Tetrahydrofolate Alleviates the Inhibitory Effect of Oxidative Stress on Neural Stem Cell Proliferation through PTEN/Akt/mTOR Pathway.

Xuyang Zhang,Yongjie Zou,Tengyuan Zhou,Hui Feng,Chao Zhang,Rong Hu,Jun Zhong,Fengchun Zhao,Wenqin Yang,Hua Feng,Hongfei Ge,Zhi Liu,Francisco J Romero

doi:10.1155/2022/9021474

Abstract

Neural stem cell (NSC) proliferation is the initial step for NSC participating in neurorehabilitation after central nervous system (CNS) injury. During this process, oxidative stress is always involved in restricting the regenerative ability of NSC. Tetrahydrofolate (THF) is susceptible to oxidative stress and exhibits a high antioxidant activity. While its effect on NSC proliferation under oxidative stress condition remains obscure. Here, NSC were isolated from embryonic mice and identified using immunofluorescent staining. Meanwhile, the results showed that THF (5 μM and 10 μM) attenuated oxidative stress induced by 50 μM hydrogen peroxide (H2O2) in NSC using mitochondrial hydroxyl radical detection and Western blotting assays. Afterward, administration of THF markedly alleviated the inhibitory effect of oxidative stress on NSC proliferation, which was evidenced by Cell Counting Kit-8 (CCK8), neurosphere formation, and immunofluorescence of Ki67 assays. Thereafter, the results revealed that PTEN/Akt/mTOR signaling pathway played a pivotal role in counteracting oxidative stress to rescue the inhibitory effect of oxidative stress on NSC proliferation using Western blotting assays and gene knockdown techniques. Collectively, these results demonstrate that THF mitigates the inhibitory effect of oxidative stress on NSC proliferation via PTEN/Akt/mTOR signaling pathway, which provides evidence for administrating THF to potentiate the neuro-reparative capacity of NSC in the treatment of CNS diseases with the presence of oxidative stress.

Highlights

Neural stem cell (NSC), residing in the dentate gyrus (DG) of hippocampus and subventricular zone (SVZ) of the lateral ventricle, are the main regenerative neural cell subtype in the central nervous system (CNS) [1–4]
To determine the effect of THF on NSC proliferation under oxidative stress condition, we firstly evaluated the effect of THF on the production of reactive oxygen species (ROS) in NSC
The results demonstrated that oxidative stress suppressed NSC proliferation, which was significantly alleviated by THF administration (5 μM and 10 μM)

Summary

Introduction

Neural stem cell (NSC), residing in the dentate gyrus (DG) of hippocampus and subventricular zone (SVZ) of the lateral ventricle, are the main regenerative neural cell subtype in the central nervous system (CNS) [1–4]. NSC dynamically keep in a delicate balance among self-renewal, differentiation, and quiescence [5]. NSC hold the ability of proliferating in situ, migrating toward the injured regions, differentiating into three main neural subpopulations (neurons, astrocytes, and oligodendrocytes), and integrating into the damaged neurovascular network to accelerate functional recovery after CNS injury [6–9]. Several factors have been identified to be associated with NSC proliferation. The level of reactive oxygen species (ROS) is one of the factors mediating NSC proliferation. Low basal dynamic ROS levels maintain NSC in a sophisticated balance among self-renewal, differentiation, and quiescence [5]. Previous studies have indicated that a slightly higher ROS level boosts NSC proliferation isolated from SVZ [5, 10–12], whereas excessive level of ROS, characterized as ROS surplus, always results in oxidative stress [13].

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