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TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence
Open accessAbstract
Inhibiting acute injury–induced senescence mediated by TGFβ signaling in regenerative epithelium improves liver regeneration.
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“Similarly, transforming growth factor-β improves liver regeneration on injury by blocking paracrine senescence in neighbouring uninjured hepatocytes188.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [188]
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“While the role of paracrine senescence in cancer is yet undefined, it has been found to contribute to liver dysfunction upon acetaminophen overdose (Bird et al. 2018).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Bird et al. 2018
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“Other times, individual SASP components, such as TGF-β, might be pinpointed as disease drivers and targeting them specifically might be appropriate (Bird et al. 2018).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Bird et al. 2018
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“Through a variable set of cytokines and chemokines, paracrine senescence is induced and maintained through mechanisms which generate reactive oxygen species (ROS) and the DNA-damage response (DDR) [76].”
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Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ
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“senescence is also linked to the age-associated loss of the regenerative capacity in the liver after severe liver injury.(40,41) Following acute liver damage, senescence occurs in hepato-”
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“strategy for treating acute and chronic liver disease has been proposed.(59,60) However, systemic and long-term inhibition of”
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“illustrated that hepatocellular senescence was macrophage-derived transforming growth factor–β1 (TGFβ1) ligand-dependent and distributed through paracrine factors [33].”
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NF‐κB/IKK activation by small extracellular vesicles within the SASP
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“Thus, an alternative approach to prevent the detrimental effects of the evSASP could be to prevent its effect on the microenvironment and neighbouring cells as described in our study, approach which has been successfully used in a model of liver regeneration (Bird et al., 2018).”
MethodFibroblasts positive for meflin have anti-fibrotic properties in pulmonary fibrosis
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Signaling pathways of liver regeneration: Biological mechanisms and implications
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“Chen et al. 190 Bird et al. 191 Heo et al. 192 Activin signaling pathway Activin A, as a transcriptional target of KLF2, negatively regulated hepatocyte proliferation and LR. Manavski et al. 197 ActRIIB eliminated the effects of miR-194 on the proliferation of hepatocytes by promoting the…”
BackgroundSen, B., Rastogi, A., Nath, R., Shasthry, S. M., Pamecha, V., Pandey, S., Gupta, K. J., Sarin, S. K., Trehanpati, N., & Ramakrishna, G. (2019) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2019.03.001 · Cited by 43
Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis
O’Sullivan, E. D., Mylonas, K. J., Bell, R., Carvalho, C., Baird, D. P., Cairns, C., Gallagher, K. M., Campbell, R., Docherty, M., Laird, A., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.154124 · Cited by 43
“Senescent cells expressed typical SASP components as well as being enriched for transcripts of Notch and Tgf signalling pathways (Supplemental Figure 4) (21, 22).”
BackgroundSpatial resolution of cellular senescence dynamics in human colorectal liver metastasis
Garbarino, O., Lambroia, L., Basso, G., Marrella, V., Franceschini, B., Soldani, C., Pasqualini, F., Giuliano, D., Costa, G., Peano, C., et al. (2023) · Aging Cell · doi:10.1111/acel.13853 · Cited by 43
“In turn, c- MYC negatively regulates p15Ink4b and p21Cip1 expression (Baba et al., 2022; Bird et al., 2018; Senturk et al., 2010; Seoane & Gomis, 2017).”
BackgroundThe dichotomous role of TGF-β in controlling liver cancer cell survival and proliferation
Zhang, K., Zhang, M., Luo, Z., Wen, Z., & Yan, X. (2020) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2020.09.005 · Cited by 45
Cellular senescence in liver diseases: From molecular drivers to therapeutic targeting
Du, K., Umbaugh, D. S., Ren, N., & Diehl, A. M. (2025) · Journal of Hepatology · doi:10.1016/j.jhep.2025.08.021 · Cited by 42
Huang, S., Mo, C., Zeng, T., Lai, Y., Zhou, C., Xie, S., Chen, L.-M., Wang, Y., Chen, Y., Huang, S., et al. (2021) · Aging · doi:10.18632/aging.202409 · Cited by 41
“Moreover, a current study discovered that TGFβ signaling was activated in acute injury and that inhibition of TGFβR1 signaling reduced hepatocellular senescence by improving liver regeneration, function and outcome in acute liver injury [46].”
