c-Maf regulates pluripotency genes, proliferation/self-renewal, and lineage commitment in ROS-mediated senescence of human mesenchymal stem cells.
c-Maf regulates pluripotency genes, proliferation/self-renewal, and lineage commitment in ROS-mediated senescence of human mesenchymal stem cells.
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DOI：
10.18632/oncotarget.6178
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发表时间：
2015-11-03
期刊：
影响因子：
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通讯作者：
Yen ML
中科院分区：
文献类型：
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作者：
Chen PM;Lin CH;Li NT;Wu YM;Lin MT;Hung SC;Yen ML
间充质干细胞(MSCs)是治疗相关的多系和免疫调节前体细胞。这些稀有细胞的体外扩增对于临床应用是必要的，可能会导致有害的衰老效应，其机制在很大程度上仍不清楚。我们发现，人脂肪组织来源的间充质干细胞(HAMSCs)的体外扩增会导致细胞增殖下降、细胞周期停滞和分化能力改变。这种衰老表型与ROS积累和G1细胞周期抑制因子p15INK4b和p16INK4a的表达增加有关，但多能基因OCT-4、SOX-2、Nanog和c-Myc以及c-Maf的表达减少，c-Maf是MSC谱系特异性转录因子的辅助因子，对氧化应激敏感。这些转录和功能上的变化，如增殖、分化和自我更新，都是由ROS诱导的对c-Maf的抑制所介导的，c-Maf与hAMSCs中多个相关基因的启动子区域结合证明了这一点，而外源ROS可以减少c-Maf的表达。我们的发现暗示了ROS对多种干细胞功能的强烈影响，其中c-Maf在干细胞衰老中起着核心作用。
Mesenchymal stem cells (MSCs) are therapeutically relevant multilineage and immunomodulatory progenitors. Ex vivo expansion of these rare cells is necessary for clinical application and can result in detrimental senescent effects, with mechanisms still largely unknown. We found that vigorous ex vivo expansion of human adipose tissue-derived MSCs (hAMSCs) results in proliferative decline, cell cycle arrest, and altered differentiation capacity. This senescent phenotype was associated with reactive oxygen species (ROS) accumulation, and with increased expression of G1 cell -cycle inhibitors— p15INK4b and p16INK4a — but decreased expression of pluripotency genes—Oct-4, Sox-2, Nanog, and c-Myc—as well as c-Maf a co-factor of MSC lineage-specific transcription factor and sensitive to oxidative stress. These global changes in the transcriptional and functional programs of proliferation, differentiation, and self-renewal were all mediated by ROS-induced suppression of c-Maf, as evidenced by binding of c-Maf to promoter regions of multiple relevant genes in hAMSCs which could be reduced by exogenous ROS. Our findings implicate the strong effects of ROS on multiple stem cell functions with a central role for c-Maf in stem cell senescence.