Impact of type 2 diabetes mellitus on the immunoregulatory characteristics of adipose tissue-derived mesenchymal stem cells

Background: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder associated with several complications. Adipose tissue-derived mesenchymal stem cells (AT-MSCs) represent an emerging type of MSCs with high plasticity and immunoregulatory capabilities and are useful for treating inflammation-related disorders such as T2DM. However, the pathogenic microenvironment of T2DM may affect their therapeutic potential. We aimed to examine the impact of the diabetic milieu on the immunomodulatory/anti-inflammatory potential of AT-MSCs. Methods: We assessed the proliferation potential, cell surface expression of MSC-characteristic markers and immunomodulatory markers, along with the gene expression and protein secretion of pro-inflammatory and antiinflammatory cytokines and adipokines in AT-MSCs derived from T2DM patients (dAT-MSCs) vs. those derived from non-diabetic volunteers (ndAT-MSCs). Furthermore, we evaluated the IFN-gamma priming effect on both groups. Results: Our data revealed comparable proliferative activities in both groups. Flow cytometric analysis results showed a lower expression of CD200 and CD276 on dAT-MSCs vs. ndAT-MSCs. qPCR demonstrated upregulation of IL-1 beta associated with a downregulation of IL-1RN in dAT-MSCs vs. ndAT-MSCs. IFN-gamma priming induced an elevation in CD274 expression associated with IDO1 and ILRN overexpression and IL-1 beta downregulation in both groups. ELISA analysis uncovered elevated levels of secreted IL-1 beta, TNF, and visfatin/NAMPT in dAT-MSCs, whereas IL-1RA and IDO levels were reduced. ELISA results were also evident in the secretome of dAT-MSCs upon IFN-gamma priming. Conclusions: This study suggests that the T2DM milieu alters the immunomodulatory characteristics of AT-MSCs with a shift towards a proinflammatory phenotype which may restrain their autologous therapeutic use. Furthermore, our findings indicate that IFN-gamma priming could be a useful strategy for enhancing dAT-MSC antiinflammatory potential.