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At least 19 recordsLinked to original sources
PubMed2002

Induction of apoptosis in human replicative senescent fibroblasts.

Cellular senescence is an irreversible growth phase characteristic of normal cells. We have found that human senescent fibroblasts can be induced to undergo programmed cell death (apoptosis) by ceramide, TNF-alpha, or okadaic acid. The most profound effects were induced by TNF-alpha and okadaic acid treatment. In the present study, we also evaluated the contribution of lysosomal activation as a possible mechanism underlying the induction of apoptosis. Four lysosomal enzyme activities were measured: beta-galactosidase, alpha-galactosidase A, beta-glucoronidase, and acid phosphatase. Using an in situ assay, we have found that the activity of beta-galactosidase, which is also a biochemical marker of senescence, is induced in young proliferating fibroblasts following exposure to all three apoptotic inducing agents. The other enzymes were not significantly induced in young fibroblasts following exposure to agents that induce apoptosis. During replicative senescence, three of the four lysosomal enzymes tested (beta-galactosidase, alpha-galactosidase A, and beta-glucoronidase) are constitutively expressed at high levels. TNF-alpha was the only agent that induced lysosomal activity in senescent fibroblasts, of which only alpha-galactosidase A activity was induced. Our studies show that senescent fibroblasts can be induced to undergo apoptosis in a signal-dependent manner. However, the lysosomal enzymes examined do not appear to be correlated with apoptotic induction.

Acid Phosphatase↗
PubMed2005

c-Myc creates an activation loop by transcriptionally repressing its own functional inhibitor, hMad4, in young fibroblasts, a loop lost in replicatively senescent fibroblasts.

c-Myc transcriptional activity in cells is dampened by the Mad family of transcriptional repressors. The expression of one member, hMad4, is increased in growth-arrested states such as quiescence or replicative senescence; hMad4 mRNA levels in replicatively senescent fibroblasts are about twice those seen in their young contact-inhibited quiescent counterparts. Moreover, the repression of hMad4 transcription following serum stimulation observed in quiescent young fibroblasts is lost in senescent cells. This loss results in persistent expression of hMad4, which leads to an inability to switch from an hMad4/Max complex to a c-Myc/Max complex on selected c-Myc target genes following serum stimulation. We have located an initiator element (Inr), a candidate for Miz-1 binding, in the hMad4 promoter. In reporter assays, Miz-1 enhances reporter GFP expression; this enhancement is inhibited by co-expressing c-Myc. Thus hMad4, as does its murine counterpart, contains the Inr element through which Miz-1 activates its expression; but this action is inhibited in the presence of c-Myc. This inhibition may explain the down-regulation of hMad4, corresponding to the up-regulation of c-Myc, in young serum-starved quiescent fibroblasts upon serum stimulation. However, this reciprocal change does not occur in replicatively senescent fibroblasts upon serum stimulation; instead, hMad4 persists in the presence of high levels of c-Myc activation. Our results suggest that: (1) replicative senescence-specific factors may block c-Myc inhibition of Miz-1 activation of hMad4 expression; and (2) the continual presence of hMad4 protein may transcriptionally repress selected c-Myc target genes, whose functions are key to the signaling pathways leading to apoptosis inhibition and permanent exit of cell cycle traverse in normal human fibroblasts.

Base Sequence↗
PubMed2026

Senescent fibroblasts drive CD8+ T cell dysfunction in colorectal cancer via CD36-mediated lipid transfer and peroxidation.

