High glucose-induced reactive oxygen species generation promotes sternness in human adipose-derived stem cells

Background aims. Adipose-derived stem cells (ASCs) represent an important source of cell therapy to treat diabetic complications. However, hyperglycemia may alter several cellular functions, so the present study aimed to investigate the influence of a diabetic environment on the sternness and differentiation capabilities of ASCs. Methods. Human ASCs were obtained from subcutaneous adipose tissues of diabetic (dASCs) and nondiabetic donors (nASCs) and characterized. To reproduce an in vitro hyperglycemia environment, the nASCs were also cultured under prolonged high-glucose (HG; 4.5 g/L) or low glucose (LG; 1.0 g/L) conditions. Results. The expression of cell surface markers in dASCs and nASC was similar and characteristic of mesenchymal stem cells. Although dASCs or HG-treated nASCs exhibited decreased proliferation, enhanced expression of the pluripotent markers Sox-2, Oct-4, and Nanog was observed. Moreover, HG-treated nASCs exhibited decreased cell migration, enhanced senescence, and significantly higher intracellular reactive oxygen species (ROS), whereas their adipogenic and osteogenic differentiation capacities remained comparable to LG-treated cells. With antioxidant treatment, HG-treated nASCs showed improved cell proliferative activity without sternness enhancement. This HG-induced biological response was associated with ROS-mediated AKT attenuation. When cultured in an appropriate induction medium, the HG-treated nASCs and dASCs exhibited enhanced potential of transdifferentiation into neuron-like cells. Discussion. Despite lower proliferative activity and higher senescence in a diabetic environment, ASCs also exhibit enhanced sternness and neurogenic transdifferentiation potential via a ROS-mediated mechanism. The information is important for future application of autologous ASCs in diabetic patients.