BackgroundRegion-specific cellular and molecular basis of liver regeneration after acute pericentral injury.
Wang, S., Wang, X., Shan, Y., Tan, Z., Su, Y., Cao, Y., Wang, S., Dong, J., Gu, J., & Wang, Y. (2024) · Cell Stem Cell · doi:10.1016/j.stem.2024.01.013 · Cited by 40
Humpton, T. J., Hall, H., Kiourtis, C., Nixon, C., Clark, W. A., Hedley, A., Shaw, R., Bird, T. G., Blyth, K., & Vousden, K. H. (2021) · Cell Death and Differentiation · doi:10.1038/s41418-021-00871-3 · Cited by 42
“However, robust activation of p21 has also been shown to promote senescence and to limit the regenerative response, and p21 loss can allow for survival after severe liver damage—suggesting that this arm of the p53 response may also impede liver regeneration [21, 23].”
BackgroundMethodSelf-citationSuda, K., Moriyama, Y., Razali, N., Chiu, Y., Masukagami, Y., Nishimura, K., Barbee, H., Takase, H., Sugiyama, S., Yamazaki, Y., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00575-6 · Cited by 43
“This was shown by the increase of p21-positive, p16-positive or SA-β-gal-positive cells in response to wounding 50–53 .”
Xing, Z., Zuo, Z., Hu, D., Zheng, X., Wang, X., Yuan, L., Zhou, L., Qi, F., & Yao, Z. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.09.015 · Cited by 38
Minnis-Lyons, S. E., Ferreira-González, S., Aleksieva, N., Man, T. Y., Gadd, V. L., Williams, M. J., Guest, R. V., Lu, W., Dwyer, B. J., Jamieson, T. J., et al. (2021) · Science Signaling · doi:10.1126/scisignal.aay9185 · Cited by 40
Self-citationEffects of senescence on the tumour microenvironment and response to therapy
Reynolds, L. E., Maallin, S., Haston, S., Martínez-Barberá, J. P., Hodivala‐Dilke, K., & Pedrosa, A. (2023) · FEBS Journal · doi:10.1111/febs.16984 · Cited by 42
“To enhance our understanding of the underlying pathways of senescence, the use of specific inhibitors and cell-type-specific transgenic models, with a focus on cell lineage tracing, would be highly informative [119,120].”
Pradhan‐Sundd, T., Kosar, K., Saggi, H., Zhang, R., Vats, R., Cornuet, P. K., Green, S., Singh, S., Zeng, G., Sundd, P., et al. (2019) · Hepatology · doi:10.1002/hep.30927 · Cited by 38
“(33) In addition to its pleiotropic roles in fibrosis and EMT, TGF-β also induces hepatocyte senescence in acute liver injury.(34) Loss of hepatocyte β-catenin causes up-regulation of TGF-β, loss of polarity, and increased inflammation, all of which contribute to an aberrant ductular response, a major cause of cellula…”
BackgroundLi, W., Zhu, X., Yuan, T., Wang, Z., Bian, Z., Jing, H., Shi, X., Chen, C., Fu, G., Huang, W., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aba5146 · Cited by 40
c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis
Leslie, J., Macia, M. G., Luli, S., Worrell, J. C., Reilly, W. J., Paish, H. L., Knox, A., Barksby, B. S., Gee, L., Zaki, M. Y. W., et al. (2020) · Nature Metabolism · doi:10.1038/s42255-020-00306-2 · Cited by 36
Self-citationLehmann, J., Narcisi, R., Franceschini, N., Chatzivasileiou, D., Boer, C. G., Koevoet, W. J. L. M., Putavet, D. A., Drabek, D., van Haperen, R., de Keizer, P. L. J., et al. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-04035-x · Cited by 35
“Since proinflammatory cytokines and TGFβ superfamily members are induced in response to tissue injury (reviewed in [115]), this mechanism might be particularly important during regenerative processes.”
