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Introducing cellular senescence in human induced pluripotent stem cells and differentiated neural lineage for modeling of age-associated diseases

ABSTRACT: Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) resets the epigenetic landscapes that mark the aging clock, and consequently cells differentiated from iPSCs resemble fetal cells rather than adult or aged cells. The lack of proper cellular aging in cells differentiated from iPSCs presents a significant problem in iPSC-based disease models to investigate the pathological progression of age-associated diseases such as neurodegeneration. To address this caveat, we introduced cellular senescence into iPSC-based cell models in this study, as senescence has been shown to play a critical role not only in aging but also in neurodegeneration. We created an inducible CRISPR interference (CRISPRi) targeting TERF2, a major component of the telomere protecting Shelterin complex. We demonstrated that suppression of TERF2 robustly activated DNA damage response, the p53/p21 signaling, cellular senescence and inflammatory response in iPSCs. The inducible approach allows the temporal control of senescence activation over the course of differentiation of iPSCs to desired cell types. We applied the CRISPRi-TERF2 system to differentiation of iPSCs into neural progenitor cells (NPCs) and showed that suppression of TERF2 efficiently activated DNA damage response, the p53/p21 signaling and senescence in differentiated NPCs. The inducible cell model of cellular senescence generated in this study has broad application in investigation of cellular senescence in the progression of age-related diseases and improvement of disease modeling with a proper cellular aging context to facilitate drug discovery.

ORGANISM(S): Homo sapiens

PROVIDER: GSE251814 | GEO | 2023/12/25

REPOSITORIES: GEO

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Programmed cell senescence during embryonic development

Project description:Cellular senescence disables the proliferation of damaged cells and it is relevant for cancer and aging. Here, we show that cellular senescence occurs during mammalian embryonic development. Specifically, we have focused on the mouse regressing mesonephros and the endolymphatic sac of the inner ear. Senescence is characterized by SAM-NM-2G activity, heterochromatinization, and proliferative arrest. Mechanistically, developmentally-programmed senescence at the mesonephros and endolymphatic sac is strictly dependent on p21, but independent of DNA damage, p53 or other cell cycle inhibitors, and it is regulated by the TGFM-NM-2/SMAD and PI3K/FOXO pathways. Developmentally-programmed senescence is followed by macrophage infiltration and clearance of senescent cells. Abrogation of senescence by p21 deletion is only partially compensated by apoptosis and originates detectable developmental abnormalities. Importantly, high levels of p21 are also associated to the regressing mesonephros and endolymphatic sac in human embryos. These findings place cellular senescence as a relevant morphogenic process during embryonic development. We microdissected mesonephric tubules from senescent (WT) and non-senescent (p21-null) embryos to get information about this new senescence that occurs during embryogenesis.

2013-11-14 | E-GEOD-49108 | biostudies-arrayexpress

Cellular Senescence in Progenitor Cells Contributes to Diminished Remyelination Potential in Progressive Multiple Sclerosis

Project description:Cellular senescence is a form of adaptive cellular physiology associated with aging. Cellular senescence causes a pro-inflammatory cellular phenotype that impairs tissue regeneration, has been linked to stress, and is implicated in several human neurodegenerative diseases. We had previously determined that neural progenitor cells (NPCs) derived from primary progressive multiple sclerosis (PPMS) patient induced pluripotent stem (iPS) cell lines failed to promote oligodendrocyte progenitor cell (OPC) maturation whereas NPCs from age-matched control cell lines did so efficiently. Herein, we report that expression of hallmarks of cellular senescence were identified in SOX2+ progenitor cells within white matter lesions of human progressive MS autopsy brain tissues and PPMS patient iPS-derived NPCs. Expression of cellular senescence genes in PPMS NPCs was found to be reversible by treatment with rapamycin which then enhanced PPMS NPC support for oligodendrocyte differentiation. A proteomic analysis of the PPMS NPC secretome identified high mobility group box-1 (HMGB1), which was found to be a senescence-associated inhibitor of oligodendrocyte differentiation. Transcriptome analysis of OPCs revealed that senescent NPCs induced expression of epigenetic regulators mediated by extracellular HMGB1. Lastly, we determined that progenitor cells are a source of elevated HMGB1 in human white matter lesions. Based on these data, we conclude that cellular senescence contributes to altered progenitor cell functions in demyelinated lesions in MS. Moreover, these data implicate cellular aging and senescence as a process that contributes to remyelination failure in progressive MS which may impact how this disease is modeled and inform development of future myelin regeneration strategies.

