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Rejuvenation of MPTP-induced human neural precursor cell senescence by activating autophagy
Liang Zhu1, Chuanming Dong2, Chenxi Sun1
1East Hospital, Tongji University School of Medicine, Shanghai, China.
Abstract:
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.
Insights
Autophagy dysfunction contributes to human neural stem cell (hNSC) aging, evidenced by premature senescence. Activating autophagy, using rapamycin, can reverse this aging process in hNSCs.
Area of Science:
- Neuroscience
- Cell Biology
- Stem Cell Research
Background:
- Neural stem cell (NSC) aging impacts brain homeostasis.
- Autophagy dysfunction is observed in aged and neurodegenerative brains.
- The specific role of autophagy in human NSC (hNSC) aging remains unclear.
Purpose of the Study:
- To investigate the relationship between autophagy and hNSC aging.
- To explore the molecular mechanisms underlying MPTP-induced hNSC senescence.
- To determine if autophagy activation can reverse hNSC aging.
Main Methods:
- Used 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) to induce senescence in human embryonic stem cell-derived neural precursor cells (hNPCs).
- Assessed senescence markers: SA-β-gal activity, reactive oxygen species (ROS) levels, and proliferation.
- Analyzed molecular changes in senescence (p53, p21, SOD2) and autophagy (Atg5, Atg7, Atg12, Beclin 1) pathways.
- Investigated the effect of rapamycin (autophagy enhancer) and Beclin 1 suppression on MPTP-treated hNPCs.
Main Results:
- MPTP treatment induced premature senescence in hNPCs, characterized by increased SA-β-gal, elevated ROS, and reduced proliferation.
- MPTP-induced senescence was linked to impaired autophagy, indicated by decreased expression of key autophagy genes (Atg5, Atg7, Atg12, Beclin 1).
- Rapamycin treatment rejuvenated senescent hNPCs, an effect abolished by Beclin 1 suppression, highlighting autophagy's crucial role.
Conclusions:
- Autophagy plays a critical role in the aging process of human neural stem cells.
- MPTP-induced hNSC senescence is associated with autophagy dysfunction.
- Activating autophagy presents a potential therapeutic strategy to reverse hNSC aging.
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