Etoposide Induces Mitochondrial Dysfunction and Cellular Senescence in Primary Cultured Rat Astrocytes

Bang, Minji; Kim, Do Gyeong; Gonzales, Edson Luck; Kwon, Kyoung Ja; Shin, Chan Young

doi:10.4062/biomolther.2019.151

Cited by 27 publications

(20 citation statements)

References 49 publications

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“…Our results showed that late passage cultivated astrocytes exhibited functional changes manifested by decreased wound healing capacity. These results are consistent with our previous reports showing the decreased wound healing capacity in aging-induced astrocytes through tenovin-1 or etoposide treatment ( Bang et al ., 2019a , 2019b ). Old satellite cells and tenocytes show impaired migration in vitro similar to aged bone marrow-derived dendritic cells ( Grolleau-Julius et al ., 2008 ; Chang et al ., 2012 ; Collins-Hooper et al ., 2012 ).…”

Section: Discussionsupporting

confidence: 94%

“…Astrocytes that underwent serial passage cultivation for several times showed aged astrocyte phenotypes. Various studies have reported nuclear enlargement of aged primary astrocytes ( Yoon et al ., 2016 ; Bang et al ., 2019a ). The increased nuclear or cell size in aged cells could be due to the increased macromolecule contents such as DNA, RNA, and proteins ( De Cecco et al ., 2011 ).…”

Section: Discussionmentioning

confidence: 99%

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Late Passage Cultivation Induces Aged Astrocyte Phenotypes in Rat Primary Cultured Cells

Bang

Gonzales

Shin

et al. 2021

Biomolecules & Therapeutics

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Astrocytes play various important roles such as maintaining brain homeostasis, supporting neurons, and secreting inflammatory mediators to protect the brain cells. In aged subjects, astrocytes show diversely changed phenotypes and dysfunctions. But, the study of aged astrocytes or astrocytes from aged subjects is not yet sufficient to provide a comprehensive understanding of their important processes in the regulation of brain function. In this study, we induced an in vitro aged astrocyte model through late passage cultivation of rat primary cultured astrocytes. Astrocytes were cultured until passage 7 (P7) as late passage astrocytes and compared with passage 1 (P1) astrocytes as early passage astrocytes to confirm the differences in phenotypes and the effects of serial passage. In this study, we confirmed the morphological, molecular, and functional changes of late passage astrocytes showing aging phenotypes through SA-β-gal staining and measurement of nuclear size. We also observed a reduced expression of inflammatory mediators including IL-1β, IL-6, TNFα, iNOS, and COX2, as well as dysregulation of wound-healing, phagocytosis, and mitochondrial functions such as mitochondrial membrane potential and mitochondrial oxygen consumption rate. Culture-conditioned media obtained from P1 astrocytes promoted neurite outgrowth in immature primary cultures of rat cortices, which is significantly reduced when we treated the immature neurons with the culture media obtained from P7 astrocytes. These results suggest that late passage astrocytes show senescent astrocyte phenotypes with functional defects, which makes it a suitable model for the study of the role of astrocyte senescence on the modulation of normal and pathological brain aging.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Late Passage Cultivation Induces Aged Astrocyte Phenotypes in Rat Primary Cultured Cells

Bang

Gonzales

Shin

et al. 2021

Biomolecules & Therapeutics

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“…On the 90th day in vitro the cells were SA-β-gal-positive and had increased expression of GFAP (Pertusa et al, 2007 ). Recently, it has been documented that treatment of astrocytes with sirtuins's inhibitor, tenovin-1 (Bang et al, 2019b ), or etoposide (Bang et al, 2019a ), increased SA-β-gal-positive cell number, induced the senescence-associated secretory phenotype, including increased expression of IL-6 and IL-1β, and of cell cycle-related proteins, such as phospho-histone H3 and CDK2 (Bang et al, 2019a ). Others showed that in human astrocytes induced to senesce by X-irradiation, there was downregulation of genes encoding glutamate and potassium transporters.…”

Section: Senescence Of Glial Cellsmentioning

confidence: 99%

Cellular Senescence in Brain Aging

Sikora

Bielak-Żmijewska

Dudkowska

et al. 2021

Front. Aging Neurosci.

