Senescence and apoptosis block hematopoietic activation of quiescent hematopoietic stem cells with short telomeres.
Senescence and apoptosis block hematopoietic activation of quiescent hematopoietic stem cells with short telomeres.
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DOI：
10.1182/blood-2014-04-568055
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发表时间：
2014-11
期刊：
影响因子：
20.3
通讯作者：
Jianwei Wang;Xin Lu;V. Sakk;C. Klein;K. Rudolph
中科院分区：
文献类型：
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作者：
Jianwei Wang;Xin Lu;V. Sakk;C. Klein;K. Rudolph
端粒缩短限制了人类细胞的增殖能力，并且端粒的年龄依赖性缩短发生在包括造血干细胞（HSC）的体组织中。目前尚不清楚在HSC中发生的由端粒缩短诱导的基因组和分子损伤是否传递到祖细胞。在这里，我们表明，端粒缩短的结果在老年小鼠静止HSC的DNA损伤积累和基因表达的变化。在激活后，具有升高水平的DNA损伤和p16表达的HSC的子集被阻止进入细胞周期，并且在进入细胞周期的HSC中诱导凋亡。这两个检查点的激活与早期祖细胞阶段DNA损伤和基因表达谱的正常化有关。这些研究结果表明，静止的HSC有一个升高的耐受性积累的基因组改变，端粒缩短，但这些畸变的祖细胞水平的传输是防止衰老和凋亡。
Telomere shortening limits the proliferative capacity of human cells, and age-dependent shortening of telomeres occurs in somatic tissues including hematopoietic stem cells (HSCs). It is currently unknown whether genomic and molecular damage that occurs in HSCs induced by telomere shortening is transmitted to the progenitor cells. Here we show that telomere shortening results in DNA damage accumulation and gene expression changes in quiescent HSCs of aged mice. Upon activation, a subset of HSCs with elevated levels of DNA damage and p16 expression are blocked from cell cycle entry, and apoptosis is induced in HSCs entering the cell cycle. Activation of both checkpoints associates with normalization of DNA damage and gene expression profiles at early progenitor stages. These findings indicate that quiescent HSCs have an elevated tolerance to accumulate genomic alterations in response to telomere shortening, but the transmission of these aberrations to the progenitor cell level is prevented by senescence and apoptosis.