Abstract
Background:Type 1 Diabetes Mellitus (T1DM) is partly driven by autoimmune destruction of the pancreatic beta cell, facilitated by the release of inflammatory cytokines, including IFN-γ, TNF-α and IL-1β by cells of the innate immune system. Mesenchymal Stem Cells (MSCs) have been used to counteract autoimmunity in a range of therapeutic settings due to their secretion of trophic and immunomodulatory factors that ameliorate disease independently of the cells themselves.Objective:The aim of this study was to assess the effect of the secretome of human bone-marrow derived MSCs on cytokine-driven beta cell apoptosis.Methods:All experiments were conducted in two insulin-secreting islet cell lines (BRIN-BD11 and βTC1.6) with selected experiments confirmed in primary islets. MSC secretome was generated by conditioning serum-free media (MSC-CM) for 24 hours on sub-confluent MSC populations. The media was then removed and filtered in readiness for use.Results:Exposure to IFN-γ, TNF-α and IL-1β induced apoptosis in cell lines and primary islets. The addition of MSC-CM to cell lines and primary islets partially reversed cytokine-driven apoptosis. MSC-CM also restored glucose-stimulated insulin secretion in cytokine-treated cell lines, which was linked to improved cell viability following from cytokine challenge. Characterization of MSC-CM revealed significant concentrations of IL-4, IL-10, PIGF and VEGF. Of these, IL-10 alone prevented cytokine-driven apoptosis. Furthermore, the inhibition of IL-10 through the addition of a blocking antibody reversed the anti-apoptotic effects of MSC-CM.Conclusion:Overall, the protective effects of MSC-CM on islet beta cell survival appear to be largely IL-10-dependent.
Highlights
IntroductionType 1 Diabetes Mellitus (T1DM) is a complex autoimmune disease in which several inflammatory cells inflict a coordinated assault on the pancreatic islets of Langerhans and the insulin-producing beta
This study reported high concentrations of IL-6, vascular endothelial growth factor-A (VEGF-A), hepatocyte growth factor (HGF), and transforming growth factor (TGF)-β found in Mesenchymal Stem Cells (MSCs)-Conditioned Media (CM)
MSCs secrete TGF-β and IL-10, which block T-cell proliferation [9, 10], while soluble factors secreted by MSCs are believed to alter the secretion profile of dendritic cells leading to increased production of anti-inflammatory cytokines including IL-10 and decreased production of inflammatory cytokines including IFN-γ [11]
Summary
T1DM is a complex autoimmune disease in which several inflammatory cells inflict a coordinated assault on the pancreatic islets of Langerhans and the insulin-producing beta. Despite the reported antidiabetogenic effects of MSCs [6], the mechanism of action remains poorly understood This is partly due to the diverse range of effects that MSCs and their secreted products have on the surrounding environment. Type 1 Diabetes Mellitus (T1DM) is partly driven by autoimmune destruction of the pancreatic beta cell, facilitated by the release of inflammatory cytokines, including IFN-γ, TNF-α and IL-1β by cells of the innate immune system. Mesenchymal Stem Cells (MSCs) have been used to counteract autoimmunity in a range of therapeutic settings due to their secretion of trophic and immunomodulatory factors that ameliorate disease independently of the cells themselves
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