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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TGF-β improves liver regeneration after injury by blocking paracrine senescence in neighbouring uninjured hepatocytes.
“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]
The Introduction says macrophage-derived TGFβ drives the spread of senescence between hepatocytes. The Results section on TGFβR1 inhibition reports that blocking TGFβ signaling—not TGFβ itself—reduced hepatocellular senescence and improved regeneration after acute liver injury. Page numbers are not provided in our copy. (LLM, conf=0.94)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredParacrine senescence contributes to liver dysfunction upon acetaminophen overdose.
“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
Individual SASP components, such as TGF-β, might be pinpointed as disease drivers and targeting them specifically might be appropriate.
“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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Cites
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Self-citationNOTCH1 mediates a switch between two distinct secretomes during senescence
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InfluentialHybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer
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Hepatic progenitor cells of biliary origin with liver repopulation capacity
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MethodSelf-citationOutcomes in Adults With Acute Liver Failure Between 1998 and 2013: An Observational Cohort Study
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Senescent Cardiac Fibroblast Is Critical for Cardiac Fibrosis after Myocardial Infarction
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Tumor Stroma-Derived TGF-β Limits Myc-Driven Lymphomagenesis via Suv39h1-Dependent Senescence
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The intestinal epithelium compensates for p53-mediated cell death and guarantees organismal survival
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Self-citationA rapid strategy to detect the recombined allele in LSL‐TβRICA transgenic mice
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- [51]Lu WY Bird TG Boulter L Tsuchiya A Cole AM Hay T Guest RV Wojtacha D Man TY Mackinnon A Ridgway RA Hepatic progenitor cells of biliary origin with liver repopulation capacity Nature cell biology 2015 PMC4612439 26192438
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Cellular senescence in ageing: from mechanisms to therapeutic opportunities
Di Micco, R., Krizhanovsky, V., Baker, D., & d’Adda di Fagagna, F. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00314-w · Cited by 2,277 · see citing works
Senescence and the SASP: many therapeutic avenues
Birch, J., & Gil, J. (2020) · Genes & Development · doi:10.1101/gad.343129.120 · Cited by 1,177 · see citing works
Liver regeneration: biological and pathological mechanisms and implications
Michalopoulos, G. K., & Bhushan, B. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-0342-4 · Cited by 998 · see citing works
TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019
Dewidar, B., Meyer, C., Dooley, S., & Meindl-Beinker, A. N. (2019) · Cells · doi:10.3390/cells8111419 · Cited by 837 · see citing works
“A number of hepatocytes undergo senescence upon acute acetaminophen (APAP) induced liver damage [253].”
BackgroundEvasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases
Hinz, B., & Lagares, D. (2019) · Nature Reviews Rheumatology · doi:10.1038/s41584-019-0324-5 · Cited by 616 · see citing works
Vizioli, M. G., Liu, T., Miller, K. N., Robertson, N. A., Gilroy, K., Lagnado, A. B., Perez-Garcia, A., Kiourtis, C., Dasgupta, N., Lei, X., et al. (2020) · Genes & Development · doi:10.1101/gad.331272.119 · Cited by 359 · see citing works
“Indeed, it has been recently shown that APAP-induced liver injury is also associated with the induction of senescent-like cells, reflected by SA-β-gal and γH2AX, and increased expression of p21 and p16, as well as growth arrest and expression of the SASP (Bird et al. 2018).”