182

115

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Aging of the brain can manifest itself as a memory and cognitive decline, which has been shown to frequently coincide with changes in the structural plasticity of dendritic spines. Decreased number and maturity of spines in aged animals and humans, together with changes in synaptic transmission, may reflect aberrant neuronal plasticity directly associated with impaired brain functions. In extreme, a neurodegenerative disease, which completely devastates the basic functions of the brain, may develop. While cellular senescence in peripheral tissues has recently been linked to aging and a number of aging-related disorders, its involvement in brain aging is just beginning to be explored. However, accumulated evidence suggests that cell senescence may play a role in the aging of the brain, as it has been documented in other organs. Senescent cells stop dividing and shift their activity to strengthen the secretory function, which leads to the acquisition of the so called senescence-associated secretory phenotype (SASP). Senescent cells have also other characteristics, such as altered morphology and proteostasis, decreased propensity to undergo apoptosis, autophagy impairment, accumulation of lipid droplets, increased activity of senescence-associated-β-galactosidase (SA-β-gal), and epigenetic alterations, including DNA methylation, chromatin remodeling, and histone post-translational modifications that, in consequence, result in altered gene expression. Proliferation-competent glial cells can undergo senescence both in vitro and in vivo, and they likely participate in neuroinflammation, which is characteristic for the aging brain. However, apart from proliferation-competent glial cells, the brain consists of post-mitotic neurons. Interestingly, it has emerged recently, that non-proliferating neuronal cells present in the brain or cultivated in vitro can also have some hallmarks, including SASP, typical for senescent cells that ceased to divide. It has been documented that so called senolytics, which by definition, eliminate senescent cells, can improve cognitive ability in mice models. In this review, we ask questions about the role of senescent brain cells in brain plasticity and cognitive functions impairments and how senolytics can improve them. We will discuss whether neuronal plasticity, defined as morphological and functional changes at the level of neurons and dendritic spines, can be the hallmark of neuronal senescence susceptible to the effects of senolytics.

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“…Studies have shown that cultured human astrocytes displayed both increased levels of γH2AX and formation of SAHFs (Myung et al, 2008;Bitto et al, 2010;Souza et al, 2015;Seoane et al, 2017; Figure 1). Senescent astrocytes showed nuclear enlargement, which is generally present in specific cell types such as fibroblasts and CNS cells (Yoon et al, 2016;Bang et al, 2019). When DNA damage and DNA repair occur during the cell cycle, the size of the cell and nucleus is slightly increased (Amodeo and Skotheim, 2016).…”

Section: Nuclear Changesmentioning

confidence: 99%

Astrocyte Senescence and Alzheimer’s Disease: A Review

Han

Zhang

Liu

et al. 2020

Front. Aging Neurosci.

110

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Astrocytes are the largest group of glial cells in the brain and participate in several essential functions of the central nervous system (CNS). Disruption of their normal physiological function can lead to metabolism disequilibrium and the pathology of CNS. As an important mechanism of aging, cellular senescence has been considered as a primary inducing factor of age-associated neurodegenerative disorders. Senescent astrocytes showed decreased normal physiological function and increased secretion of senescence-associated secretory phenotype (SASP) factors, which contribute to Aβ accumulation, tau hyperphosphorylation, and the deposition of neurofibrillary tangles (NFTs) in Alzheimer's disease (AD). Astrocyte senescence also leads to a number of detrimental effects, including induced glutamate excitotoxicity, impaired synaptic plasticity, neural stem cell loss, and blood-brain barrier (BBB) dysfunction. In this review article, we have summarized the growing findings regarding astrocyte senescence and its putative role in the pathologic progress of AD. Additionally, we also focus on the significance of targeting astrocyte senescence as a novel and feasible therapeutic approach for AD.

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Etoposide Induces Mitochondrial Dysfunction and Cellular Senescence in Primary Cultured Rat Astrocytes

Cited by 27 publications

References 49 publications

Late Passage Cultivation Induces Aged Astrocyte Phenotypes in Rat Primary Cultured Cells

Late Passage Cultivation Induces Aged Astrocyte Phenotypes in Rat Primary Cultured Cells

Cellular Senescence in Brain Aging

Astrocyte Senescence and Alzheimer’s Disease: A Review

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