Tetraploidization or autophagy: The ultimate fate of senescent human endometrial stem cells under ATM or p53 inhibition.
Tetraploidization or autophagy: The ultimate fate of senescent human endometrial stem cells under ATM or p53 inhibition.
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DOI：
10.1080/15384101.2015.1121326
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Burova EB
中科院分区：
文献类型：
--
作者：
Borodkina AV;Shatrova AN;Deryabin PI;Grukova AA;Nikolsky NN;Burova EB
之前，我们证明了子宫内膜源性人间充质干细胞（hMESCs）通过激活ATM/p53/p21/Rb通路进入氧化应激反应的过早衰老。该信号通路的关键组分，特别是ATM和p53，对应激hMESCs命运的下调作用尚未被研究。本研究利用特异性抑制剂Ku55933和聚氟乙烯酯-α，证实了ATM和p53在h2o2诱导的hMESCs衰老中的作用。ATM或p53下调被证明对h2o2处理的hMESCs的细胞命运有不同的调节作用。ATM抑制使h2o2刺激的hMESCs逃脱了由于失去功能性ATM/p53/p21/Rb通路而导致的永久性细胞周期阻滞，并诱导有丝分裂旁路并重新进入S期，从而产生四倍体细胞。相反，抑制p53转录活性通过自噬诱导h2o2处理的hMESCs细胞明显死亡。所获得的数据清楚地表明，下调ATM或p53使人子宫内膜干细胞的衰老向四倍体化或自噬方向转变。
Previously we demonstrated that endometrium-derived human mesenchymal stem cells (hMESCs) via activation of the ATM/p53/p21/Rb pathway enter the premature senescence in response to oxidative stress. Down regulation effects of the key components of this signaling pathway, particularly ATM and p53, on a fate of stressed hMESCs have not yet been investigated. In the present study by using the specific inhibitors Ku55933 and Pifithrin-α, we confirmed implication of both ATM and p53 in H2O2-induced senescence of hMESCs. ATM or p53 down regulation was shown to modulate differently the cellular fate of H2O2-treated hMESCs. ATM inhibition allowed H2O2-stimulated hMESCs to escape the permanent cell cycle arrest due to loss of the functional ATM/p53/p21/Rb pathway, and induced bypass of mitosis and re-entry into S phase, resulting in tetraploid cells. On the contrary, suppression of the p53 transcriptional activity caused a pronounced cell death of H2O2-treated hMESCs via autophagy induction. The obtained data clearly demonstrate that down regulation of ATM or p53 shifts senescence of human endometrial stem cells toward tetraploidization or autophagy.