BackgroundInfluentialAging, senescence, and cutaneous wound healing—a complex relationship
O’Reilly, S., Markiewicz, E., & Idowu, O. C. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1429716 · Cited by 41
Umbaugh, D. S., & Jaeschke, H. (2020) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2021.1857238 · Cited by 37
Carbon monoxide alleviates senescence in diabetic nephropathy by improving autophagy
Chen, L., Mei, G., Jiang, C., Cheng, X., Li, D., Zhao, Y., Chen, H., Wan, C., Yao, P., Gao, C., et al. (2021) · Cell Proliferation · doi:10.1111/cpr.13052 · Cited by 33
Context‐dependent roles of cellular senescence in normal, aged, and disease states
Moiseeva, V., Cisneros, A., Cobos, A. C., Tarrega, A. B., Oñate, C. S., Perdiguero, E., Serrano, A. L., & Muñoz‐Cánoves, P. (2023) · The FEBS Journal · doi:10.1111/febs.16573 · Cited by 34
Feng, Y., Zhang, X., Li, J., Fu, S., Xu, W., Liu, J., Yang, Y., Chen, T., Zhao, Y., Li, D., et al. (2024) · Theranostics · doi:10.7150/thno.103746 · Cited by 38
Cell therapy in end-stage liver disease: replace and remodel
Hu, X.-H., Chen, L., Wu, H., Tang, Y., Zheng, Q.-M., Wei, X., Wei, Q., Huang, Q., Chen, J., & Xu, X. (2023) · Stem Cell Research & Therapy · doi:10.1186/s13287-023-03370-z · Cited by 38
“They also secrete transforming growth factor-β (TGF-β), which causes hepatocytes in the liver to undergo replicative senescence, which is then transmitted to the transplanted cells [53].”
BackgroundHan, X., Zhang, T., Zhang, X., Zhang, R., Lao, K., Mi, Y., & Gou, X. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111347 · Cited by 33
Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis
Mukherjee, A., Epperly, M. W., Shields, D. S., Hou, W., Fisher, R., Hamade, D. F., Wang, H., Huq, M. S., Bao, R., Tabib, T., et al. (2021) · Cell Death Discovery · doi:10.1038/s41420-021-00741-4 · Cited by 33
“Targeted reduction of SASP, through TGF-β inhibition helps restore hepatocyte proliferation, decreases fibrosis, and improves, overall, liver function [47].”
BackgroundMaeso‐Díaz, R., Du, K., Pan, C. C., Guy, C. D., Oh, S., Chen, T., Wang, L., Ko, D. C., Tang, L., Dutta, R. K., et al. (2023) · Hepatology · doi:10.1097/hep.0000000000000401 · Cited by 30
Zhang, B., Meng, F., Liu, Y. Z., Yuan, Y., Wang, J., Wu, D., Cui, Y., Zhang, S., Guo, H., Liang, S., et al. (2021) · Theranostics · doi:10.7150/thno.52102 · Cited by 30
“It was reported that TGFβ inhibition restores regenerative response by suppressing senescence [40].”
BackgroundCellular Senescence in Hepatocellular Carcinoma: The Passenger or the Driver?
Cai, X., Guillot, A., & Liu, H. (2022) · Cells · doi:10.3390/cells12010132 · Cited by 31
“As a well-known medical compound, excessive paracetamol exposure may affect hepatocytes, which then upregulate senescenceassociated β-galactosidase (SA-β-gal), p21 and γH2AX [26].”
BackgroundInfluentialSenescence landscape in the liver following sepsis and senolytics as potential therapeutics
Lavarti, R., Cai, L., Alvarez‐Diaz, T., Medina‐Rodriguez, T., Bombin, S., & Raju, R. P. (2024) · Aging Cell · doi:10.1111/acel.14354 · Cited by 27
“Studies have also showed that the senes - cence process in acute liver injury may be therapeutically possible by SASP inhibition (Bird et al., 2018).”
Umbaugh, D. S., Nguyen, N. T., Smith, S. H., Ramachandran, A., & Jaeschke, H. (2024) · Toxicology · doi:10.1016/j.tox.2024.153804 · Cited by 27
Iron chelation as a new therapeutic approach to prevent senescence and liver fibrosis progression
Amengual, J., Alay, A., Vaquero, J., Gonzalez‐Sanchez, E., Bertrán, E., Sánchez, A., Herrera, B. M., Meyer, K. R., Maus, M., Serrano, M., et al. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-07063-0 · Cited by 27
Self-citationQian, Y., Zhao, J., Wu, H., & Kong, X. (2024) · Archives of Toxicology · doi:10.1007/s00204-024-03886-0 · Cited by 28
“Even after the current therapeutic window for APAP intoxication, TGFβR1 inhibition still can slow senescence and enhance liver regeneration (Bird et al. 2018).”