InfluentialSelf-citationJin, S., He, D., Luo, D., Wang, Y., Yu, M.-G., Guan, B., Fu, Y., Li, Z.-X., Zhang, T., Zhou, Y.-H., et al. (2019) · ACS Nano · doi:10.1021/acsnano.9b00489 · Cited by 304 · see citing works
Liver regeneration and inflammation: from fundamental science to clinical applications
Campana, L., Esser, H., Huch, M., & Forbes, S. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00373-7 · Cited by 307 · see citing works
Self-citationA Senescence-Centric View of Aging: Implications for Longevity and Disease
Borghesan, M., Hoogaars, W. M. H., Varela-Eirin, M., Talma, N., & Demaria, M. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.07.002 · Cited by 267 · see citing works
Single-cell technologies in hepatology: new insights into liver biology and disease pathogenesis
Ramachandran, P., Matchett, K. P., Dobie, R., Wilson-Kanamori, J. R., & Henderson, N. C. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-0304-x · Cited by 253 · see citing works
Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury
Jaeschke, H., & Ramachandran, A. (2024) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-051122-094016 · Cited by 272 · see citing works
Li, M., Sun, X., Zhao, J., Xia, L., Li, J., Xu, M., Wang, B., Guo, H., Yu, C., Gao, Y., et al. (2020) · Cellular & Molecular Immunology · doi:10.1038/s41423-019-0279-0 · Cited by 225 · see citing works
“In addition to inflammatory resolution, hepatocyte regeneration is also critical for liver repair and recovery in ALF patients.(25,26) Here we also examined hepatocyte regeneration in both genotypes after APAP treatment.”
BackgroundSenescence as a therapeutic target in cancer and age-related diseases
McHugh, D., Durán, I., & Gil, J. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01074-4 · Cited by 199 · see citing works
“Treatment with TGFβR1 small molecule inhibitors (AZ12601011 or SB525334) reduced senescence and facilitated liver regeneration in a mouse model of liver poisoning by acetaminophen overdose 159 .”
Xiang, X., Feng, D., Hwang, S., Ren, T., Wang, X., Trojnar, E., Matyas, C., Mo, R., Shang, D., He, Y., et al. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2019.11.013 · Cited by 189 · see citing works
Hepatic stellate cell senescence in liver fibrosis: Characteristics, mechanisms and perspectives
Zhang, M., Salas, S. S., Damba, T., Borghesan, M., Demaria, M., & Moshage, H. J. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111572 · Cited by 180 · see citing works
Liver Regeneration after Acetaminophen Hepatotoxicity
Bhushan, B., & Apte, U. (2019) · The American Journal of Pathology · doi:10.1016/j.ajpath.2018.12.006 · Cited by 179 · see citing works
Self-citationTGF-β, EMT, and resistance to anti-cancer treatment
Wang, X., Eichhorn, P. J. A., & Thiery, J. P. (2023) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2023.10.004 · Cited by 180 · see citing works
Notch Signaling Mediates Secondary Senescence
Teo, Y. V., Rattanavirotkul, N., Olova, N., Salzano, A., Quintanilla, A., Tarrats, N., Kiourtis, C., Müller, M., Green, A. R., Adams, P. D., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.03.104 · Cited by 149 · see citing works
Self-citationCell therapy for advanced liver diseases: repair or rebuild
Dwyer, B. J., Macmillan, M. T., Brennan, P. N., & Forbes, S. J. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2020.09.014 · Cited by 141 · see citing works
Self-citationTGF-β signaling in intervertebral disc health and disease
Chen, S., Liu, S., Ma, K., Zhao, L., Lin, H., & Shao, Z. (2019) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2019.05.005 · Cited by 147 · see citing works
Immunomodulatory Role of the Extracellular Matrix Within the Liver Disease Microenvironment
McQuitty, C. E., Williams, R., Chokshi, S., & Urbani, L. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.574276 · Cited by 146 · see citing works
“org 5 predominantly in hepatocytes in vivo, and this was amplified and transmitted between hepatocytes in a feedback loop TGF-b1dependent produced by macrophages (68).”
BackgroundJin, S., Wang, Y., Wu, X., Li, Z., Zhu, L., Niu, Y., Zhou, Y., & Liu, Y. (2023) · Advanced Materials · doi:10.1002/adma.202211602 · Cited by 147 · see citing works
Dissecting Aging and Senescence—Current Concepts and Open Lessons
Schmeer, C. W., Kretz, A., Wengerodt, D., Stojiljkovic, M. R., & Witte, O. W. (2019) · Cells · doi:10.3390/cells8111446 · Cited by 148 · see citing works
“In contrast, senescence might also impede the regenerative liver response as exemplified in an acute acetaminofen-mediated injury model [133].”