BACKGROUND: Functional exhaustion of tumor-infiltrating CD8+ T cells represents a hallmark of colorectal cancer (CRC) immunosuppression, though its mechanistic drivers remain elusive. Given the established correlation between CRC progression and stromal senescence characterized by pathological lipid accumulation and impaired immunity, we investigated whether and how senescent fibroblasts actively regulate CD8+ T cell dysfunction. METHODS: Single-cell RNA sequencing (scRNA-seq) analysis was conducted to unveil the diverse fibroblast populations and the significant lipid metabolism changes between senescent fibroblasts and non-senescent fibroblasts in human CRC specimens and adjacent normal mucosa. Machine-learning identified senescent fibroblasts with a distinct gene signature. Cell-cell communication analysis was used to evaluate the interactions between senescent fibroblasts and CD8+ T cells in colorectal cancer. Co-culture experiments were conducted among senescent fibroblasts, CD8+ T cells and patient-derived organoids of CRC (CRC-PDOs), with the results evaluated with high-content imaging and propidium iodide/Hoechst 33,342 staining. Flow cytometry, ELISA and lipid pulse-chase with BODIPY FL C16 were performed to detect the alterations of CD8+ T cell cytotoxic function and metabolic status. AOM/DSS-induced CRC mouse model was used to conduct in vivo validation to evaluate whether senolytics could suppress CRC progression. Patients from the Cancer Genome Atlas colorectal cancer cohort were stratified into CD36-high and CD36-low groups by median expression, and drug sensitivity for GDSC2 compounds was predicted computationally using the oncoPredict R package. RESULTS: ScRNA-seq demonstrated the specific cell population presence and divergence of senescent fibroblasts between neoplastic and histologically normal adjacent cell clusters in CRC. Random Forest was employed for cell senescence classification. Feature importance analysis identified five genes as key contributors to the model’s decision process. Cell-cell communication analysis revealed enhanced interactions between senescent fibroblasts and CD8+ T cells in CRC. Co-culture of senescent fibroblasts significantly impaired the cytotoxic functions of CD8+ T cells on CRC-PDOs, which was reflected by the declined proportions of granzyme B (GZMB) + and interferon gamma (IFNγ) + CD8+ T cells and enhanced viability of CRC-PDOs. Mechanistically, the co-culture with senescent fibroblasts promoted the lipid shuttling into CD8+ T cells to induce lipid peroxidation and downstream impairment of cytotoxicity. Furthermore, the inhibition of CD36, the specific scavenger receptor for lipid uptake of CD8+ T cells, effectively suppressed lipid transfer and peroxidation thereby preserving the effector functions of CD8+ T cells and ultimately promoting tumor apoptosis. Complementarily, in vivo senolytic treatment significantly suppressed CRC progression in AOM-DSS CRC mouse models. Top 12 therapeutic agents were identified significantly enhanced predicted efficacy in CD36-high tumors. CONCLUSIONS: Our study identified a substantial population of senescent fibroblasts in human CRC through single cell transcriptomics, machine-learning and clinical biopsies. These senescent fibroblasts impair CD8+ T cell-mediated killing of CRC-PDOs via CD36-dependent lipid transfer, suggesting senolytic targeting of stromal cells as a promising immunotherapeutic strategy for CRC.

Colorectal Neoplasms↗
PubMed2005

Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation.

Cellular senescence suppresses cancer by arresting cells at risk of malignant tumorigenesis. However, senescent cells also secrete molecules that can stimulate premalignant cells to proliferate and form tumors, suggesting the senescence response is antagonistically pleiotropic. We show that premalignant mammary epithelial cells exposed to senescent human fibroblasts in mice irreversibly lose differentiated properties, become invasive and undergo full malignant transformation. Moreover, using cultured mouse or human fibroblasts and non-malignant breast epithelial cells, we show that senescent fibroblasts disrupt epithelial alveolar morphogenesis, functional differentiation and branching morphogenesis. Furthermore, we identify MMP-3 as the major factor responsible for the effects of senescent fibroblasts on branching morphogenesis. Our findings support the idea that senescent cells contribute to age-related pathology, including cancer, and describe a new property of senescent fibroblasts - the ability to alter epithelial differentiation - that might also explain the loss of tissue function and organization that is a hallmark of aging.

Animals↗
PubMed2026

Integrated single-cell and bulk transcriptomic analysis identifies a novel senescent fibroblast subtype associated with poor prognosis in acral melanoma.

