The Spectrum of Reactive Cholangiocytes in Primary Sclerosing Cholangitis

Abstract

Cholangiocytes are the target of a group of chronic liver diseases termed the “cholangiopathies,” in which cholangiocytes react to exogenous and endogenous insults, leading to disease initiation and progression. In primary sclerosing cholangitis (PSC), the focus of this review, the cholangiocyte response to genetic or environmental insults can lead to a heterogeneous response; that is, a subpopulation acquires a ductular reactive and proliferative phenotype, while another subpopulation undergoes senescence and growth arrest. Both ductular reactive cholangiocytes and senescent cholangiocytes can modify the periductal microenvironment through their ability to secrete various cytokines, chemokines, and growth factors, initiating and perpetuating inflammatory and profibrotic responses. This review discusses the similarities and differences, the interrelationships, and the potential pathogenic roles of these reactive proliferative and senescent cholangiocyte subpopulations in PSC.

Senescent cholangiocytes release extracellular vesicles that alter target cell phenotype via the epidermal growth factor receptor

“…Together, our data support that EVs are an essential component of the cholangiocyte SASP. Our findings also suggest that EVs from senescent cholangiocytes may influence both the proliferative cholangiocyte niche (ie ductular reactive), at least in part through EGFR activation, as well as promote nonproliferative, senescent niche, both of which are implicated in the pathogenesis of cholestatic disease 5 . We further demonstrate that target malignant cholangiocyte proliferation and migration are enhanced by senescent cholangiocyte EVs, again through an EGFR‐dependent manner.…”

“…The cholangiocyte (biliary epithelia) response to injurious stimuli plays a critical role in initiating, modulating and exacerbating PSC disease progression 4,5 . We have previously shown that senescent cholangiocytes are abundant in livers of patients with PSC 6,7 .…”

Cholangiocyte senescence in primary sclerosing cholangitis is associated with disease severity and prognosis

“…In fact, cholangiocytes seem to respond to endogenous or exogenous insults by acquiring the ability to proliferate and secrete different pro-inflammatory mediators acting in a paracrine and/or autocrine manner. This determines the recruitment and stimulation of immune cells and fibroblasts, which induce the development of the typical PSC fibro-inflammatory lesions [4,5]. In case of persisting chronic injury, the reparative process becomes ineffective, and the inflammatory response perseveres, promoting ductular reaction (DR) and inducing cellular senescence (CS) J o u r n a l P r e -p r o o f in chronic injured cholangiocytes [4,5].…”

“…This determines the recruitment and stimulation of immune cells and fibroblasts, which induce the development of the typical PSC fibro-inflammatory lesions [4,5]. In case of persisting chronic injury, the reparative process becomes ineffective, and the inflammatory response perseveres, promoting ductular reaction (DR) and inducing cellular senescence (CS) J o u r n a l P r e -p r o o f in chronic injured cholangiocytes [4,5]. CS is a cell state triggered by stressful insults and certain physiological processes, characterized by a prolonged and generally irreversible cellcycle arrest in the G 1 phase, associated to the acquisition of secretory features, the so-called senescence-associated secretory phenotype (SASP), macromolecular damage, and altered metabolism [6].…”

Knockout of the Tachykinin Receptor 1 in the Mdr2−/− (Abcb4−/−) Mouse Model of Primary Sclerosing Cholangitis Reduces Biliary Damage and Liver Fibrosis

“…2e5 PSC is a liver disease (more frequent in middle-aged men) 4 that targets extrahepatic and/or intrahepatic bile ducts and is characterized by biliary strictures and activation of hepatic stellate cells (HSCs), causing excessive collagen deposition. 2,3,6,7 PSC phenotypes can also progress to severe disorders, such as cholangiocarcinoma and pancreatic and colorectal cancer. 4 There is growing evidence that during the progression of cholangiopathies, cholangiocytes undergo cellular senescence, thereby secreting several cytokines (ie, senescence-associated secretory phenotypes), including transforming growth factor-b1 (TGF-b1), IL-6, IL-8, C-C motif chemokine ligand 2, and plasminogen activator inhibitor-1, which trigger activation of HSCs by paracrine mechanisms.…”