Abstract
BackgroundIslets of Langerhans transplantation is a promising therapy for type 1 diabetes mellitus, but this technique is compromised by transplantation stresses including inflammation. In other tissues, co-transplantation with mesenchymal stem cells has been shown to reduce damage by improving anti-inflammatory and anti-oxidant defences. Therefore, we probed the protection afforded by bone marrow mesenchymal stem cells to islets under pro-inflammatory cytokine stress.MethodsIn order to evaluate the cytoprotective potential of mesenchymal stem cells on rat islets, co-cultures were exposed to the interleukin-1, tumour necrosis factor α and interferon γ cocktail for 24 h. Islet viability and functionality tests were performed. Reactive oxygen species and malondialdehyde were measured. Expression of stress-inducible genes acting as anti-oxidants and detoxifiers, such as superoxide dismutases 1 and 2, NAD(P)H quinone oxidoreductase 1, heme oxygenase-1 and ferritin H, was compared to non-stressed cells, and the corresponding proteins were measured. Data were analysed by a two-way ANOVA followed by a Holm-Sidak post hoc analysis.ResultsExposure of rat islets to cytokines induces a reduction in islet viability and functionality concomitant with an oxidative status shift with an increase of cytosolic ROS production. Mesenchymal stem cells did not significantly increase rat islet viability under exposure to cytokines but protected islets from the loss of insulin secretion. A drastic reduction of the antioxidant factors heme oxygenase-1 and ferritin H protein levels was observed in islets exposed to the cytokine cocktail with a prevention of this effect by the presence of mesenchymal stem cells.ConclusionsOur data evidenced that MSCs are able to preserve islet insulin secretion through a modulation of the oxidative imbalance mediated by heme and iron via heme oxygenase-1 and ferritin in a context of cytokine exposure.
Highlights
Islets of Langerhans transplantation is a promising therapy for type 1 diabetes mellitus, but this technique is compromised by transplantation stresses including inflammation
Mesenchymal stem cell (MSC) co-cultured with islets protect insulin secretion but not islet viability under exposure to cytokines After exposure to cytokines, we observed a significant decrease in islet viability with an islet viability of 64.8% [60.4%–71.7%] in islets exposed to cytokines vs. 100% [83.8–102.6%] in control islets (p < 0.001; n = 6)
MSCs co-cultured with islets did not statistically impact viability of islets exposed to cytokines (72.5% [68.4– 82.9%]) compared to islets alone exposed to cytokines (64.8% [60.4–71.7%]) (p = 0.21; n = 6) (Fig. 1a)
Summary
Islets of Langerhans transplantation is a promising therapy for type 1 diabetes mellitus, but this technique is compromised by transplantation stresses including inflammation. We probed the protection afforded by bone marrow mesenchymal stem cells to islets under pro-inflammatory cytokine stress. 50–70% of islet grafts are lost in the early post-transplant period due to various factors such as ischemia reperfusion, immunosuppressive therapy toxicity or instant blood-mediated inflammatory reaction mediated by pro-inflammatory cytokines [3]. Due to their poor oxidative defences [4, 5], islets are sensitive to oxidative stress induced by inflammatory cytokines [6,7,8]. Its overexpression by transfection or chemical induction leads to reduced islet sensitivity to oxidative stress induced by inflammatory cytokines [13,14,15]
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