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Comparing the intrahepatic and renal subcapsular sites for human islet engraftment into diabetic immunodeficient mice

R. Damaris Molano^1,6, Sergio San Jose^1,6, Susana Villate^1,6, Elsie Zahr-Akrawi^1,6, Camillo Ricordi^1,2,3,4,5,6, Antonello Pileggi^1,3,4,5,6

¹Diabetes Research Institute, University of Miami; ²Medicine, University of Miami Miller School of Medicine; ³Surgery, University of Miami Miller School of Medicine; ⁴Microbiology & Immunology, University of Miami Miller School of Medicine; ⁵Biomedical Engineering, University of Miami; ⁶The JDRF Center for Islet Transplantation at the University of Miami – Diabetes Research Institute, Miami, FL, United States

We evaluated the success of human islet engraftment into two sites of implantation: the liver and the renal subcapsular space. Athymic nu/nu (nude) mice were induced diabetic by a single injection of the beta-cell toxin streptozotocin and maintained on exogenous insulin given subcutaneously (either glargine insulin injections or implantation of slow release insulin pellets) until research human islet preparations become available. We compared the islet mass that was used in recent years for the kidney subcapsular space as either ‘full’ and ‘suboptimal’ mass (namely, 2,000 and 1,000 IEQ/recipient, respectively). Using the same human islet preparations each time, we performed subcapsular kidney space transplants in parallel to the intrahepatic ones (done in heparinized saline) in order to compare side-by-side the rate of engraftment in the two sites using eight individual human islet preparations.

Transplantation of 2,000 IEQ per recipient mouse resulted in diabetes reversal in 21.2±2.3 days in all recipients (12/12, 7 preparations). Transplantation of 1,000 IEQ per mouse also resulted in diabetes reversal in all recipients (15/15, 8 preparations) in a tempo of 5.2±8.5 days. Transplantation of comparable islet masses in the intrahepatic site resulted in lower engraftment rates. In particular, intrahepatic transplantation of 2,000 IEQ resulted in diabetes reversal in 78% of the recipients (7/9, 7 preparations) within 11.9±21.3 days, while transplantation of 1,000 IEQ led to normoglycemia in 44% (4/7, 6 preparations) within 30.4±49.5 days.

Collectively, our data indicates that the intrahepatic site may lead to higher degrees of injury resulting in reduced viability and engraftment of human islets in our model. Indeed, primary non-function was observed in 22% and 56% of the recipients of 2,000 and 1,000 IEQ intrahepatic grafts, respectively. Conversely, all animals receiving the grafts under the kidney subcapsular space achieved normoglycemia after transplantation.

Supported by JDRF (4-2004-361) and Diabetes Research Institute Foundation.