2019-11-12 | PXD013060 | Pride

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Project description:Cells expressing features of cellular senescence, including upregulation of p21 and p16, appear transiently following tissue injury, yet the properties of these cells or how they contrast with age-induced senescent cells remains unclear. Using skeletal fracture as a model of acute injury, we identified rapidly-appearing senescent-like cells, marked by p21 expression, that negatively affected fracture healing. p21+ callus cells, which consisted predominantly of neutrophils and osteochondroprogenitors, existed as transient cells specific to injury and expressed high levels of senescence-associated factors known to impair bone formation and induce paracrine senescence. Targeted genetic clearance of p21+ cells suppressed senescence-associated signatures within the fracture callus and accelerated fracture healing. By contrast, p21+ cell clearance did not alter bone loss due to aging; conversely, p16+ cell clearance, known to alleviate skeletal aging, did not affect fracture healing. Together, our findings establish contextual roles of senescent/senescent-like cells that may be leveraged for therapeutic opportunities.

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Programmed cell senescence during embryonic development

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2013-11-14 | GSE49108 | GEO

Chronic p53-independent p21 expression deregulates replication licensing, leading to genomic instability II

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2016-05-24 | GSE81753 | GEO

Chronic p53-independent p21 expression deregulates replication licensing, leading to genomic instability I

2016-05-24 | GSE81752 | GEO

Intracellular differential gene expression detected by transcriptome sequencing after lactate treatment of nucleus pulposus cells

Project description:The accumulation of metabolites in the intervertebral disc is regarded as an important inducement of intervertebral disc degeneration (IVDD). Lactate, a metabolite produced by the cellular anaerobic glycolysis process, has been proved to be closely associated with IVDD. However, little was known about the role of lactate in nucleus pulposus cells (NPCs) senescence. This study attempted to investigate the effect and molecular mechanism of lactate on NPCs senescence in vitro and in vivo. A puncture-induced disc degeneration model was established in rats. Metabolomics analysis proved that lactate was significantly increased in the rat degenerated intervertebral disc. Eliminating extra lactate using lactate oxidase (LOx)-overexpressing lentivirus alleviated the progression of IVDD. In vitro experiments showed that high concentration lactate could induce senescence and oxidative stress in NPCs. High-throughput RNA sequencing (RNA-seq) results and bioinformatic analysis exhibited that lactate-stimulated NPCs senescence may be related to the PI3K/Akt signaling pathway. Further study verified that high concentration lactate could induce NPCs senescence and oxidative stress via inhibiting PI3K/Akt signaling and downstream Akt/p21/p27/cyclinD1 and Akt/Nrf2/HO-1 pathway. Utilizing molecular docking, we found that lactate may suppress the Akt phosphoactivation via binding to Lys39 and Leu52 in the PH domain of Akt. In conclusion, this study illuminates that lactate could promote the senescence of NPCs to aggravate IVDD by suppressing the PI3K/Akt signaling pathway and the expression of its downstream genes. These results highlight the involvement of lactate NPCs senescence, which may become a novel potential therapeutic target for the treatment of IVDD.

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Transcriptome analysis of IMR90 fibroblasts expressing OSKM or control vector and OSKM-induced senescent IMR90 fibroblasts upon p21CIP or mTOR knockdown

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2018-02-09 | GSE94928 | GEO

Kinase inhibitor GW8510 rejuvenates yeast and mice through multiple pathways including SRC, PAKs, JAKs

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Project description:The downstream events and target genes of p53 in senescence responses are not fully understood. Here, we report a novel function of the forkhead transcription factor Foxp3, a key player in mediating T cell inhibitory function, in p53-mediated cellular senescence. Overexpression of Foxp3 in mouse embryonic fibroblasts (MEFs) accelerates senescence, whereas Foxp3 knockdown leads to escape from p53-mediated senescence in p53-expressing MEFs. Consistently, Foxp3 expression resulted in the induction of senescence in epithelial cancer cells, including MCF7 and HCT116. Foxp3 overexpression also increased the intracellular levels of reactive oxygen species (ROS). The ROS inhibitor N-acetyl-L-cysteine rescued Foxp3 expression-induced senescence. Furthermore, the elevated ROS levels that accompanied Foxp3 overexpression were paralleled by an increase in p21 expression. Knockdown of p21 in Foxp3-expressing MEFs abrogated the Foxp3-dependent increase in ROS levels, indicating that Foxp3 acts through p21 induction and subsequent ROS elevation to trigger senescence. Collectively, these results suggest that Foxp3 is a downstream target of p53 that is sufficient to induce p21 expression and ROS production and is necessary for p53-mediated senescence. control and treated samples (human), young passage (p3) or old passage (p7) samples (mouse)

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