Senescence of Activated Stellate Cells Limits Liver Fibrosis

Abstract

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.

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

“…As our data demonstrate that early passage human fibroblasts with dysfunctional telomeres transdifferentiate into functional myofibroblasts while displaying some features of senescence, they suggest that functional myofibroblasts and senescent (myo)fibroblasts are difficult to distinguish. The observations that fibroblast with senescence features detected in damaged tissue frequently display features of myofibroblasts, such as high expression levels of α‐SMA, are consistent with this conclusion (Jun & Lau, 2010) (Demaria et al, 2014; Krizhanovsky et al, 2008). It is important to note, however, that human fibroblasts serially passaged into replicative senescence and those that underwent oncogene‐induced senescence, both lacked features of myofibroblasts, demonstrating that not all fibroblasts induced to senesce by telomere dysfunction or other stresses are functional myofibroblasts.…”

“…After tissue damage, the transient generation of senescent stromal cells at the site of injury is critical to suppress fibrosis (Jun & Lau, 2010; Krizhanovsky et al, 2008), attract immune modulatory cells (Krizhanovsky et al, 2008), and promote the generation of myofibroblasts in a paracrine manner (Demaria et al, 2014). While the formation of myofibroblasts during wound healing in a mouse model system was reported to be stimulated by SASP factors secreted from senescent fibroblasts and endothelial cells generated at the site of injury (Demaria et al, 2014), other studies demonstrated that, paradoxically, the SASP causes bystander senescence in somatic human fibroblasts (Acosta et al, 2013; Hubackova et al, 2012; Nelson et al, 2012).…”

“…Aside from functioning to suppress malignant cancer development, cellular senescence has been demonstrated to play important roles also in other biological processes such as aging, embryonic development, and wound healing (Munoz‐Espin & Serrano, 2014). During tissue repair and wound healing, senescent cells transiently accumulate at the site of injury, where they are thought to limit fibrosis (Jun & Lau, 2010; Krizhanovsky et al, 2008), promote transdifferentiation of fibroblasts into myofibroblasts (Demaria et al, 2014), and attract immune modulatory cells that eventually eliminate newly generated senescent cells at the site of injury (Krizhanovsky et al, 2008). Many of these functions are mediated in a paracrine manner and by a complex mixture of factors that are secreted from senescent cells, collectively called the senescence‐associated secretory phenotype or SASP.…”

Cellular senescence impact on immune cell fate and function

“…NK cells, macrophages, and cytotoxic CD8 + T cells are chemo‐attracted by the inflamed tissues to promote cell death, thus facilitating senescent cell replacement and a return to tissue homeostasis (Hoenicke & Zender, 2012; Davies et al ., 2013). NK cells are especially important in the immunosurveillance of senescent cells during tissue repair (Krizhanovsky et al ., 2008a,b). They are attracted to senescent cells through a p53‐dependent secretion of CCL2 [chemokine (C‐C) ligand 2] (Iannello et al ., 2013).…”

Cellular and molecular mechanisms in liver fibrogenesis

“…In addition, activated NK cells also produce large amount of IFN-γ, which can induce HSC apoptosis and cell cycle arrest, as well as by enhancing NK cell killing of early activated HSC [131,132]. In addition, NK cells can selectively kill senescent activated HSC, which are cell cycle arrested cells that accumulate in fibrotic septa during chronic liver injury and become inefficient in ECM synthesis but able to up-regulate expression of extracellular matrixdegrading enzymes [133,134]. It has been proposed that senescence-activated HSCs express elevated levels of NK cell-activating ligands, becoming then sensitive to NK cell killing [133].…”