Evidence that hematopoietic stem cell function is preserved during aging in long-lived S6K1 mutant mice.
Evidence that hematopoietic stem cell function is preserved during aging in long-lived S6K1 mutant mice.
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DOI：
10.18632/oncotarget.8729
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发表时间：
2016-05-24
期刊：
影响因子：
--
通讯作者：
Withers DJ
中科院分区：
文献类型：
--
作者：
Selman C;Sinclair A;Pedroni SM;Irvine EE;Michie AM;Withers DJ
雷帕霉素（mTOR）信号通路的机制靶标在衰老中起着高度保守的作用;缺乏核糖体蛋白S6激酶1（S6 K1 −/−）的小鼠相对于野生型（WT）对照具有延长的寿命和健康寿命。尽管保留干细胞功能可能很重要，但mTOR信号传导减少到底是如何诱导这种效应的尚不清楚。我们使用基因表达分析表明，与年龄匹配的WT小鼠相比，年轻（12周）和老年（80周）S6 K1 −/− BM衍生的c-Kit+细胞中细胞周期基因的表达减少，表明这些细胞在S6 K1 −/−小鼠中更静止。此外，我们研究了年轻和老年S6 K1 −/−和WT小鼠的造血干细胞（HSC）频率和功能。与WT对照组相比，年轻而非老年的S6 K1 −/−小鼠具有更多的LSK（谱系−，c-Kit+，Sca-1+）细胞（占骨髓（BM）的%），包括最原始的长期再增殖HSC（LT-HSC）。供体来源的LT-HSC在受体小鼠中的植入不受年轻小鼠基因型的影响，但在使用来自老年S6 K1 −/−小鼠的LT-HSC的移植中得到增强。我们的研究结果是第一个提供证据表明，在长寿的mTOR突变小鼠中，年龄相关的HSC功能下降得到改善。
The mechanistic target of rapamycin (mTOR) signalling pathway plays a highly conserved role in aging; mice lacking ribosomal protein S6 kinase 1 (S6K1−/−) have extended lifespan and healthspan relative to wild type (WT) controls. Exactly how reduced mTOR signalling induces such effects is unclear, although preservation of stem cell function may be important. We show, using gene expression analyses, that there was a reduction in expression of cell cycle genes in young (12 week) and aged (80 week) S6K1−/− BM-derived c-Kit+ cells when compared to age-matched WT mice, suggesting that these cells are more quiescent in S6K1−/− mice. In addition, we investigated hematopoietic stem cell (HSC) frequency and function in young and aged S6K1−/− and WT mice. Young, but not aged, S6K1−/− mice had more LSK (lineage−, c-Kit+, Sca-1+) cells (% of bone marrow (BM)), including the most primitive long-term repopulating HSCs (LT-HSC) relative to WT controls. Donor-derived engraftment of LT-HSCs in recipient mice was unaffected by genotype in young mice, but was enhanced in transplants using LT-HSCs derived from aged S6K1−/− mice. Our results are the first to provide evidence that age-associated HSC functional decline is ameliorated in a long-lived mTOR mutant mouse.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
影响因子：
--
作者：
Leontieva OV;Demidenko ZN;Blagosklonny MV
通讯作者：
Blagosklonny MV
影响因子：
7.8
作者：
Mair W;McLeod CJ;Wang L;Jones DL
通讯作者：
Jones DL
影响因子：
23.9
作者：
Magee, Jeffrey A.;Ikenoue, Tsuneo;Nakada, Daisuke;Lee, Jae Y.;Guan, Kun-Liang;Morrison, Sean J.
通讯作者：
Morrison, Sean J.
DOI：
10.1084/jem.20081297
发表时间：
2008-09-29
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chen C;Liu Y;Liu R;Ikenoue T;Guan KL;Liu Y;Zheng P
通讯作者：
Zheng P