BACKGROUND: Acral melanoma (AM) exhibits significant intratumoral heterogeneity, but its tumor microenvironment (TME) and immune regulation remain unclear. This study aims to dissect TME heterogeneity and establish a prognostic model based on key cell subpopulations. METHODS: We collected AM single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA). Unsupervised clustering, CellChat, and Scissor analysis were performed to characterize cellular heterogeneity, cell-cell communication, and prognosis-related cell subpopulations. Kaplan-Meier analysis was used to assess the prognostic value of key genes, which were further validated by multiplex immunohistochemistry (mIHC). RESULTS: In AM, Mel_C2, C7, and C9 with high SEMA6A and KIT expression were strongly linked to poor prognosis. We further identified a senescent fibroblast subpopulation (sCAF_CDKN2A) characterized by high fibroblast senescence signature (FSS) scores. Integrating Scissor analysis of fibroblast subtypes with bulk prognostic data, we identified COL3A1, VCAN, and KIT as prognosis-associated genes upregulated in poor-outcome-related fibroblast subsets. Cell-cell communication analysis revealed that sCAF_CDKN2A engages in an immunosuppressive network, interacting with regulatory T cells (Tregs) via MIF signaling and receiving signals from exhausted CD8+ T cells through PPIA-BSG interactions. Using transcription factor expression patterns from these fibroblast subtypes, we constructed a prognostic model that effectively stratified patients into distinct risk groups with significant differences in overall survival (OS). mIHC confirmed significantly higher protein levels of SEMA6A and COL3A1 in tumor tissues compared to matched normal tissues. CONCLUSIONS: We established a novel prognostic model for AM and identified sCAF_CDKN2A as an immunosuppressive senescent fibroblast subpopulation driving poor prognosis.

Acral melanoma↗
PubMedDate not supplied

Senescent fibroblasts resist apoptosis by downregulating caspase-3.

In replicative senescence, cells undergo permanent exit from cell cycle traverse; this is traditionally thought to occur at the end of a culture's in vitro life span, after serial passaging. In general, the checkpoint for replicative senescence is found at the G(1)/S border, controlled by the modulation of a battery of proteins, typified by gaining inhibitors of cell cycle traverse, such as cyclin-dependent kinases or RB hyperphosphorylation, and losing pro-proliferation gene expressions such as c-fos, c-myc, and a cadre of proliferation-dependent kinases. Here, we present evidence that replicatively senescent fibroblasts are resistant to apoptotic death, associated with a lack of key enzyme activities, caspase-3 being the chief executioner. This observation, coupled with our earlier report that senescent fibroblasts maintain persistently high levels of pro-survival factor Bcl-2, suggests that the molecular signaling program present in fibroblasts at the end of their in vitro life span may not only cater to the state of permanent exit from cell cycle traverse, but also dictate an inability to commit cellular suicide. Future experiments will reveal whether replicatively senescent fibroblasts that can neither proliferate nor die contribute to organismic aging, and whether their accumulation over time in tissue becomes detrimental to the normal aging process.

Apoptosis↗
PubMed1978

Actin in young and senescent fibroblasts.

Double labelling and the isolation of peptides specific to muscle actin were used to determine the amount of actin in young and senescent fibroblasts from chicken embryo. A 20-residue peptide produced from the C-terminus of muscle actin was found in amounts that indicated 6.9% of the protein of young fibroblasts and 11.5% of the protein of senescent fibroblasts to be actin. Two other peptides of muscle actin were present in very small amounts. This indicates that the actin of both young and senescent fibroblasts is homologous to, but not identical with, muscle actin. Increased actin content of senescent fibroblasts may be related to their loss of proliferative capacity and low cell density at confluence.

Actins↗
PubMedDate not supplied

Fibroblast senescence in pressure ulcers.

Pressure ulcers appear as localized chronic wounds in the middle of normal functioning skin. This study focuses on pressure ulcer fibroblasts cultured from the ulcer bed, ulcer margin, and normal, nonulcerated skin adjacent to the wound. From these areas we show that pressure ulcer fibroblasts become prematurely senescent. Verification of senescence was based on failure of cell populations to undergo a 0.5 population doubling after 1 week in culture, light microscopic appearance of late-passage senescent cells in culture, light microscopic verification of senescence in vivo and in vitro by anti-terminin staining, and ultrastructural identification of senescent fibroblasts by anti-terminin colloidal gold labeling. Although not all ulcer fibroblasts are senescent, there is a range of proliferative ability. The senescent phenotype of ulcer fibroblasts remains intact in vitro as these cells remain viable but are unable to complete DNA synthesis. Fibroblast senescence is not uniform in chronic wounds but varies within areas of the ulcer bed and from patient to patient. Although ulcer fibroblasts exhibit limited proliferative ability, fibroblasts from the ulcer margin and adjacent normal skin show a continued ability to divide. However, in all areas of the wound, the mean generation time of the fibroblast population is longer than commonly observed for cultured human diploid fibroblasts. At first passage, the mean generation time for fibroblasts from all patients is significantly different (p = .001, analysis of variance) among fibroblasts from the ulcer bed (4.2 2.2 days), ulcer margin (2.9 +/- 1.3 days), and adjacent normal skin (1.9 +/- 0.6 days). Analysis of the three cell groups by the post hoc Tukey test, using corrected p values shows that the difference between mean generation times among fibroblast populations from adjacent normal skin and ulcer bed are significantly different (p < 0.05), whereas the difference between fibroblasts from adjacent normal skin and ulcer margin and ulcer margin and ulcer bed are not significantly different (p > 0.05). These data may help to explain the poor response of certain pressure sores to aggressive medical treatment.

