title: A stress-induced cellular aging model with postnatal neural stem cells.
abstract: Aging refers to the physical and functional decline of the tissues over time that often leads to age-related degenerative diseases. Accumulating evidence implicates that the senescence of neural stem cells (NSCs) is of paramount importance to the aging of central neural system (CNS). However, exploration of the underlying molecular mechanisms has been hindered by the lack of proper aging models to allow the mechanistic examination within a reasonable time window. In the present study, we have utilized a hydroxyurea (HU) treatment protocol and effectively induced postnatal subventricle NSCs to undergo cellular senescence as determined by augmented senescence-associated-β-galactosidase (SA-β-gal) staining, decreased proliferation and differentiation capacity, increased G0/G1 cell cycle arrest, elevated reactive oxygen species (ROS) level and diminished apoptosis. These phenotypic changes were accompanied by a significant increase in p16, p21 and p53 expression, as well as a decreased expression of key proteins in various DNA repair pathways such as xrcc2, xrcc3 and ku70. Further proteomic analysis suggests that multiple pathways are involved in the HU-induced NSC senescence, including genes related to DNA damage and repair, mitochondrial dysfunction and the increase of ROS level. Intriguingly, compensatory mechanisms may have also been initiated to interfere with apoptotic signaling pathways and to minimize the cell death by downregulating Bcl2-associated X protein (BAX) expression. Taken together, we have successfully established a cellular model that will be of broad utilities to the molecular exploration of NSC senescence and aging.
authors.affiliation: 1] East Hospital, Tongji University School of Medicine, Shanghai 200120, People's Republic of China [2] Tenth People's Hospital Affiliated to Tongji University, Shanghai, People's Republic of China [3] Department of Anatomy and Neurobiology, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, People's Republic of China.
authors.forename: C-M
authors.initials: CM
authors.lastname: Dong
authors.affiliation: East Hospital, Tongji University School of Medicine, Shanghai 200120, People's Republic of China.
authors.forename: X-L
authors.initials: XL
authors.lastname: Wang
authors.affiliation: East Hospital, Tongji University School of Medicine, Shanghai 200120, People's Republic of China.
authors.forename: G-M
authors.initials: GM
authors.lastname: Wang
authors.affiliation: Department of Hematology, Tongji Hospital of Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: W-J
authors.initials: WJ
authors.lastname: Zhang
authors.affiliation: East Hospital, Tongji University School of Medicine, Shanghai 200120, People's Republic of China.
authors.forename: L
authors.initials: L
authors.lastname: Zhu
authors.affiliation: East Hospital, Tongji University School of Medicine, Shanghai 200120, People's Republic of China.
authors.forename: S
authors.initials: S
authors.lastname: Gao
authors.affiliation: East Hospital, Tongji University School of Medicine, Shanghai 200120, People's Republic of China.
authors.forename: D-J
authors.initials: DJ
authors.lastname: Yang
authors.affiliation: East Hospital, Tongji University School of Medicine, Shanghai 200120, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Qin
authors.affiliation: 1] Tenth People's Hospital Affiliated to Tongji University, Shanghai, People's Republic of China [2] Advanced Institute of Translational Medicine, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Q-J
authors.initials: QJ
authors.lastname: Liang
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing, People's Republic of China.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Chen
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing, People's Republic of China.
authors.forename: H-T
authors.initials: HT
authors.lastname: Deng
authors.affiliation: 1] East Hospital, Tongji University School of Medicine, Shanghai 200120, People's Republic of China [2] Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: K
authors.initials: K
authors.lastname: Ning
authors.affiliation: Department of Hematology, Tongji Hospital of Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: A-B
authors.initials: AB
authors.lastname: Liang
authors.affiliation: 1] Tenth People's Hospital Affiliated to Tongji University, Shanghai, People's Republic of China [2] Advanced Institute of Translational Medicine, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Z-L
authors.initials: ZL
authors.lastname: Gao
authors.affiliation: East Hospital, Tongji University School of Medicine, Shanghai 200120, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Xu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D045643:DNA Repair Enzymes / Q000378:metabolism; D006918:Hydroxyurea / Q000494:pharmacology; D051379:Mice; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D025941:Protein Interaction Mapping; D040901:Proteomics / Q000379:methods; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular; D013312:Stress, Physiological / Q000187:drug effects; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D045643:DNA Repair Enzymes; D006918:Hydroxyurea