The potential role of senescence in limiting fibrosis caused by aging

Meng, Xinghua; Wang, Haoran; Song, Xiaopeng; Clifton, Alancia C.; Xiao, Jianhua

doi:10.1002/jcp.29313

Cited by 13 publications

(13 citation statements)

References 88 publications

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“…In the intestine, senescent fibroblasts secrete growth differentiation factor 15 (GDF15), a senescence-associated factor, which stimulates dysregulated epithelial cell proliferation, migration, and, ultimately, tumor formation 195 . On the other hand, other reports propose that cell senescence, occurring at least transiently, is key to limit fibrosis [196][197][198] . In the heart, senescent fibroblasts accumulate in the injury area after myocardial infarction and limit collagen production.…”

Section: Fibrosis Vs Regeneration: the Impact Of Agingmentioning

confidence: 99%

The bright side of fibroblasts: molecular signature and regenerative cues in major organs

2021

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Fibrosis is a pathologic process characterized by the replacement of parenchymal tissue by large amounts of extracellular matrix, which may lead to organ dysfunction and even death. Fibroblasts are classically associated to fibrosis and tissue repair, and seldom to regeneration. However, accumulating evidence supports a pro-regenerative role of fibroblasts in different organs. While some organs rely on fibroblasts for maintaining stem cell niches, others depend on fibroblast activity, particularly on secreted molecules that promote cell adhesion, migration, and proliferation, to guide the regenerative process. Herein we provide an up-to-date overview of fibroblast-derived regenerative signaling across different organs and discuss how this capacity may become compromised with aging. We further introduce a new paradigm for regenerative therapies based on reverting adult fibroblasts to a fetal/neonatal-like phenotype.

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Section: Fibrosis Vs Regeneration: the Impact Of Agingmentioning

confidence: 99%

The bright side of fibroblasts: molecular signature and regenerative cues in major organs

2021

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“…Even so, that the effects of cardiac fibroblasts' senescence on the cardiac fibrosis are promotional or inhibitory are still inconclusive. 25 Meyer et al found that Trp53 −/-Cdkn2a −/− mice displayed aggravated cardiac fibrosis after transverse aortic constriction compared with wildtype controls. 26 In contrast, Zhu et al reported that p53 −/− mice showed less accumulated senescent cardiac fibroblasts and less infiltrated macrophages with less released levels of MMPs, but more collagen deposition after myocardial 27 How do we explain these seemingly contradictory observations?…”

Section: Discussionmentioning

confidence: 99%

Ezh2 Inhibits Replicative Senescence of Atrial Fibroblasts Through Promotion of H3K27me3 in the Promoter Regions of CDKN2a and Timp4 Genes

Li¹,

Fang²,

Cao³

et al. 2022

JIR

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Background In most cell types, replicative senescence (RS) is supposed to be a principle causative factor for aging. Atrial fibrosis, pathologically characterized by proliferation of atrial fibroblasts (AFs) and excessive accumulation of extracellular matrix proteins, is the most common substrate of atrial fibrillation (Afib) in the elderly. However, whether AFs’ RS develops in the aged and fibrotic left atrium (LA) and, if yes, what is the key regulator for the pathogenesis of AFs’ RS remain largely unknown. Methods We obtained the left atrial tissues from young (6–8 weeks old) and aged (24 months old) C57BL/6 male mice. Screening and validation of differential genes were performed using comparative analysis of RNA-seq results. Replicative senescence was examined in primary AFs after cell passage. Further gain-of-function and loss-of-function experiments were performed to explore the regulation of the AFs’ RS progression. Results In the present study, we demonstrated that there was a considerable extent of AFs’ RS in the aged and fibrotic LA. Transcriptome screening showed that Ezh2 (Enhancer of zeste homolog 2) was significantly downregulated in the LA tissue of aged mice. Ezh2 is a histone methyltransferase that catalyzes H3K27me3 and mediates transcriptional silencing. We confirmed that Ezh2 was downregulated in the isolated pure senescent AFs. Knockdown of Ezh2 by siRNA or inhibition of Ezh2ʹs methyltransferase activities by GSK-126 and GSK-343 accelerated RS in the early passage of AFs, while its overexpression deaccelerated RS in the late passage of AFs. Mechanistically, Ezh2 suppressed CDKN2a (p16, p19) and Timp4 gene transcription by forming canonical H3K27me3 modifications in their promoter regions. Furthermore, the functional balance between Timp4 and MMP8 in AFs could be collapsed by changes in Ezh2 expression. Conclusion These results thus indicate that Ezh2 is a key regulator of AFs’ RS and this work may provide a basis for future treatments for atrial fibrosis in the elderly.

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“…The role of Cdkn2a locus in heart myofibroblasts regulation is under debate, with findings indicating that both Cdkn2 haploinsufficiency and overexpression can result in induction of fibrosis [93,94]. This indicates that fine-tuned regulation of the Cdkn2a locus is a key factor in determining the right amount of cardiac myofibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Role of Cdkn2a in the Emery–Dreifuss Muscular Dystrophy Cardiac Phenotype

et al. 2021

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The Cdkn2a locus is one of the most studied tumor suppressor loci in the context of several cancer types. However, in the last years, its expression has also been linked to terminal differentiation and the activation of the senescence program in different cellular subtypes. Knock-out (KO) of the entire locus enhances the capability of stem cells to proliferate in some tissues and respond to severe physiological and non-physiological damages in different organs, including the heart. Emery–Dreifuss muscular dystrophy (EDMD) is characterized by severe contractures and muscle loss at the level of skeletal muscles of the elbows, ankles and neck, and by dilated cardiomyopathy. We have recently demonstrated, using the LMNA Δ8–11 murine model of Emery–Dreifuss muscular dystrophy (EDMD), that dystrophic muscle stem cells prematurely express non-lineage-specific genes early on during postnatal growth, leading to rapid exhaustion of the muscle stem cell pool. Knock-out of the Cdkn2a locus in EDMD dystrophic mice partially restores muscle stem cell properties. In the present study, we describe the cardiac phenotype of the LMNA Δ8–11 mouse model and functionally characterize the effects of KO of the Cdkn2a locus on heart functions and life expectancy.

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The potential role of senescence in limiting fibrosis caused by aging

Cited by 13 publications

References 88 publications

The bright side of fibroblasts: molecular signature and regenerative cues in major organs

The bright side of fibroblasts: molecular signature and regenerative cues in major organs

Ezh2 Inhibits Replicative Senescence of Atrial Fibroblasts Through Promotion of H3K27me3 in the Promoter Regions of CDKN2a and Timp4 Genes

Role of Cdkn2a in the Emery–Dreifuss Muscular Dystrophy Cardiac Phenotype

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