Senescence of activated stellate cells limits liver fibrosis

By V. Krizhanovsky, Monica Yon, R. Dickins, Stephen A Hearn, Janelle Simon, C. Miething, H. Yee, Lars Zender, Scott W. Lowe. Cell, 2008

1,898 citations recorded by the source corpus.

Summary Cellular senescence acts as a potent mechanism of tumor suppression; however, its functional contribution to non-cancer pathologies has not been examined. Here we show that senescent cells accumulate in murine livers treated to produce fibrosis, a precursor pathology to cirrhosis. The senescent cells are derived primarily from activated hepatic stellate cells, which initially proliferate in response to liver damage and produce the extracellular matrix deposited in the fibrotic scar. In mice lacking key senescence regulators, stellate cells continue to proliferate, leading to excessive liver fibrosis. Furthermore, senescent activated stellate cells exhibit gene expression profile consistent with cell cycle exit, reduced secretion of extracellular matrix components, enhanced secretion of extracellular matrix degrading enzymes, and enhanced immune surveillance. Accordingly natural killer cells preferentially kill senescent activated stellate cells in vitro and in vivo, thereby facilitating the resolution of fibrosis. Therefore, the senescence program limits the fibrogenic response to acute tissue damage.

Subfields: Cancer Research, Immunology, Physiology

View Paper: https://www.semanticscholar.org/paper/ce5e5a42201ddcfa8349e137ece0309db96e4616

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. J. Campisi
2. S. Friedman
3. Stephen J. Elledge
4. L. Galluzzi
5. Guido Kroemer
6. Christoph Borner
7. Zhijian J. Chen
8. Jesús Gil

In Immunology

1. J. Campisi
2. J. Kirkland
3. T. Tchkonia
4. M. Demaria
5. Adam Freund
6. Guido Kroemer
7. Jesús Gil
8. L. Galluzzi

In Physiology

1. J. Campisi
2. Jesús Gil
3. J. Kirkland
4. M. Demaria
5. T. Tchkonia
6. Adam Freund
7. Manuel Serrano
8. D. Baker

Citations in the corpus

• Senescence-messaging secretome: SMS-ing cellular stress (2009, background): “In a model of liver fibrosis, activated hepatic stellate cells were shown to be able to undergo senescence in vivo”
• Hepatic Stellate Cells and Liver Fibrosis (2013, positive): “Based on these observations, elegant in vivo approaches confirmed the development of senescence in HSCs in vivo (155, 169).”
• Regulation of ligands for the NKG2D activating receptor (2013, background): “p53 activation has been documented in fibrotic livers and healing cutaneous wounds (56, 57), and it may also enhance transcription of NKG2D ligand genes (72, 73) in the context of injury.”
• Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders (2011, positive): “There were no overt side effects of senescent cell clearance in our model, even though it has been postulated that senescent cells enhance certain types of tissue repai”
• Mechanisms and functions of cellular senescence. (2018, neutral): “Senescence also limits fibrotic responses (78).”
• Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion (2009, background): “, and senescent cells in injured liver seem to limit fibrosis before being cleared by the immune syste”
• Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL (2016, neutral): “To examine the resistance of senescent cells to intrinsic and extrinsic apoptotic pathways, we induced senescence in normal primary human fibroblasts (IMR-90), one of the most widely used cell models for the study of this program 5,22,23 .”
• Decoding cell death signals in liver inflammation. (2013, background): “, MICA, ULBP2, PVR) on the surface of senescent HSCs for allows their elimination by tissue-resident NK cells, an immunosurveillance mechanism that contributes to the resolution of fibrosis [161].”
• Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence (2017, positive): “SA-β Gal staining on frozen liver sections was performed at pH = 5.5 as previously described 54.”
• Evolving challenges in hepatic fibrosis (2010, background): “The tumor suppressor protein p53 has entered the field of hepatic fibrosis through evidence demonstrating that it drives senescence of activated HSCs during resolution of experimental fibrosis”