Paracrine cellular senescence exacerbates biliary injury and impairs regeneration
Open accessAbstract
Cellular senescence is a mechanism that provides an irreversible barrier to cell cycle progression to prevent undesired proliferation. However, under pathological circumstances, senescence can adversely affect organ function, viability and regeneration. We have developed a mouse model of biliary senescence, based on the conditional deletion of Mdm2 in bile ducts under the control of the Krt19 promoter, that exhibits features of biliary disease. Here we report that senescent cholangiocytes induce profound alterations in the cellular and signalling microenvironment, with recruitment of myofibroblasts and macrophages causing collagen deposition, TGFβ production and induction of senescence in surrounding cholangiocytes and hepatocytes. Finally, we study how inhibition of TGFβ-signalling disrupts the transmission of senescence and restores liver function. We identify cellular senescence as a detrimental mechanism in the development of biliary injury. Our results identify TGFβ as a potential therapeutic target to limit senescence-dependent aggravation in human cholangiopathies.
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TGF-β1 inhibition attenuates liver fibrosis in a biliary senescence model.
“In contrast, TGF-β1 inhibition attenuated liver fibrosis in a biliary senescence model (127), underscoring the strong context dependence of its effects.”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [127]
The Results section (‘Inhibition of TGFβ in vivo improves liver function’; page unavailable) reports decreased collagen deposition after treatment with a TGFβR1 antagonist in the biliary senescence model. It says this may reflect a reduced fibrogenic response, rather than establishing that liver fibrosis was attenuated. The intervention inhibited TGFβ receptor signaling, not TGF-β1 specifically. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn aged organisms, senescent cells can contribute to a variety of age-related pathologies, including pulmonary fibrosis, biliary liver damage, arteriosclerosis, retinopathy, osteoarthritis, dementia and diabetes mellitus.
“In aged organisms, senescent cells can contribute to a variety of age- related pathologies, including pulmonary fibrosis, biliary liver damage, arteriosclerosis, retinopathy, osteoarthritis, dementia and diabetes mellitus 13-19 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [18]
Cellular senescence plays crucial roles in a variety of physiological and pathological processes, including embryonic development, cancer, aging, and multiple other diseases.
“Cellular senescence, which was initially described by Leonard Hayflick and colleagues in 1961,1 plays crucial roles in a variety of physiological and pathological processes, including embryonic development, cancer, aging, and multiple other diseases.2,3,4,5,6,7”
From Identifying specific functional roles for senescence across cell types (2024) · cites this paper as [7]
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References 51 · Cited by 161
- Authors
- Ferreira-Gonzalez, S., Lu, W.-Y., Raven, A., Dwyer, B., Man, T. Y., O’Duibhir, E., Lewis, P. J. S., Campana, L., Kendall, T. J., Bird, T. G., Tarrats, N., Acosta, J.-C., Boulter, L., & Forbes, S. J.
- Affiliations
- MRC Centre for Regenerative Medicine (GB)
- Edinburgh Cancer Research (GB)
- Institute of Genetics and Cancer (GB)
- Corresponding author
- Forbes, Stuart J.
- ORCID
- Venue
- Nature Communications
- Published
- 2018-03-09
- Volume
- 9
- Issue
- 1
- Pages
- 1020-1020
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5844882
- OpenAlex
- W2790830382
- Cited by
- 161
- References
- 51
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 17 · 2023: 23 · 2022: 27 · 2021: 36 · 2020: 21 · 2019: 8 · 2018: 1
- FWCI
- 10.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (107492/Z/15/Z)
- Cancer Research UK (16243)
- UK Regenerative Medicine Platform (K026666, MR/K026666/1)
- Medical Research Council (MR/K026666, MR/P016839/1, MR/L012766/1, MR/K017047/1, MR/K026666/1)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- cellular senescence, biliary injury, cholangiocytes, TGF-beta signaling, macrophage recruitment, collagen deposition, liver regeneration, cholangiopathy, hepatocytes
- MeSH terms
- Animals, Bile Ducts, Cells, Cultured, Collagen, Disease Models, Animal, Female, Humans, Liver, Liver Cirrhosis, Biliary, Macrophages, Male, Mice, Inbred C57BL, Regeneration, Cholangitis, Sclerosing, Cellular Senescence, Mice, Knockout, Hepatocytes, Mice, Proto-Oncogene Proteins c-mdm2, Keratin-19, Transforming Growth Factor beta1, Myofibroblasts
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