title: High glucose induces bone marrow-derived mesenchymal stem cell senescence by upregulating autophagy.
abstract: Hyperglycemia was reported to cause bone marrow hematopoietic niche dysfunction, and high glucose (HG) in the cultured medium induces MSC senescence. The underlying mechanism is unclear. Here, we investigated the role of HG-induced autophagy in bone-marrow-derived mesenchymal stem cell (BMSC) senescence. HG (25 mM) increased expression of Beclin-1, Atg 5, 7 and 12, generation of LC3-II and autophagosome formation which was correlated with development of cell senescence. Pretreatment of HG-MSC with 3-methyladenine (3-MA) prevented senescence but increased apoptosis. N-acetylcysteine (NAC) was effective in abrogating HG-induced autophagy accompanied by prevention of senescence. Diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase, blocked autophagy and senescence in a manner comparable to NAC. 3-MA, NAC and DPI inhibited HG-induced interleukin-6 production in BMSCs. These results suggest that hyperglycemia induces MSC senescence and local inflammation via a novel oxidant-mediated autophagy which contributes to bone marrow niche dysfunction and hematopoietic impairment.
authors.affiliation: Metabolomic Medicine Research Center, China Medical University Hospital, Taichung, Taiwan; Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Tzu-Ching
authors.initials: TC
authors.lastname: Chang
authors.affiliation: Metabolomic Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Min-Fen
authors.initials: MF
authors.lastname: Hsu
authors.affiliation: Metabolomic Medicine Research Center, China Medical University Hospital, Taichung, Taiwan; Graduate Institute of Basic Medicine, China Medical University, Taichung, Taiwan; National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Wu
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology*; D002478:Cells, Cultured; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D015850:Interleukin-6 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D015850:Interleukin-6; D017382:Reactive Oxygen Species; D005947:Glucose