The Spectrum of Reactive Cholangiocytes in Primary Sclerosing Cholangitis - PubMed (original) (raw)
Review
The Spectrum of Reactive Cholangiocytes in Primary Sclerosing Cholangitis
Maria Eugenia Guicciardi et al. Hepatology. 2020 Feb.
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.
© 2020 by the American Association for the Study of Liver Diseases.
Figures
Figure 1.. Divergent cholangiocyte fates in the pathogenesis of PSC.
Genetic and environmental insults targeting the cholangiocytes result in their acquisition of a reactive phenotype characterized by increased proliferation and upregulation of pro-inflammatory mediators. In a physiologic context, the expansion of this proliferative compartment and the cross-talk with recruited and resident cells, including hepatocytes, leukocytes and fibroblasts (known as the ductular reaction), promote the repair of the damaged epithelium and tissue homeostasis. During this process, cells that have sustained unrepairable DNA damage, either as a direct consequence of the insult or of their proliferative activity, are generally eliminated by apoptosis. Among these damaged cells, those that have developed resistance to apoptosis acquire a senescent phenotype characterized by growth arrest, which prevents the propagation of potentially oncogenic mutations. Senescent cells are also frequently hypersecretory and release pro-inflammatory cytokines, chenokines, growth factors and extracellular matrix proteins aimed to promote the reparative process. In the presence of a chronic injury, the secretory state of both the proliferative and the senescent cholangiocyte compartment leads to persistent inflammation, aberrant fibrogenic response and progressive liver injury, with increased oncogenic risk. Based on experimental data and supported by their anatomical location, we propose that, in PSC, senescent cholangiocytes and portal fibroblasts participate mainly in the development and persistence of the peribiliary fibrosis, whereas ductular reactive cells and hepatic stellate cells would be involved in the formation of the parenchymal fibrosis.
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