$54,000
$19,257

Senescent Cells Involved in the Inflammation and Scarring of Bile Ducts

Given the past few years of research results, it is becoming quite clear that wherever researchers observe inflammation and scarring in the body, senescent cells should be high on the list of suspected causes. Senescent cells are created constantly in large numbers, the normal fate for cells that become damaged or reach the end of their replicative life span. Near all quickly self-destruct, or are destroyed by the immune system, but some few manage to linger - or more, in medical conditions that create a harmful tissue environment that encourages senescence. Over time a population of lasting senescent cells contributes greatly to the progression of aging and age-related disease.

Senescent cells cause issues through the potent mix of signal molecules that they generate; even a comparatively small number can degrade the function of surrounding tissue. To pick one example, there is a good deal of evidence linking the accumulation of senescent cells to the development of fibrosis in various tissues, this being a harmful process by which tissue maintenance runs awry, disrupted by inappropriate levels of inflammation, and scar-like deposits form in place of normal, healthy structures. Targeted removal of senescent cells can help to reverse these conditions, and this is one of many reasons to speed the clinical development of senolytic therapies that can destroy these unwanted cells.

Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are the most prevalent type of cholangiopathies, a diverse group of genetic and acquired disorders that affect the biliary population of the liver. PSC/PBC have variable prognoses but frequently evolve into end-stage liver disease, with limited treatment options. The aetiologies remain unclear, although a role of cellular senescence in the development of PSC/PBC has been suggested.

Senescence is an irreversible cell cycle arrest, driven by dominant cell-cycle inhibitors and characterized by the activation of the senescence-associated secretory phenotype (SASP). The SASP is a pro-inflammatory response that activates and reinforces the senescent phenotype in the surrounding cells, modulates fibrosis, and promotes regeneration. The SASP is composed by a variable set of secreted cytokines and chemokines, responsible for the beneficial and deleterious effects of senescence within the tissue. However, despite a number of studies suggesting a potential link between senescence and biliary disease, it has not been shown whether senescence is actually a driver of the damage rather than solely a consequence. We have therefore investigated the relationship between senescence and biliary disease, focusing on SASP-related mechanisms to explain part of the pathophysiology of PSC/PBC.

Here, we present a model of biliary disease, based on the conditional deletion of Mdm2 in bile ducts under the control of the Krt19 cholangiocyte promoter. In this model, senescent cholangiocytes induce profound alterations in the cellular and signalling microenvironment. The presence of senescent cholangiocytes in this model promotes ductular reaction, increases deposition of collagen, and impairs liver regeneration after injury. The presence of ╬▒SMA-positive cells in the proximities of the senescent cholangiocytes suggests that senescence might have a role in the development of fibrosis, characteristic of human PSC/PBC.

We suggest that senescence may contribute to the development of biliary disease through complementary mechanisms. First, through an impaired regenerative response of cholangiocytes, unable to compensate biliary damage, and second, through SASP expression, that can induce paracrine senescence in hepatocytes (thus diminishing the regenerative capacity of the liver during injury), promote collagen deposition, and enhance fibrogenesis. Overall, we have shown that cellular senescence is likely to be a driver of biliary injury by affecting the microenvironment, impairing liver parenchyma regeneration, and impairing biliary function.

Link: https://doi.org/10.1038/s41467-018-03299-5

Comments

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.