University of Alberta
Mesenchymal stem cells co-transplanted with neonatal porcine islets improve revascularization, more rapid correction of diabetes and long-term graft function in diabetic mice
Julie Hayward1,2, Cara Ellis1,2, Adetola Adesida1, Gregory Korbutt1,2.
1Surgery, University of Alberta, Edmonton, AB, Canada; 2Alberta Diabetes Institute, Edmonton, AB, Canada
Background: Neonatal porcine islets (NPIs) are a viable source of islets for clinical transplantation however following transplantation they require a transient period to achieve normogycemia in mice. Mesenchymal stem cells (MSCs) have been shown to exhibit angiogenic, regenerative, immunoregulatory and anti-inflammatory properties through the secretion of a myriad of trophic factors. MSCs have also been shown to have a beneficial effect on islet graft function. In this study we investigated whether co-transplantation of human bone marrow derived MSCs and NPIs promotes revascularization, a more rapid correction of diabetes and improves long-term islet function in an immune-incompetent diabetic mouse model.
Method: Neonatal porcine islets were transplanted under the kidney capsule of streptozotocin-induced diabetic B6.129S7-Rag1tm1Mom/J mice with (n=14) or without (n=14) 1 x 106 reaggregated MSCs. Blood glucose and body weight were monitored weekly and when normal blood glycemia was obtained (<11 mmol/L) recipients underwent an oral glucose tolerance test. Survival nephrectomies were subsequently performed and recovered grafts were morphologically assessed for total ß-cell mass or graft insulin content. In a separate cohort of mice transplanted with or without MSCs, grafts were collected at 3 weeks post-transplant and assessed for the degree of re-vascularization by CD31 staining.
Results: Mice co-transplanted with NPIs and MSCs exhibited significantly lower glycemias from weeks 2 to 32 post-transplant. Moreover, at 20 weeks post-transplant 64% of mice co-transplanted with MSCs and NPIs were normalized whereas none were normalized when transplanted with islets alone. At the end of the follow-up period (35 weeks) 100% of mice in either transplant group were normalized. During an oral glucose tolerance test recipients of NPIs alone were glucose intolerant compared to mice implanted with NPIs and MSCs (area under the curve; 1278 vs. 1072 mmol·min/L, respectively). Following nephrectomy of graft bearing kidneys, all mice returned to hyperglycemia. In addition insulin content of harvested grafts obtained from co-transplanted mice (17.5 μg ± 2.4) was significantly higher (p=0.02) than islet alone grafts (12.0 μg ± 0.8). However, total ß-cell mass in both groups was comparable. Assessment of graft vascularization at 3 weeks post-transplant indicated that NPI and MSC composite grafts exhibited significantly more CD31+ cells than islet alone grafts, indicating a higher degree of re-vascularization.
Conclusion: In this study, we have demonstrated that when NPIs are transplanted with human MSCs there is a beneficial effect on the efficacy of the NPI grafts; they induce earlier angiogenesis and graft re-vascularization resulting in faster induction of normoglycemia and result in improved glucose tolerance. These data thereby support the clinical application of co-transplantation of neonatal porcine islets with human bone marrow derived mesenchymal stem cells.
Karen Seeberger. Lynne Postovit. Aillette Sierra. Deb Dixon. Sheena Lesyk. Lynette Elder. Telford Yeung.
15:30 - 17:00
|Modifying Islet Immunity - Adaptive, Innate, and Xenoimmunity||Mesenchymal stem cells co-transplanted with neonatal porcine islets improve revascularization, more rapid correction of diabetes and long-term graft function in diabetic mice||Plenary Room 1|