Mesenchymal stromal cells support early beta cell function post-transplantation in a marginal islet mass diabetic mouse model

D. Borg, M. Weigelt, C. Wilhelm, A. Hommel, E. Bonifacio
Center for Regenerative Therapies Dresden, Dresden, Germany

Objectives: Islet transplantation for the treatment of type 1 diabetes is performed by infusion of islets into the portal vein. A large number of islet beta cells do not survive exposure to the ensuing blood-mediated inflammatory reaction and low oxygen tension occurring at and soon after infusion. We reasoned that cells capable of exerting survival support should improve early islet graft function. To this end, we used bone marrow derived-mesenchymal stromal cells (MSCs) as an accessory cell for islet transplantation.

Methods: To evaluate the effect of the MSC co-transplantation on islet function, we transplanted a marginal syngeneic islet mass (200 IEQ) with or without 250,000 MSCs under the kidney capsule of diabetic C57BL6/J recipients. To study the MSC support mechanisms, additional diabetic mice were transplanted with the same protocol and sacrificed at day 2, 7 or 14 for immunohistological examination of islets.

Results: After 28 days, the proportion of mice to reach euglycemia, when transplanted with islets and MSCs, was significantly increased compared to mice ransplanted with islets alone (60% vs 20%; n = 14 per group; p=0.01). The percentage of proliferating Ki67 positive, insulin positive nuclei did not differ between mice transplanted with islets alone or islets and MSCs at the different time points, indicating that mechanisms involving increased beta cell proliferation were unlikely. Caspase 3 staining, however, showed markedly decreased cell death at day 14 in islets that were co-transplanted with MSCs. No differences were seen at days 2 and 7 suggesting that the reduced apoptosis is an end result of improved islet survival secondary to another mechanism.

Conclusions: Our results show that the addition of MSCs to islet transplantation markedly improves islet graft function, potentially allowing a smaller islet mass to be transplanted.