Silencing of the small GTPase DIRAS3 induces cellular senescence in human white adipose stromal/progenitor cells.
Silencing of the small GTPase DIRAS3 induces cellular senescence in human white adipose stromal/progenitor cells.
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DOI：
10.18632/aging.101197
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发表时间：
2017-03-17
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影响因子：
--
通讯作者：
Zwerschke W
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作者：
Ejaz A;Mattesich M;Zwerschke W
抑制 Akt-mTOR 信号传导可以防止动物肥胖并延长寿命。在本研究中，我们分析了小 GTP 酶、GTP 结合 RAS 样 3 (DIRAS3)（一种最近发现的减肥目标基因）对源自人皮下白色脂肪组织 (sWAT) 的脂肪基质/祖细胞 (ASC) 细胞衰老的影响。我们证明 ASC 中的 DIRAS3 敲低 (KD) 会诱导 Akt-mTOR 信号传导激活和增殖抑制。 DIRAS3 KD ASC 失去形成集落的潜力，且 Ki-67 呈阴性。此外，DIRAS3 的沉默会导致早衰表型。其特征是衰老相关的 β-半乳糖苷酶阳性 ASC 增大，含有增加的 p16INK4A 水平和激活的视网膜母细胞瘤蛋白。 DIRAS3 KD ASC 形成衰老相关的异染色质灶，如 γ-H2A.X 阳性灶水平增加所示。此外，这些细胞表达衰老相关的分泌表型，其特征是白细胞介素8分泌增加。人类 DIRAS3 KD ASC 在 SCID 小鼠的 swAT 中也形成衰老表型。最后，我们发现 ASC 中的 DIRAS3 KD 会刺激脂肪形成分化和过早衰老。总之，我们的数据表明 ASC 中 DIRAS3 的沉默以及随后 Akt-mTOR 的过度激活会驱动脂肪生成和过早衰老。此外，分化的ASC和/或成熟脂肪细胞可能获得细胞衰老的特征。
Inhibition of Akt-mTOR signaling protects from obesity and extends life span in animals. In the present study, we analyse the impact of the small GTPase, GTP-binding RAS-like 3 (DIRAS3), a recently identified weight-loss target gene, on cellular senescence in adipose stromal/progenitor cells (ASCs) derived from human subcutaneous white adipose tissue (sWAT). We demonstrate that DIRAS3 knock-down (KD) in ASCs induces activation of Akt-mTOR signaling and proliferation arrest. DIRAS3 KD ASCs lose the potential to form colonies and are negative for Ki-67. Moreover, silencing of DIRAS3 results in a premature senescence phenotype. This is characterized by senescence-associated β-galactosidase positive enlarged ASCs containing increased p16INK4A level and activated retinoblastoma protein. DIRAS3 KD ASCs form senescence-associated heterochromatic foci as shown by increased level of γ-H2A.X positive foci. Furthermore, these cells express a senescence-associated secretory phenotype characterized by increased interleukin-8 secretion. Human DIRAS3 KD ASCs develop also a senescence phenotype in sWAT of SCID mice. Finally, we show that DIRAS3 KD in ASCs stimulates both adipogenic differentiation and premature senescence. In conclusion, our data suggest that silencing of DIRAS3 in ASCs and subsequently hyper-activation of Akt-mTOR drives adipogenesis and premature senescence. Moreover, differentiating ASCs and/or mature adipocytes may acquire features of cellular senescence.