Enhanced effect of human mesenchymal stem cells expressing human TNF-R-Fc and HO-1 gene on porcine islet xenotransplantation in humanized mice

초록

BackgroundPorcine islet xenotransplantation is considered an attractive alternative treatment for type 1 diabetes mellitus. However, it is largely limited because of initial rejection due to Instant Blood-Mediated Inflammatory Reaction (IBMIR), oxidative stress, and inflammatory responses. Recently, soluble tumor necrosis factor-? receptor type I (sTNF-R) and heme oxygenase (HO)-1 genes (HO-1/sTNF-R) have been shown to improve the viability and functionality of porcine islets after transplantation. MethodsIn this study, genetically modified mesenchymal stem cells (MSCs) expressing the HO-1/sTNF-R genes (HO-1/sTNF-R-MSC) were developed using an adenoviral system, and porcine islet viability and function were confirmed by in vitro tests such as GSIS, AO/PI, and the ADP/ATP ratio after coculturing with HO-1/sTNF-R-MSCs. Subsequently, isolated porcine islets were transplanted underneath the kidney capsule of diabetic humanized mice without MSCs, with MSCs or with HO-1/sTNF-R-MSCs. ResultsAccording to the results, the HO-1/sTNF-R-MSC-treated group exhibited improved survival of porcine islets and could reverse hyperglycemia more than porcine islets not treated with MSCs or islets cotransplanted with MSCs. Moreover, the HO-1/sTNF-R-MSC group maintained its morphological characteristics and the insulin secretion pattern of transplanted porcine islets similar to endogenous islets in immunocompetent humanized mice. ConclusionsOur results suggest that HO-1/sTNF-R-MSCs are efficient tools for porcine islet xenotransplantation, and this study may provide basic information forpre-clinical animal models and future clinical trials of porcine islet xenotransplantation.

키워드