Chang Tzu-Ching, Hsu Min-Fen, Wu Kenneth K
Metabolomic Medicine Research Center, China Medical University Hospital, Taichung, Taiwan; Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
Metabolomic Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.
PLoS One. 2015 May 11;10(5):e0126537. doi: 10.1371/journal.pone.0126537. eCollection 2015.
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.
据报道，高血糖会导致骨髓造血微环境功能障碍，培养基中的高糖（HG）会诱导间充质干细胞（MSC）衰老。其潜在机制尚不清楚。在此，我们研究了HG诱导的自噬在骨髓间充质干细胞（BMSC）衰老中的作用。HG（25 mM）增加了Beclin-1、Atg 5、7和12的表达、LC3-II的生成以及自噬体的形成，这与细胞衰老的发展相关。用3-甲基腺嘌呤（3-MA）预处理HG-MSC可防止衰老，但增加细胞凋亡。N-乙酰半胱氨酸（NAC）可有效消除HG诱导的自噬，并预防衰老。二苯基碘鎓（DPI）是一种NADPH氧化酶抑制剂，其阻断自噬和衰老的方式与NAC相当。3-MA、NAC和DPI抑制HG诱导的BMSC中白细胞介素-6的产生。这些结果表明，高血糖通过一种新的氧化剂介导的自噬诱导MSC衰老和局部炎症，这导致骨髓微环境功能障碍和造血损伤。
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