Islet transplantation is a promising therapeutic option for type 1 diabetes, and actively performed in the clinic as well as in the animal experiments. For the rodent experiments, islet transplantation into kidney subcapsule is widely used to assess islet quality, however, it is often difficult to do using a polyethylene tubing and fine needle because of inherent dead volume of needle and stickiness of the tubing to islets. This problem makes it difficult to interpret the physiological response to different islet doses. Here, we developed a simple fibrin gel carrier system for islet transplantation into kidney subcapsule and utilized it to determine the marginal islet mass sufficient for correction of hyperglycemia in diabetic nude mice.
Islet transplantation is limited by the difficulties in isolating the pancreatic islets from the cadaveric donor and maintaining them in culture. To increase islet viability and function after isolation, here we present a novel culture technique involving an histone deacetylase inhibitor (HDACi) to rejuvenate the isolated islets. Pancreatic islets were isolated from Sprague-Dawley (SD) rats and one group (FIs; freshly isolated islets) was used after overnight culture and the other group (RIs; rejuvenated islet) was subjected to rejuvenation culture procedure, which is composed of three discrete steps including degranulation, chromatin remodeling, and regranulation. FIs and RIs were compared with regard to intracellular insulin content, glucose-stimulated insulin secretion (GSIS) capacity, gene expression profile, viability and apoptosis rate under oxidative stresses, and the engraftment efficacy in the xenogeneic islet transplantation models. RIs have been shown to have 1.9 ± 0.28-and 1.7 ± 0.31-fold greater intracellular insulin content and GSIS capacity, respectively, than FIs. HDACi increased overall histone acetylation levels, with inducing increased expression of many genes including insulin 1, insulin 2, GLUT2, and Ogg1. This enhanced islet capacity resulted in more resistance against oxidative stresses and increase of the engraftment efficacy shown by reduction of twofold marginal mass of islets in xenogeneic transplantation model. In conclusion, a novel rejuvenating culture technique using HDACi as chromatin remodeling agents improved the function and viability of the freshly isolated islets, contributing to the reduction of islet mass for the control of hyperglycemia in islet transplantation.
These findings suggest that adult beta cells have the potential to proliferate while maintaining their endocrine function, which can be improved through careful regulation of proliferation and differentiation.
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