Analysis of Variance↗
PubMed2005

Wound chronicity and fibroblast senescence--implications for treatment.

A proportion of chronic wounds fail to heal in response to standard therapy. For venous leg ulcers, a correlation exists between longer duration before treatment initiation and poor healing response to compression therapy. Differences identified between the healing wound microenvironment and that of the non healing chronic wound suggests that many potential mechanisms exist to impair healing. One contributory mechanism may be inhibition of fibroblast proliferation and induction of a stress-induced premature senescence phenotype by the continuing inflammation found in chronic wounds. Senescent fibroblasts exhibit an extracellular matrix degradative phenotype that contributes to wound chronicity. Accumulation of greater than 15% senescent fibroblasts has been described as a threshold beyond which wounds become hard to heal. The ratio of senescent : non senescent cells is therefore critical to determining response to treatment, and adjunctive therapies that modulate this ratio in favour of non senescent cells are likely to enhance therapeutic healing rates. A number of tissue-engineered dermal replacements contain non senescent fibroblasts and can donate cells to the wound environment additional to releasing growth factors and reversing the antiproliferative activity of chronic wound exudate. Recognition of the role of fibroblast senescence in wound chronicity may allow for identification of those wounds that will respond positively to these products.

Cellular Senescence↗
PubMed2006

The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms.

The greatest risk factor for developing carcinoma of the prostate is advanced age. Potential molecular and physiologic contributors to the frequency of cancer occurrence in older individuals include the accumulation of somatic mutations through defects in genome maintenance, epigenetic gene silencing, oxidative stress, loss of immune surveillance, telomere dysfunction, chronic inflammation, and alterations in tissue microenvironment. In this context, the process of prostate carcinogenesis can be influenced through interactions between intrinsic cellular alterations and the extrinsic microenvironment and macroenvironment, both of which change substantially as a consequence of aging. In this study, we sought to characterize the molecular alterations that occur during the process of prostate fibroblast senescence to identify factors in the aged tissue microenvironment capable of promoting the proliferation and potentially the neoplastic progression of prostate epithelium. We evaluated three mechanisms leading to cell senescence: oxidative stress, DNA damage, and replicative exhaustion. We identified a consistent program of gene expression that includes a subset of paracrine factors capable of influencing adjacent prostate epithelial growth. Both direct coculture and conditioned medium from senescent prostate fibroblasts stimulated epithelial cell proliferation, 3-fold and 2-fold, respectively. The paracrine-acting proteins fibroblast growth factor 7, hepatocyte growth factor, and amphiregulin (AREG) were elevated in the extracellular environment of senescent prostate fibroblasts. Exogenous AREG alone stimulated prostate epithelial cell growth, and neutralizing antibodies and small interfering RNA targeting AREG attenuated, but did not completely abrogate the growth-promoting effects of senescent fibroblast conditioned medium. These results support the concept that aging-related changes in the prostate microenvironment may contribute to the progression of prostate neoplasia.

Cell Proliferation↗
PubMed1996

Senescent fibroblasts as feeder cells for lymphoid cell cloning.

