title: High glucose-induced reactive oxygen species generation promotes stemness in human adipose-derived stem cells.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Nai-Chen
authors.initials: NC
authors.lastname: Cheng
authors.affiliation: Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan.
authors.forename: Tsung-Yu
authors.initials: TY
authors.lastname: Hsieh
authors.affiliation: Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
authors.forename: Hong-Shiee
authors.initials: HS
authors.lastname: Lai
authors.affiliation: Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan. Electronic address: thyoung@ntu.edu.tw.
authors.forename: Tai-Horng
authors.initials: TH
authors.lastname: Young
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D054338:Cell Transdifferentiation / Q000187:drug effects; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism* / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000473:pathology; D008875:Middle Aged; D010012:Osteogenesis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism* / Q000494:pharmacology; D050151:Subcutaneous Fat / Q000473:pathology*
chemical_list: D015415:Biomarkers; D017382:Reactive Oxygen Species; D005947:Glucose
keywords: adipose-derived stem cell; diabetes; differentiation; reactive oxygen species; stemness