres (5 mm diameter) or noodles (0.5x3 cm). Nonencapsulated and encapsulated BB fragments were transplanted intraperitoneally into streptozotocin-diabetic (nonfasting blood glucose >400 mg/dl) nu/nu and BALB/c mice. Glucose levels were monitored at least 3 times a week. Results. Encapsulated BB grafts uniformly survived >50 days (10/10) or > 100 days (3/3) in nu/nu recipients. The mean graft survival time was 27±13 days in BALB/c recipients (n=7). Daily intraperitoneal administration of 2.5 mg/kg 15-deoxyspergualin, in combination with encapsulation, resulted in uniform long-term BB graft function in BALB/c recipients (n=5). Similarly, long-term function was achieved in four of six BALB/c recipients with daily intraperitoneal administration of 10 mg/kg cyclosporine (two grafts failed after 39 and 45 days). Nonencapsulated BB grafts transplanted intraperitoneally into BALB/c or nu/nu recipients functioned for <7 days; immunosuppression alone did not permit graft survival in BALB/c recipients. In all cases of graft survival of >50 days, grafts were surgically removed from the peritoneal cavity, and blood sugar levels returned to a diabetic state within a few days. Historical sections of grafts, stained with hematoxylin and eosin and immunoperoxidase for insulin, showed viable, well- granulated BB tissue. Conclusions. This study demonstrates that tilapia BBs are suitable for encapsulation and that encapsulated BBs can be made to function long term in diabetic mice.