Senescence of Activated Stellate Cells Limits Liver Fibrosis

Krizhanovsky, Valery; Yon, Monica; Dickins, Ross A.; Hearn, Stephen; Simon, Janelle; Miething, Cornelius; Yee, Herman; Zender, Lars; Lowe, Scott W.

doi:10.1016/j.cell.2008.09.015

Cited by 171 publications

(308 citation statements)

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“…In the carbon tetrachloride liver fibrosis model, myofibroblasts senesce during spontaneous resolution, and produce a gene expression profile consistent with cell cycle exit, down-regulated genes encoding ECM components, and up-regulated ECM-degrading enzymes, including MMPs. 81 Senescent myofibroblasts also up-regulated genes predicted to enhance immune surveillance, where they were eventually cleared by natural killer cells, thus removing the myofibroblasts and accelerating the resolution of fibrosis. When the injury was performed on mice deficient in the p53/p21 and p16 pathways, representing mice deficient in a senescence response, healing was accompanied by a marked increase in fibrosis.…”

Section: Role Of Senescence and Aging In Removing Myofibroblastsmentioning

confidence: 99%

“…When the injury was performed on mice deficient in the p53/p21 and p16 pathways, representing mice deficient in a senescence response, healing was accompanied by a marked increase in fibrosis. 81 Similarly, in a mouse model of skin wounding, recruited myofibroblasts are driven into senescence at later stages of wound healing, whereupon they stopped proliferating and up-regulated expression of MMPs while also down-regulating expression of collagen and TGFb. 82 This myofibroblast senescence is triggered by the matricellular protein CCN1, which directly binds to integrin a 6 b 1 activating RAC1 to trigger accumulation of reactive oxygen species and damage response pathways inducing senescence.…”

Section: Role Of Senescence and Aging In Removing Myofibroblastsmentioning

confidence: 99%

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Mechanisms of Lung Fibrosis Resolution

Glasser

Hagood

Wong

et al. 2016

The American Journal of Pathology

107

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Section: Role Of Senescence and Aging In Removing Myofibroblastsmentioning

confidence: 99%

Section: Role Of Senescence and Aging In Removing Myofibroblastsmentioning

confidence: 99%

Mechanisms of Lung Fibrosis Resolution

Glasser

Hagood

Wong

et al. 2016

The American Journal of Pathology

107

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“…Substantial evidence indicates that senescent cells play a role in physiological changes associated with degenerative phenotypes of aging, and in the suppression or promotion of cancer (Campisi 2013;Chang et al 2016). Recent studies have also shown that senescent cells contribute to tissue injury repair (Kim et al 2013;Krizhanovsky et al 2008) and wound healing (Demaria et al 2014;Jun and Lau 2010b), where senescent cells can play an anti-fibrotic role.…”

Section: Introductionmentioning

confidence: 99%

CCN2 induces cellular senescence in fibroblasts

Jun

Lau

2016

J. Cell Commun. Signal.

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The expression of Ccn2 (CTGF) has been linked to fibrosis in many tissues and pathologies, although its activities in fibroblastic cells and precise mechanism of action in fibrogenesis are still controversial. Here, we showed that CCN2 can induce cellular senescence in fibroblasts both in vitro and in vivo, whereupon senescent cells express an anti-fibrotic Bsenescence-associated secretory phenotype( SASP) that includes upregulation of matrix metalloproteinases and downregulation of collagen. Mechanistically, CCN2 induces fibroblast senescence through integrin α 6 β 1 -mediated accumulation of reactive oxygen species, leading to activation of p53 and induction of p16 INK4a . In cutaneous wound healing, Ccn2 expression is highly elevated only during the initial inflammatory phase and quickly declines thereafter to a low level during the proliferation and maturation phases of healing when myofibroblasts play a major role. Consistent with this expression kinetics, knockdown of Ccn2 has little effect on the rate of wound closure, formation of senescent cells, or collagen content of the wounds. However, application of purified CCN2 protein on cutaneous wounds leads to induction of senescent cells, expression of SASP, and reduction of collagen content. These results show that CCN2 can induce cellular senescence in fibroblasts and is capable of exerting an anti-fibrotic effect in a context-dependent manner.

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“…For instance, some of the proteins secreted by senescent cells stimulate angiogenesis and promote growth and invasion of neighboring cancer cell (Coppe´et al, 2010;Freund et al, 2010). On the other hand, the SASP has at least two beneficial roles: factors secreted by senescent cells function in an autocrine manner to reinforce the senescence growth arrest (Acosta et al, 2008;Kuilman et al, 2008;Wajapeyee et al, 2008), and the SASP stimulates clearance of senescent cells by NK cells (Krizhanovsky et al, 2008). Most components of SASP are transcriptionally regulated by the transcription factors NF-kB and C/ EBPb (Acosta et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

NF-κB-dependent cytokine secretion controls Fas expression on chemotherapy-induced premature senescent tumor cells

et al. 2011

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Induction of a senescent phenotype in tumor cells has been linked to anticancer immune response, however, the molecular mechanisms mediating these phenomenon have not yet been determined. In this study, we present evidence that induction of premature senescence in human cancer cell lines induces Fas expression, and loss of resistance to Fas-induced apoptosis. Triggering of Fas by using the agonistic antibody CH11 or the recombinant ligand APO010, activates an apoptotic pathway responsible for cell death. Secretion of pro-inflammatory cytokines by the senescent cells, particularly TNF-a and IFN-c, mediates Fas upregulation. Indeed, treatment of proliferating cancer cell lines with TNF-a and IFN-c, upregulates Fas expression, while blocking TNF-a and IFN-c by using neutralizing antibodies, decreases Fas expression in senescent cells. We also demonstrate that NF-jB has a central role in controlling the senescence-associated secretory phenotype (SASP) by the premature senescent cells, and that TNF-a and IFN-c, transcriptionally controlled by NF-jB, are the main mediators of Fas upregulation. Our data suggest the existence of an NF-jB-dependent autocrine loop, mediated by TNF-a and IFN-c, responsible for expression of Fas on the surface of senescent cells, and for their killing.

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Senescence of Activated Stellate Cells Limits Liver Fibrosis

Cited by 171 publications

References 0 publications

Mechanisms of Lung Fibrosis Resolution

Mechanisms of Lung Fibrosis Resolution

CCN2 induces cellular senescence in fibroblasts

NF-κB-dependent cytokine secretion controls Fas expression on chemotherapy-induced premature senescent tumor cells

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