Functional Role of Cellular Senescence in Biliary Injury

Abstract

Cellular senescence is a state of irreversible cell cycle arrest that has been involved in many gastrointestinal diseases, including human cholestatic liver disorders. Senescence may play a role in biliary atresia, primary sclerosing cholangitis, cellular rejection, and primary biliary cirrhosis, four liver diseases affecting cholangiocytes and the biliary system. In this review, we examine proposed mechanisms of senescence-related biliary diseases, including hypotheses associated with the senescence-associated phenotype, induction of senescence in nearby cells, and the depletion of stem cell subpopulations. Current evidence for the molecular mechanisms of senescence in the previously mentioned diseases is discussed in detail, with attention to recent advances on the role of pathways associated with senescence-associated phenotype, stress-induced senescence, telomere dysfunction, and autophagy.

Redox control of senescence and age-related disease

“…In many prevalent neurodegenerative conditions including Alzheimer's Disease, brain tissue biopsies are present with increased levels of p16 INK4a - positive astrocytes, MMP-1 and IL-6 [99], [100]. Other prevalent pathologies which share several damaging SASP profiles including IL-6, IL-8, GM-CSF, MMP-1 [101] are chronic obstructive pulmonary disease (COPD), biliary cirrhosis and cholangitis [102], and osteoarthritis [103].…”

Bile Acids and Deregulated Cholangiocyte Autophagy in Primary Biliary Cholangitis

“…CCL2/ monocyte chemotactic protein-1 and CX3CL1/fractalkine) and various growth factors [25,[33][34][35][36][37] . Therefore, senescent cholangiocytes may modulate inflammatory microenvironment around affected small bile ducts by recruiting monocytes and possibly other types of inflammatory cells via secretion of CCL2 and CX3CL1 as SASP [1,[38][39][40] . Interestingly, chemokines CCL2 and CX3CL1 can cause cellular senescence in cholangiocytes, suggesting SASPs may induce cellular senescence in bystander cholangiocytes at the site of CNSDC and further exacerbate inflammation.…”

Is Cellular Senescence Involved in Progressive Loss of Canals of Hering in Primary Biliary Cirrhosis?

“…Although these cells are metabolically still active, this process is followed by eventual loss of affected cells. Recent studies showed that cellular senescence was implicated in several biliary diseases and also premature or stress-induced senescence was discussed with respect to senescence-associated secretory phenotype (SASP) which is associated with microenvironments of affected cells or tissues [11,12]. Interestingly, Sasaki et al reported that bile ductules showed cellular senescence in PBC, and that sustained cellular senescence might lead to the eventual loss of bile ductules and CoH loss [9,10].…”

“…Interestingly, Sasaki et al reported that bile ductules showed cellular senescence in PBC, and that sustained cellular senescence might lead to the eventual loss of bile ductules and CoH loss [9,10]. It is, moreover, reported that senescence is propagated through positive feedback by nearby senescent cells, causing senescence of adjacent bile ductules and CoH in PBC [11,12]. Recently, we have reported that cellular senescence may play an important role in the pathogenesis of fibrosing cholangiopathies including PBC, and senescence of biliary epithelial cells may be induced by several senescent stimuli, particularly impaired autophagy and oxidative stresses [11].…”

“…Recently, we have reported that cellular senescence may play an important role in the pathogenesis of fibrosing cholangiopathies including PBC, and senescence of biliary epithelial cells may be induced by several senescent stimuli, particularly impaired autophagy and oxidative stresses [11]. Alpini et al also reviewed cellular senescence and cholangiopathy, indicating that cellular senescence of cholangiocytes may be linked to the development of cholangiopathies of several biliary diseases, particularly PBC, primary sclerosing cholangitis, biliary atresia and chronic allograft rejection [12]. While exact mechanisms for occurrence of cellular senescence of CoH remains speculative, multiple senescent stimuli including autophagy or oxidative stress might be involved in this critical process leading to progression of stage of PBC.…”