Oxidized SOD1 accelerates cellular senescence in neural stem cells

作者全名："Guan, Teng; Guo, Ying; Zhou, Ting; Yu, Qiang; Sun, Jingyi; Sun, Baoliang; Zhang, Guohui; Kong, Jiming"

作者地址："[Guan, Teng; Guo, Ying; Zhou, Ting; Yu, Qiang; Kong, Jiming] Univ Manitoba, Dept Human Anat & Cell Sci, Winnipeg, MB, Canada; [Guo, Ying; Zhang, Guohui] Hebei North Univ, Dept Forens Med, Zhangjiakou, Hebei, Peoples R China; [Zhou, Ting] Chongqing Med Univ, Affiliated Hosp 2, Dept Pharm, Chongqing, Peoples R China; [Sun, Jingyi; Sun, Baoliang] Shandong First Med Univ & Shandong Acad Med Sci, Jinan 250117, Shandong, Peoples R China"

通信作者："Kong, JM (通讯作者)，Univ Manitoba, Dept Human Anat & Cell Sci, Winnipeg, MB, Canada."

来源：STEM CELL RESEARCH & THERAPY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001176673600003

JCR分区：Q1

影响因子：7.1

年份：2024

卷号：15

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："BackgroundNeural stem cells (NSCs), especially human NSCs, undergo cellular senescence characterized by an irreversible proliferation arrest and loss of stemness after prolonged culture. While compelling correlative data have been generated to support the oxidative stress theory as one of the primary determinants of cellular senescence of NSCs, a direct cause-and-effect relationship between the accumulation of oxidation-mediated damage and cellular senescence of NSCs has yet to be firmly established. Human SOD1 (hSOD1) is susceptible to oxidation. Once oxidized, it undergoes aberrant misfolding and gains toxic properties associated with age-related neurodegenerative disorders. The present study aims to examine the role of oxidized hSOD1 in the senescence of NSCs.MethodsNSCs prepared from transgenic mice expressing the wild-type hSOD1 gene were maintained in culture through repeated passages. Extracellular vesicles (EVs) were isolated from culture media at each passage. To selectively knock down oxidized SOD1 in NSCs and EVs, we used a peptide-directed chaperone-mediated protein degradation system named CT4 that we developed recently.ResultsIn NSCs expressing the hSOD1 from passage 5, we detected a significant increase of oxidized hSOD1 and an increased expression of biomarkers of cellular senescence, including upregulation of P53 and SA-beta-Gal and cytoplasmic translocation of HMGB1. The removal of oxidized SOD1 remarkably increased the proliferation and stemness of the NSCs. Meanwhile, EVs derived from senescent NSCs carrying the wild-type hSOD1 contained high levels of oxidized hSOD1, which could accelerate the senescence of young NSCs and induce the death of cultured neurons. The removal of oxidized hSOD1 from the EVs abolished their senescence-inducing activity. Blocking oxidized SOD1 on EVs with the SOD1 binding domain of the CT4 peptide mitigated its toxicity to neurons.ConclusionOxidized hSOD1 is a causal factor in the cellular senescence of NSCs. The removal of oxidized hSOD1 is a strategy to rejuvenate NSCs and to improve the quality of EVs derived from senescent cells."

基金机构：ALS Society of Canada

基金资助正文：Not applicable.