Human Hepatocyte Transplantation: Three Decades of Clinical Experience and Future Perspective
Nulty, J., Anand, H., & Dhawan, A. K. (2023) · Stem Cells Translational Medicine · doi:10.1093/stcltm/szad084 · Cited by 29
“32 The severe acute hepatic necrosis present during ALF induces the spread of senescence to remaining viable hepatocytes, thus impairing hepatocyte-mediated regeneration.”
Background
Metadata
- Authors
- Bird, T. G., Müller, M., Boulter, L., Vincent, D. F., Ridgway, R. A., Lopez-Guadamillas, E., Lu, W.-Y., Jamieson, T., Govaere, O., Campbell, A. D., Ferreira-Gonzalez, S., Cole, A. M., Hay, T., Simpson, K. J., Clark, W., Hedley, A., Clarke, M., Gentaz, P., Nixon, C., Bryce, S., Kiourtis, C., Sprangers, J., Nibbs, R. J. B., Van Rooijen, N., Bartholin, L., McGreal, S. R., Apte, U., Barry, S. T., Iredale, J. P., Clarke, A. R., Serrano, M., Roskams, T. A., Sansom, O. J., & Forbes, S. J.
- Affiliations
- MRC Centre for Regenerative Medicine (GB)
- Cancer Research UK Scotland Institute (GB)
- Spanish National Cancer Research Centre (ES)
- Universitair Ziekenhuis Leuven (BE)
- Medical Research Council (MRC) Centre for Regenerative Medicine, University of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SB, UK.
- Cardiff University (GB)
- University of Glasgow (GB)
- Vrije Universiteit Medical Center, Department of Molecular Cell Biology, Van der Boechorststraat 7, 1081 BT Amsterdam, Netherlands.
- Lyon 1 Université (FR)
- University of Kansas Medical Center (US)
- AstraZeneca (United Kingdom) (GB)
- University of Bristol (GB)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Bird, Thomas G.
- Clarke, Alan R.
- ORCID
- Bird, Thomas G.
- Müller, Miryam
- Boulter, Luke
- Vincent, David F.
- Ridgway, Rachel A.
- Lopez-Guadamillas, Elena
- Lu, Wei-Yu
- Jamieson, Thomas
- Govaere, Olivier
- Campbell, Andrew D.
- Ferreira-Gonzalez, Sofía
- Cole, Alicia M.
- Hay, Trevor
- Clark, William
- Hedley, Ann
- Clarke, Mairi
- Gentaz, Pauline
- Nixon, Colin
- Bryce, Steven
- Kiourtis, Christos
- Nibbs, Robert J. B.
- Van Rooijen, Nico
- Bartholin, Laurent
- McGreal, Steven R.
- Apte, Udayan
- Barry, Simon T.
- Iredale, John P.
- Clarke, Alan R.
- Serrano, Manuel
- Roskams, Tania A.
- Sansom, Owen J.
- Forbes, Stuart J.
- Venue
- Science Translational Medicine
- Published
- 2018-08-15
- Volume
- 10
- Issue
- 454
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC6420144
- OpenAlex
- W2887276938
- Cited by
- 261
- References
- 61
- Citations by year
- 2026: 16 · 2025: 34 · 2024: 47 · 2023: 42 · 2022: 31 · 2021: 28 · 2020: 37 · 2019: 24 · 2018: 2
- FWCI
- 14.26
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- other-oa
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- Edinburgh Research Explorer (University of Edinburgh) (publishedVersion, other-oa)
- Bristol Research (University of Bristol) (publishedVersion, other-oa)
- Explore Bristol Research (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- National Institutes of Health (R01 DK98414)
- Wellcome Trust (107492Z, 081604AIA)
- Medical Research Council (G1000868, G0900992)
- Cancer Research UK (2016-CRUK core running, A12481)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Keywords
- acute liver injury, liver regeneration, hepatocyte senescence, paracrine senescence, TGF-β1, acetaminophen toxicity, p21, macrophages, hepatocyte proliferation, acute liver failure
- MeSH terms
- Animals, Disease Models, Animal, Humans, Liver, Liver Regeneration, Macrophages, Male, Mice, Inbred C57BL, Necrosis, Signal Transduction, Transforming Growth Factor beta, Cellular Senescence, Paracrine Communication, Hepatocytes, Cyclin-Dependent Kinase Inhibitor p21
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