Cellular senescence in the cholangiopathies: a driver of immunopathology and a novel therapeutic target

Trussoni, Christy E.; O’Hara, Steven P.; LaRusso, Nicholas F.

doi:10.1007/s00281-022-00909-9

Cited by 25 publications

(22 citation statements)

References 109 publications

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“…During chronic senescence, the surrounding tissues are susceptible to senescence associated secretory phenotype (SASP) related damage, resulting in persistent inflammatory and fibrosis responses. Moreover, destructive SASP not only maintains the inflammatory response, but can also activate the senescent phenotype in surrounding non-senescent cells [ 201 ].…”

Section: Primary Sclerosing Cholangitismentioning

confidence: 99%

Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: Current Knowledge of Pathogenesis and Therapeutics

Park

Kim

et al. 2022

Biomedicines

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Cholangiopathies encompass various biliary diseases affecting the biliary epithelium, resulting in cholestasis, inflammation, fibrosis, and ultimately liver cirrhosis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most important progressive cholangiopathies in adults. Much research has broadened the scope of disease biology to genetic risk, epigenetic changes, dysregulated mucosal immunity, altered biliary epithelial cell function, and dysbiosis, all of which interact and arise in the context of ill-defined environmental triggers. An in-depth understanding of the molecular pathogenesis of these cholestatic diseases will help clinicians better prevent and treat diseases. In this review, we focus on the main underlying mechanisms of disease initiation and progression, and novel targeted therapeutics beyond currently approved treatments.

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Section: Primary Sclerosing Cholangitismentioning

confidence: 99%

Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: Current Knowledge of Pathogenesis and Therapeutics

Park

Kim

et al. 2022

Biomedicines

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“…Overactivation of the Notch signaling pathway was found in both diseases, further indicating aberrant biliary repair conditions ( 142 , 143 ). As immune-mediated diseases, the immune cells recruited by cholangiocyte secretion significantly altered the composition of intrahepatic immune cells and are involved in disease pathogenesis and regulation of biliary repair ( 144 ). ScRNA-seq of liver of PBC patients indicated that ORMDL3 + cholangiocytes displayed higher interaction with immune cells such as macrophages and monocytes, which might play a role in the pathogenesis of PBC ( 145 ).…”

Section: Role Of Immune Cells In Biliary Repair In Cholangiopathiesmentioning

confidence: 99%

Role of Immune Cells in Biliary Repair

et al. 2022

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The biliary system is comprised of cholangiocytes and plays an important role in maintaining liver function. Under normal conditions, cholangiocytes remain in the stationary phase and maintain a very low turnover rate. However, the robust biliary repair is initiated in disease conditions, and different repair mechanisms can be activated depending on the pathological changes. During biliary disease, immune cells including monocytes, lymphocytes, neutrophils, and mast cells are recruited to the liver. The cellular interactions between cholangiocytes and these recruited immune cells as well as hepatic resident immune cells, including Kupffer cells, determine disease outcomes. However, the role of immune cells in the initiation, regulation, and suspension of biliary repair remains elusive. The cellular processes of cholangiocyte proliferation, progenitor cell differentiation, and hepatocyte-cholangiocyte transdifferentiation during biliary diseases are reviewed to manifest the underlying mechanism of biliary repair. Furthermore, the potential role of immune cells in crucial biliary repair mechanisms is highlighted. The mechanisms of biliary repair in immune-mediated cholangiopathies, inherited cholangiopathies, obstructive cholangiopathies, and cholangiocarcinoma are also summarized. Additionally, novel techniques that could clarify the underlying mechanisms of biliary repair are displayed. Collectively, this review aims to deepen the understanding of the mechanisms of biliary repair and contributes potential novel therapeutic methods for treating biliary diseases.

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“…58 In some mouse models of liver damage, senescent cells were shown to help reduce liver tissue injury and support a homeostatic environment while supporting the immune system. 58 However, when this phenotype persists, the cell experiences a chronic senescent state characterized by high levels of inflammation leading to fibrosis and cirrhosis. 57,58 This pathology is demonstrated in the proinflammatory environments of the PBC and PSC pathology.…”

Section: Heterogeneity In Response To Tissue Injurymentioning

confidence: 99%

Recent Advances in Intrahepatic Biliary Epithelial Heterogeneity

et al. 2022

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Biliary epithelium (i.e., cholangiocytes) is a heterogeneous population of epithelial cells in the liver, which line small and large bile ducts and have individual responses and functions dependent on size and location in the biliary tract. We discuss the recent findings showing that the intrahepatic biliary tree is heterogeneous regarding (1) morphology and function, (2) hormone expression and signaling (3), response to injury, and (4) roles in liver regeneration. This review overviews the significant characteristics and differences of the small and large cholangiocytes. Briefly, it outlines the in vitro and in vivo models used in the heterogeneity evaluation. In conclusion, future studies addressing biliary heterogeneity's role in the pathogenesis of liver diseases characterized by ductular reaction may reveal novel therapeutic approaches.

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Cellular senescence in the cholangiopathies: a driver of immunopathology and a novel therapeutic target

Cited by 25 publications

References 109 publications

Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: Current Knowledge of Pathogenesis and Therapeutics

Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: Current Knowledge of Pathogenesis and Therapeutics

Role of Immune Cells in Biliary Repair

Recent Advances in Intrahepatic Biliary Epithelial Heterogeneity

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