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

• Published in: Cytotherapy (Oxford, England) England), 2016-03, Vol.18 (3), p.371-383
• Main Authors: Cheng, Nai-Chen, Hsieh, Tsung-Yu, Lai, Hong-Shiee, Young, Tai-Horng
• Format: Article
• Language: English
• Subjects: Adipocytes - cytology; Adipocytes - drug effects; Adipocytes - physiology; adipose-derived stem cell; Adult; Advanced Basic Science; Aged; Biomarkers - metabolism; Case-Control Studies; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Cell Transdifferentiation - drug effects; Cells, Cultured; diabetes; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; differentiation; Glucose - pharmacology; Humans; Hyperglycemia - metabolism; Hyperglycemia - pathology; Mesenchymal Stromal Cells - drug effects; Mesenchymal Stromal Cells - pathology; Middle Aged; Osteogenesis - drug effects; Other; reactive oxygen species; Reactive Oxygen Species - metabolism; Reactive Oxygen Species - pharmacology; stemness; Subcutaneous Fat - pathology
• ISSN: 1465-3249; 1477-2566
• DOI: 10.1016/j.jcyt.2015.11.012

Abstract 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 stemness 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 stemness 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 stemness and neurogenic transdifferentiation potential via a ROS-mediated mechanism. The information is important for future application of autologous ASCs in diabetic patients.