Functional analysis of Protection of Telomeres 1a (Pot1a) in regulation of hematopoietic stem cell aging
Functional analysis of Protection of Telomeres 1a (Pot1a) in regulation of hematopoietic stem cell aging
复制标题
端粒1a（Pot1a）保护调节造血干细胞衰老的功能分析
DOI：
10.11406/rinketsu.58.942
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Arai F.
中科院分区：
文献类型：
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作者：
Hosokawa K;Macarthur BD;Ikushima Y;Toyama H;Masuhiro Y;Hanazawa S;Suda T;Arai F.
反复的细胞分裂会导致DNA损伤积累，从而在衰老过程中损害干细胞的功能。然而，发生这种情况的一般分子机制仍不清楚。在此，我们证明了保护性端粒1a(Pot1a)的表达对于预防端粒DNA损伤反应(DDR)和在衰老过程中维持造血干细胞(HSC)的活性至关重要。我们观察到HSC在发育过程中表达高水平的Pot1a，并且这种表达随着年龄的增长而下降。Pot1a基因敲除诱导了一种与年龄相关的表型，其特征是端粒DDR增加，长期重建活性降低。相比之下，用外源Pot1a蛋白治疗可以阻止端粒DDR，端粒DDR降低干细胞活性并部分恢复HSC活性。这些结果突出了一种普遍的、可逆的机制，即衰老损害哺乳动物干细胞的活性，这对再生医学具有广泛的影响。
Repeated cell divisions induce DNA damage accumulation, which impairs stem cell function during aging. However, the general molecular mechanisms by which this occurs remain unclear. Herein, we show that the expression of protection of telomeres 1a (Pot1a), a component of shelterin, is crucial for prevention of telomeric DNA damage response (DDR) and maintenance of hematopoietic stem cell (HSC) activity during aging. We observed that HSCs express high levels of Pot1a during development, and this expression declines with aging. Knockdown of Pot1a induced an age-related phenotype, characterized by increased telomeric DDR and reduced long-term reconstitution activity. In contrast, treatment with exogenous Pot1a protein prevented telomeric DDR, which decreased stem cell activity and partially rejuvenated HSC activity. These results highlight a general, reversible mechanism by which aging compromises mammalian stem cell activity, with widespread implications for regenerative medicine.