166-OR: Coinfusion of Mesenchymal Stem Cells Improves Human Islet Survival in the Hepatic Islet Transplantation Mouse Model

Islet survival is improved when islets are co-transplanted with mesenchymal stromal cells (MSCs) under the kidney capsule. We assessed whether co-infusion of MSCs with human islets into the liver, as performed in patients, would protect those islets from death post-transplantation (PT) in streptozotocin-induced diabetic NOD-SCID mice (blood glucose, BG >350mg/dl). Blood glucose levels were measured as surrogate markers for islet survival and function. Transplantation of a suboptimal islet number led to normoglycemia (BG<200mg/dl) at 60 days PT in 33% of 6 mice. In contrast, 91% (n=12) of mice receiving islets co-infused with MSCs (Islet+MSC) reached and remained normoglycemic. Mice receiving islet+MSC showed lower non-fasting glucose levels, higher baseline and stimulated c-peptide levels and better function when challenged with high glucose during an intravenous glucose tolerance test. Immunohistochemistry staining of beta cells identified that significantly more islets and islet positive area were observed in the livers of islet+MSC compared to islets alone mice (even in mice with normoglycemia). We show that MSCs led to better islet survival in MSC-co-infused mice after transplantation. By using firefly luciferase-expressing MSCs, we found that co-transplanted luciferase⁺ (Luc⁺) MSC was detected up to 7 days in the liver PT. Insulin expressing MSCs were detected at 60 days PT, suggesting MSCs can stay in the liver long-term and may convert into insulin+ cells. Inflammatory-related chemokines, including IL-6, KC, and MCP-1, were also significantly reduced in islet+MSC mice serum at day 1-3 PT. The protective effects of MSC on beta cell survival was confirmed in vitro when human islets were co-cultured with MSCs in a Transwell system. These data suggest that the mechanisms of MSC protection were mediated through suppression of the innate immune response and inflammation-induced β cell death when MSC and islets were co-transplanted into the liver.