Senescent primary human skin fibroblasts were used as feeder layers for cloning lymphoid cells by limiting dilution. B-cells including mouse hybridoma cells, human multiple myeloma cells C1R and DIG, as well as an immortalized T-cell line (Jurkat cells) were cloned using this approach. From heterogenous populations, homogeneous (clonal) populations were obtained and further analyzed. The major advantages of senescent fibroblasts as feeder cells are (i) the need to establish primary cultures from experimental animals for preparing feeder cells is obviated; (ii) the risk of contamination with infectious agents is diminished; (iii) primary skin fibroblasts are easily maintained in culture, can be kept at confluence for extended periods of time, and do not undergo spontaneous transformation; and (iv) lymphoid cells are readily separated from fibroblast monolayers. The use of senescent fibroblasts overcomes limitations inherent with primary mouse cell cultures and irradiated cells commonly used as feeder cells in cloning techniques.

Animals↗
PubMed1976

Specific chromosome aberrations in senescent fibroblast cell lines derived from human embryos.

In senescent fibroblast cell lines derived from human embryos, the number of chromosome aberrations were found to increase rapidly. In addition to an increase in aneuploidy and polyploidy, a high frequency of dicentrics occurred, but the number of other chromosome abnormalities remained approximately constant. Banding revealed that many of the dicentrics appeared to be end-to-end fusions of whole chromosomes. The involvement of chromosomes was nonrandom. This "telomeric binding" may reflect a progressive decrease in the stability of telomeric sequences or associated enzymes which may also occur in vivo.

Cell Line↗
PubMed1994

Control of fibroblast senescence and activation of programmed cell death.

We have characterized a nuclear phosphoprotein of 57 kda, statin, found only in nonproliferating cells of both quiescent and senescent natures. Emerging results suggest that statin may function as a sequester to block the early G1 phase phosphorylation for the RB protein. A second protein, terminin, undergoes senescence-specific posttranslational modification from 90 to 60 kda, and further death-specific conversion from 60 to 30 kda. We also found that apoptotic mouse 3T3 fibroblasts express c-fos, c-myc, c-jun, and cdc2, as well as the upregulation of RB phosphorylation and BrdU incorporation, just before final DNA fragmentation and death. It seems that en route to death, cells re-enter the cell-cycle transverse and experience early G1 and part of S Phase; however, this cycling event is an abortive one. In contrast, senescent fibroblasts are resistant to the initiation of the death program, since they are unable to enter cell cycle traverse. Long-term serial passaging of normal human fibroblasts may be inadvertently selecting those, while termed as senescent, are also specialized survivors, and thus a good culture model to study both the control of permanent departure from cell cycle traverse and the mechanism underlying the survival or antideath cellular program.

Animals↗
PubMed1994

Overexpression of plasminogen activator inhibitor type-1 in senescent fibroblasts from normal subjects and those with Werner syndrome.

We previously reported that plasminogen activator inhibitor type-1 (PAI-1) mRNA was present at higher steady-state levels in prematurely senescent fibroblasts derived from a subject with Werner syndrome (WS) compared to early passage (EP) fibroblasts from an age-matched normal subject (Murano et al., 1991, Mol. Cell. Biol. 11:3905-3914). To explore the generally of this phenomenon with respect to chronological age of donor (in vivo aging) and the late-passage (LP) or senescent phase of the fibroblast replicative lifespan, we assayed PAI-1 mRNA in cells and PAI-1 antigen in medium conditioned by 20 normal fibroblast strains at EP and LP and six WS strains during their curtailed replicative lifespans. The lowest accumulations of PAI-1 were found in medium conditioned by fetal and newborn cells with a shallow but progressive rise seen in postnatal cells from normal donors of increasing chronological age. With few exceptions, normal LP fibroblasts showed increased PAI-1 accumulations in medium compared to their EP counterparts. Conditioned medium from four of the six WS strains showed PAI-1 accumulations that were significantly higher than the media of any normal controls at EP and LP. PAI-1 mRNa levels were generally commensurate with the cumulative amount of PAI-1 in the medium but the frequent exceptions indicate that translational and post-translational mechanisms also regulate PAI-1 output. The augmentation in PAI-1 output of fibroblasts as a direct function of chronological age and during in vitro senescence suggests that PAI-1 may play an important role in the reduced capacity for wound healing and the increasing tendency to thrombogenesis and atherogenesis seen during biological aging and in particular in persons with Werner syndrome.

Adult↗
PubMed1991

The steady-state levels of type I collagen mRNA are reduced in senescent fibroblasts.

