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Induction, regulation and roles of neural adhesion molecule L1CAM in cellular senescence.

ABSTRACT: Aging involves tissue accumulation of senescent cells (SC) whose elimination through senolytic approaches may evoke organismal rejuvenation. SC also contribute to aging-associated pathologies including cancer, hence it is imperative to better identify and target SC. Here, we aimed to identify new cell-surface proteins differentially expressed on human SC. Besides previously reported proteins enriched on SC, we identified 78 proteins enriched and 73 proteins underrepresented in replicatively senescent BJ fibroblasts, including L1CAM, whose expression is normally restricted to the neural system and kidneys. L1CAM was: 1) induced in premature forms of cellular senescence triggered chemically and by gamma-radiation, but not in Ras-induced senescence; 2) induced upon inhibition of cyclin-dependent kinases by p16INK4a; 3) induced by TGFbeta and suppressed by RAS/MAPK(Erk) signaling (the latter explaining the lack of L1CAM induction in RAS-induced senescence); and 4) induced upon downregulation of growth-associated gene ANT2, growth in low-glucose medium or inhibition of the mevalonate pathway. These data indicate that L1CAM is controlled by a number of cell growth- and metabolism-related pathways during SC development. Functionally, SC with enhanced surface L1CAM showed increased adhesion to extracellular matrix and migrated faster. Our results provide mechanistic insights into senescence of human cells, with implications for future senolytic strategies.

SUBMITTER: Mrazkova B

PROVIDER: S-EPMC5892697 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Induction, regulation and roles of neural adhesion molecule L1CAM in cellular senescence.

Mrazkova Blanka B Dzijak Rastislav R Imrichova Terezie T Kyjacova Lenka L Barath Peter P Dzubak Petr P Holub Dusan D Hajduch Marian M Nahacka Zuzana Z Andera Ladislav L Holicek Petr P Vasicova Pavla P Sapega Olena O Bartek Jiri J Hodny Zdenek Z

Aging 20180301 3

Aging involves tissue accumulation of senescent cells (SC) whose elimination through senolytic approaches may evoke organismal rejuvenation. SC also contribute to aging-associated pathologies including cancer, hence it is imperative to better identify and target SC. Here, we aimed to identify new cell-surface proteins differentially expressed on human SC. Besides previously reported proteins enriched on SC, we identified 78 proteins enriched and 73 proteins underrepresented in replicatively sene ...[more]

PMID: 29615539

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Project description:UnlabelledTherapeutic applications of mesenchymal stem cells (MSCs) for treating various diseases have increased in recent years. To ensure that treatment is effective, an adequate MSC dosage should be determined before these cells are used for therapeutic purposes. To obtain a sufficient number of cells for therapeutic applications, MSCs must be expanded in long-term cell culture, which inevitably triggers cellular senescence. In this study, we investigated the surface markers of human umbilical cord blood-derived MSCs (hUCB-MSCs) associated with cellular senescence using fluorescence-activated cell sorting analysis and 242 cell surface-marker antibodies. Among these surface proteins, we selected the melanoma cell adhesion molecule (MCAM/CD146) for further study with the aim of validating observed expression differences and investigating the associated implications in hUCB-MSCs during cellular senescence. We observed that CD146 expression markedly decreased in hUCB-MSCs following prolonged in vitro expansion. Using preparative sorting, we found that hUCB-MSCs with high CD146 expression displayed high growth rates, multilineage differentiation, expression of stemness markers, and telomerase activity, as well as significantly lower expression of the senescence markers p16, p21, p53, and senescence-associated β-galactosidase, compared with that observed in hUCB-MSCs with low-level CD146 expression. In contrast, CD146 downregulation with small interfering RNAs enhanced the senescence phenotype. In addition, CD146 suppression in hUCB-MSCs caused downregulation of other cellular senescence regulators, including Bmi-1, Id1, and Twist1. Collectively, our results suggest that CD146 regulates cellular senescence; thus, it could be used as a therapeutic marker to identify senescent hUCB-MSCs.SignificanceOne of the fundamental requirements for mesenchymal stem cell (MSC)-based therapies is the expansion of MSCs during long-term culture because a sufficient number of functional cells is required. However, long-term growth inevitably induces cellular senescence, which potentially causes poor clinical outcomes by inducing growth arrest and the loss of stem cell properties. Thus, the identification of markers for evaluating the status of MSC senescence during long-term culture may enhance the success of MSC-based therapy. This study provides strong evidence that CD146 is a novel and useful marker for predicting senescence in human umbilical cord blood-derived MSCs (hUCB-MSCs), and CD146 can potentially be applied in quality-control assessments of hUCB-MSC-based therapy.

Project description: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-β-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.

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Induction, regulation and roles of neural adhesion molecule L1CAM in cellular senescence.

Publications

Induction, regulation and roles of neural adhesion molecule L1CAM in cellular senescence.

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