Abstract
Cellular senescence is a pathophysiological phenomenon in which proliferative cells enter cell cycle arrest following DNA damage and other stress signals. Natural, permanent DNA damage can occur after repetitive cell division; however, acute stress or other injuries can push cells into premature senescence and eventually a senescence-associated secretory phenotype (SASP). In recent years, there has been increased evidence for the role of premature senescence in disease progression including diabetes, cardiac diseases, and end-stage liver diseases including cholestasis. Liver size and function change with aging, and presumably with increasing cellular senescence, so it is important to understand the mechanisms by which cellular senescence affects the functional nature of the liver in health and disease. As well, cells in a SASP state secrete a multitude of inflammatory and pro-fibrogenic factors that modulate the microenvironment. Cellular SASP and the associated, secreted factors have been implicated in the progression of liver diseases, such as cholestatic injury that target the biliary epithelial cells (i.e., cholangiocytes) lining the bile ducts. Indeed, cholangiocyte senescence/SASP is proposed to be a driver of disease phenotypes in a variety of liver injuries. Within this review, we will discuss the impact of cholangiocyte senescence and SASP in the pathogenesis of cholestatic disorders.
Highlights
Cholangiocytes, which are morphologically heterogenous, polarized cells lining the biliary epithelium (Han et al, 2013; Banales et al, 2019), have high absorptive/secretory functions and play a role in the 1) modification of canalicular bile, 2) paracrine communication with portal cells, and 3) regulation of immune cell infiltration (Nathanson and Boyer, 1991; Chen et al, 2008; Banales et al, 2019)
DR and biliary senescence/senescence-associated secretory phenotype (SASP) are characteristic of cholangiopathies and are increasing in incidence during fatty liver disease progression and Alcoholic Liver Disease (ALD), confirming biliary involvement, mechanisms remain unclear
Future work should utilize cholangiocyte-specific mouse models to target biliary senescence and SASP factors to evaluate the role that these factors may play in the progression of cholangiopathies, Non-Alcoholic Fatty Liver Disease (NAFLD)/Non-Alcoholic Steatohepatitis (NASH) and ALD
Summary
Cholangiocytes, which are morphologically heterogenous, polarized cells lining the biliary epithelium (Han et al, 2013; Banales et al, 2019), have high absorptive/secretory functions and play a role in the 1) modification of canalicular bile, 2) paracrine communication with portal cells, and 3) regulation of immune cell infiltration (Nathanson and Boyer, 1991; Chen et al, 2008; Banales et al, 2019). Biliary secretory functions regulate liver inflammation and fibrosis (by both autocrine and paracrine pathways) through secretion of cytokines and other factors which may contribute to liver damage (Kennedy et al, 2021; Kyritsi et al, 2021). Cellular senescence increases in cholangiocytes of PSC patients, likely contributing to disease progression (Tabibian et al, 2014a). Senescence and SASP secretion have gained considerable attention in studies of cholestatic liver disease progression, demonstrating a new role for senescent cholangiocytes in the pathogenesis of liver diseases (Knop et al, 1987; Wu et al, 2016)
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