The decreased collagen content in aging skin could be a consequence of decreased synthesis or increased degradation. The possibility that decreased synthesis of collagen results from decreased synthesis of mRNAs for Type I collagen, the major collagen in skin, was investigated by assessing the steady-state levels of alpha 1(I) and alpha 2(I) collagen mRNAs in actively proliferating and senescent WI-38 fibroblasts. The levels of both alpha 1(I) mRNA and alpha 2(I) mRNA were significantly lower in senescent fibroblasts, suggesting that one factor contributing to the decreased collagen content of aging skin may be decreased synthesis of these collagen mRNAs by senescent fibroblasts. Both mRNAs were reduced to the same extent, suggesting that coordinate regulation of the two Type I collagen genes is maintained in senescent fibroblasts.

Aging↗
PubMed2006

Senescent fibroblasts induce moderate stress in lung epithelial cells in vitro.

Epithelial-mesenchymal interactions contribute to functionality and integrity of the lung epithelium, which might change during ageing and associated cellular ageing. Therefore, we studied the effect of senescent versus pre-senescent lung fibroblasts (WI-38) on mitogenic and stress-protective factors in lung epithelial cells (H358). By use of conditioned medium, we found a growth promoting impact of fibroblasts compared with control medium from epithelial cells associated with activation of ERK1/2, Akt, p70S6K, and EGF receptor. Although senescent fibroblasts mediated similar growth stimulation compared with pre-senescent cells, we observed less protection against spontaneous mitochondrial dysfunction in vitro, higher production of reactive oxygen species and activation of copper/zinc superoxide dismutase. Moreover, senescent cells induced activation of caspase-3/7 in epithelial cells, which was associated with down-regulation of the caspase-inhibitory protein XIAP. In summary, senescent lung fibroblasts induce moderate stress in lung epithelial cells in vitro without affecting growth signaling.

Cell Communication↗
PubMed2026

DNA methylation as a driver of lung fibroblast senescence in COPD.

Cellular senescence is increasingly recognized as a hallmark of chronic obstructive pulmonary disease (COPD), with higher levels in lung fibroblasts from COPD patients. Upon senescence, both hypomethylation and hypermethylation have been described but not in COPD-derived fibroblasts yet. This study investigated whether altered DNA methylation can be a driver of fibroblast senescence in COPD. Genome-wide gene expression and DNA methylation data were generated from primary lung fibroblasts of 11 COPD stage IV patients and 10 matched controls. Gene expression of six well-known senescence genes was compared between COPD and control. COPD-associated senescence genes were correlated with their related CpG sites in an expression quantitative trait methylation (eQTM) analysis. Methylation levels of significant eQTMs were compared between COPD and control fibroblasts. A causal relationship between altered DNA methylation and senescence was validated in 5-Aza-2'-deoxycytidine (5-Aza-2'-dC)-treated primary lung fibroblasts. Gene expression of CDKN1A, CDKN2A, and CDKN2B was higher, while LMNB1 expression was lower in COPD-derived fibroblasts compared to controls. A total of 19 eQTMs were found for the COPD-associated senescence genes CDKN1A (9), CDKN2A (1), and LMNB1 (9). Among these, seven CpG sites (4 for CDKN1A and 3 for LMNB1) exhibited differential methylation between COPD and control. Treatment with 5-Aza-2'-dC led to global demethylation and increased senescence and, importantly, confirmed the association between senescence and hypomethylation of the COPD-associated CpG site cg04924375. Altered DNA methylation is linked to fibroblast senescence in COPD, and seven CpG sites are identified as potential epigenetic regulators of the senescence genes CDKN1A and LMNB1.NEW & NOTEWORTHY This study identifies DNA methylation as a mechanistic contributor to lung fibroblast senescence in chronic obstructive pulmonary disease (COPD). By integrating DNA methylation data with the transcriptomic data of senescence-related genes, we uncovered seven COPD-associated CpG sites linked to the senescence regulators CDKN1A and LMNB1. Pharmacological demethylation induces fibroblast senescence and is consistent with a functional role for hypomethylation at cg04924375, providing new insight into epigenetic regulation of cellular senescence in COPD lung fibroblasts.

Humans↗