Rejuvenation of MPTP-induced human neural precursor cell senescence by activating autophagy
Rejuvenation of MPTP-induced human neural precursor cell senescence by activating autophagy
复制标题
通过激活自噬恢复 MPTP 诱导的人神经前体细胞衰老
DOI：
10.1016/j.bbrc.2015.06.174
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发表时间：
2015
影响因子：
3.1
通讯作者：
Xu Jun
中科院分区：
文献类型：
--
作者：
Zhu Liang;Dong Chuanming;Sun Chenxi;Ma Rongjie;Yang Danjing;Zhu Hongwen;Xu Jun
神经干细胞的衰老可能是由多种细胞机制引起的，它可以影响大脑的稳态。在老年和神经退行性脑中发现了自噬功能障碍。然而，自噬与人类神经干细胞（hNSC）衰老之间的关系尚不清楚。本研究利用1-甲基-4-苯基- 1,2,3,6 -四氢吡啶（MPTP）处理人胚胎干细胞（hESC） H9系神经前体细胞（NPCs），并探讨其分子机制。经mptp处理的npc经历了过早衰老[由衰老相关-β-半乳糖苷酶（SA-β-gal）活性增加、细胞内活性氧水平升高和增殖减少决定]，并与自噬受损有关。此外，细胞衰老表型在分子水平上表现为p21、p53表达显著升高，SOD2表达显著降低，Atg5、Atg7、Atg12、Beclin 1等自噬相关关键基因表达降低。此外，我们发现，mptp处理的hNPCs的衰老样表型通过一种众所周知的自噬增强剂雷帕霉素（rapamycin）处理而恢复，这种自噬增强剂通过抑制必要的自噬基因Beclin 1而被阻断。综上所述，这些发现揭示了自噬在hNSC衰老过程中的关键作用，并且该过程可以通过激活自噬来逆转。
Aging of neural stem cell, which can affect brain homeostasis, may be caused by many cellular mechanisms. Autophagy dysfunction was found in aged and neurodegenerative brains. However, little is known about the relationship between autophagy and human neural stem cell (hNSC) aging. The present study used 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) to treat neural precursor cells (NPCs) derived from human embryonic stem cell (hESC) line H9 and investigate related molecular mechanisms involved in this process. MPTP-treated NPCs were found to undergo premature senescence [determined by increased senescence-associated-β-galactosidase (SA-β-gal) activity, elevated intracellular reactive oxygen species level, and decreased proliferation] and were associated with impaired autophagy. Additionally, the cellular senescence phenotypes were manifested at the molecular level by a significant increase in p21 and p53 expression, a decrease in SOD2 expression, and a decrease in expression of some key autophagy-related genes such as Atg5, Atg7, Atg12, and Beclin 1. Furthermore, we found that the senescence-like phenotype of MPTP-treated hNPCs was rejuvenated through treatment with a well-known autophagy enhancer rapamycin, which was blocked by suppression of essential autophagy gene Beclin 1. Taken together, these findings reveal the critical role of autophagy in the process of hNSC aging, and this process can be reversed by activating autophagy.