Targeting senescent cholangiocytes and activated fibroblasts with B‐cell lymphoma‐extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2−/− ) mice
Open accessAbstract
Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secretion of growth factors by senescent cholangiocytes leads to the activation of stromal fibroblasts (ASFs), which are drivers of fibrosis. The activated phenotype of ASFs is characterized by an increased sensitivity to apoptotic stimuli. Here, we examined the mechanisms of apoptotic priming in ASFs and explored a combined targeting strategy to deplete senescent cholangiocytes and ASFs from fibrotic tissue to ameliorate liver fibrosis. Using a coculture system, we determined that senescent cholangiocytes promoted quiescent mesenchymal cell activation in a platelet‐derived growth factor (PDGF)‐dependent manner. We also identified B‐cell lymphoma‐extra large (Bcl‐xL) as a key survival factor in PDGF‐activated human and mouse fibroblasts. Bcl‐xL was also up‐regulated in senescent cholangiocytes. In vitro , inhibition of Bcl‐xL by the small molecule Bcl‐2 homology domain 3 mimetic, A‐1331852, or Bcl‐xL‐specific small interfering RNA induced apoptosis in PDGF‐activated fibroblasts, but not in quiescent fibroblasts. Likewise, inhibition of Bcl‐xL reduced the survival and increased apoptosis of senescent cholangiocytes, compared to nonsenescent cells. Treatment of multidrug resistance 2 gene knockout ( Mdr2−/− ) mice with A‐1331852 resulted in an 80% decrease in senescent cholangiocytes, a reduction of fibrosis‐inducing growth factors and cytokines, decrease of α‐smooth muscle actin–positive ASFs, and finally in a significant reduction of liver fibrosis. Conclusion: Bcl‐xL is a key survival factor in ASFs as well as in senescent cholangiocytes. Treatment with the Bcl‐xL‐specific inhibitor, A‐1331852, reduces liver fibrosis, possibly by a dual effect on activated fibroblasts and senescent cholangiocytes. This mechanism represents an attractive therapeutic strategy in biliary fibrosis. (H epatology 2018;67:247‐259).
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In primary biliary cirrhosis, senescence-associated markers are found in cholangiocytes.
“In the context of primary biliary cirrhosis, which is an autoimmune disease characterized by chronic, progressive cholestasis and liver failure, senescence-associated markers have been found in cholangiocytes165.”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [165]
The Introduction and Results report senescent cholangiocytes in primary sclerosing cholangitis (PSC). The Discussion also describes senescent cholangiocytes in livers of patients with PSC, but the cited paper does not establish the claim for primary biliary cirrhosis. (LLM, conf=0.86)
Experimental — accuracy not yet measuredA recent report shows that removing senescent cells expressing high p16 can lead to fibrosis in mice, whereas small-molecule senolytics appear to reduce fibrosis in several mouse tissues.
“This is in agreement with a recent report showing that the removal of senescent cells expressing high levels of p16INK4a can lead to fibrosis in mice101, whereas small-molecule senolytics appear to reduce fibrosis in several mouse tissues22,71,73,75,102.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [22]
Treatment of a mouse model of biliary liver fibrosis with a senolytic drug reduces fibrosis.
“Treatment of a mouse model of biliary liver fibrosis with a senolytic drug reduced fibrosis99.”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [99]
In preclinical aging models, senescent cell accumulation is associated with chronic diseases, geriatric syndromes, multimorbidity, and accelerated aging phenotypes.
“In pre-clinical aging models, accumulation of senescent cells is associated with multiple chronic diseases and disorders, geriatric syndromes, multi-morbidity, and accelerated aging phenotypes.”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [5]
In animals, genetic and pharmacologic reduction of senescent cell burden prevents, delays, or alleviates various aging-related diseases and sequelae.
“In animals, genetic and pharmacologic reduction of senescent cell burden results in the prevention, delay, and/or alleviation of a variety of aging-related diseases and sequelae.”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [5]
Senolytics have been used to prevent, delay, or alleviate many age-onset diseases and syndromes in preclinical models.
“Senolytics have been used to prevent, delay, or alleviate a plethora of age-onset diseases and syndromes in pre-clinical models.”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [5]
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- Authors
- Moncsek, A., Al‐Suraih, M. S., Trussoni, C. E., O'Hara, S. P., Splinter, P. L., Zuber, C., Patsenker, E., Valli, P. V., Fingas, C. D., Weber, A., Zhu, Y., Tchkonia, T., Kirkland, J. L., Gores, G. J., Müllhaupt, B., LaRusso, N. F., & Mertens, J. C.
- Affiliations
- University Hospital Zurich (CH)
- Division of Gastroenterology and Hepatology and Center for Cell Signaling in Gastroenterology,Mayo Clinic,Rochester,MN
- Mayo Clinic (US)
- Essen University Hospital (DE)
- Corresponding author
- Mertens, Joachim C.
- ORCID
- Venue
- Hepatology
- Published
- 2017-11-29
- Volume
- 67
- Issue
- 1
- Pages
- 247-259
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC5739965
- OpenAlex
- W2784796582
- Cited by
- 136
- References
- 20
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 13 · 2023: 18 · 2022: 14 · 2021: 16 · 2020: 23 · 2019: 16 · 2018: 13 · 2017: 1
- FWCI
- 8.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Science Foundation
- Mayo Clinic
- American Association for the Study of Liver Diseases
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (154691)
- National Institutes of Health (AG013925)
- National Institute on Aging (AG013925, R01AG013925, R37AG013925)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK057993, R01DK063947, P30DK084567, R01DK057993)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- activated fibroblasts, Bcl-xL, Bcl-xL inhibitors, A-1331852, liver fibrosis, biliary fibrosis, primary sclerosing cholangitis, Mdr2 knockout mice, PDGF signaling, apoptosis, alpha-smooth muscle actin
- MeSH terms
- Animals, Bile Ducts, Biopsy, Needle, Cell Survival, Cells, Cultured, Disease Models, Animal, Fibroblasts, Immunohistochemistry, Isoquinolines, Mice, Inbred BALB C, Platelet-Derived Growth Factor, Random Allocation, Reference Values, Cholangitis, Sclerosing, Cellular Senescence, Mice, Knockout, Drug Resistance, Multiple, Cell Proliferation, Mice, Benzothiazoles, Molecular Targeted Therapy
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