Mesenchymal stem cells improve islet function and revascularisation

C. Rackham, N. Buckner, P. Dhadda, P. Jones, A. King
King's College London, Division of Diabetes and Nutritional Sciences, London, U.K.

Objective: We have previously shown that mesenchymal stem cell (MSC) co-transplantation with islets improved the rate and extent of return to glycaemic control in diabetic mice. We have now investigated potential mechanisms that might explain improved graft function in the presence of MSCs.

Methods: In vitro: Mouse islets were cultured alone or with kidney-derived MSCs for three days and their secretory responses to glucose assessed using static incubation assays. Insulin release was measured by radioimmunoassay. In vivo: Islets were syngeneically transplanted, either alone or with MSCs underneath the kidney capsule of streptozotocin-induced diabetic mice. Immunohistochemistry, utilizing CD34 and CD31 antisera, was used to quantify endothelial cells within the graft at 3, 7 and 28 days post transplantation.

Results: In vitro: MSCs had no effect on insulin secretion in the presence of a sub-stimulatory glucose concentration (2mM), but significantly potentiated glucose-stimulated (20mM) insulin secretion (1.68±0.21 vs 2.78±0.32 ng/islet/hr, P<0.05, n=5). In vivo: At three days post transplantation, the graft endocrine tissue was essentially avascular, as assessed by the number of CD34+ endothelial cells with no differences observed between transplant groups. The number of CD31+ endothelial cells was similarly low. However, there was differential expression of endothelial cell markers within the non-endocrine tissue surrounding the islets in both transplant groups. At seven days post transplantation, the density of both CD34+ and CD31+ endothelial cells within the endocrine tissue was higher in MSC co-transplanted, compared with islet-alone recipients (310±24 and 411±54 vs 539±57 and 667±56 CD34+ and CD31+ endothelial cells/mm² respectively, P<0.05, n=4). In both transplant groups, vascularisation of the endocrine tissue increased at 28 days, with significantly higher densities of CD34+ and CD31+ ECs in MSC co-transplanted mice.

Conclusions: MSCs enhance glucose-stimulated insulin secretion in vitro and increase the rate and overall extent to which transplanted islets revascularise in vivo.