BackgroundDuan, J., Ruan, B., Song, P., Fang, Z., Yue, Z., Liu, J., Dou, G., Han, H., & Wang, L. (2021) · Hepatology · doi:10.1002/hep.32209 · Cited by 145 · see citing works
“observed that TGFβ receptor 1 inhibition reduced hepatocellular senescence and enhanced liver regeneration.[16] The same group also found that cellular senescence deteriorated the biliary injury.”
BackgroundWhen dormancy fuels tumour relapse
Santos-de-Frutos, K., & Djouder, N. (2021) · Communications Biology · doi:10.1038/s42003-021-02257-0 · Cited by 140 · see citing works
TGF-β as A Master Regulator of Aging-Associated Tissue Fibrosis
Ren, L.-L., Miao, H., Wang, Y.-N., Liu, F., Li, P., & Zhao, Y.-Y. (2023) · Aging and disease · doi:10.14336/ad.2023.0222 · Cited by 139 · see citing works
Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics
Ma, X., Huang, T., Chen, X., Li, Q., Liao, M., Fu, L., Huang, J., Yuan, K., Wang, Z., & Zeng, Y. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02104-8 · Cited by 133 · see citing works
Li, S., Livingston, M. J., Ma, Z., Hu, X., Wen, L., Ding, H., Zhou, D., & Dong, Z. (2023) · JCI Insight · doi:10.1172/jci.insight.166643 · Cited by 130 · see citing works
“reported that inhibition of paracrine hepatocellular senescence after acute liver injury restored liver regeneration (40).”
Role of macrophage in intervertebral disc degeneration
Dou, Y., Zhang, Y., Liu, Y., Sun, X., Liu, X., Li, B., & Yang, Q. (2025) · Bone Research · doi:10.1038/s41413-024-00397-7 · Cited by 127 · see citing works
Cell senescence in liver diseases: pathological mechanism and theranostic opportunity
Sanfeliu-Redondo, D., Gibert-Ramos, A., & Gracia-Sancho, J. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-024-00913-4 · Cited by 117 · see citing works
“Liver-resident macrophages also participate in senescence spreading to bystander cells through TGFβ1 ligand 108 .”
InfluentialSenescent cells and macrophages: key players for regeneration?
Elder, S. S., & Emmerson, E. (2020) · Open Biology · doi:10.1098/rsob.200309 · Cited by 109 · see citing works
“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].”
BackgroundRitschka, B., Knauer-Meyer, T., Gonçalves, D. S., Mas, A., Plassat, J.-L., Durik, M., Jacobs, H., Pedone, E., Di Vicino, U., Cosma, M. P., et al. (2020) · Genes & Development · doi:10.1101/gad.332643.119 · Cited by 105 · see citing works
Cellular senescence as a potential mediator of COVID‐19 severity in the elderly
Nehme, J., Borghesan, M., Mackedenski, S., Bird, T. G., & Demaria, M. (2020) · Aging Cell · doi:10.1111/acel.13237 · Cited by 94 · see citing works
“SASP factors IL-6, IL-8, IL-1, and TNF-α might be crucial for chronic inflammation (Kumar et al., 2014; Tsuji et al., 2010), while TGF-β, PAI-1, and MMPs might contribute to fibrosis (Lomas et al., 2012) and stimulate the expression of fibrotic genes, such as ACTA2, COL1A1, COL1A2, and FN1, in surrounding non-senescen…”
BackgroundInfluentialSelf-citationHepatic senescence, the good and the bad
Huda, N., Liu, G., Hong, H., Yan, S., Khambu, B., & Yin, X.-M. (2019) · World Journal of Gastroenterology · doi:10.3748/wjg.v25.i34.5069 · Cited by 100 · see citing works
Huang, S., Wang, Y., Xie, S., Lai, Y., Mo, C., Zeng, T., Kuang, S., Deng, G., Zhou, C., Chen, Y., et al. (2022) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2022.02.009 · Cited by 97 · see citing works
“Macrophages are a known source of TGFb ligands, particularly in the context of tissue injury.(21) TGFb was expressed both by nonparenchymal cells and hepatocytes, in our study, we found that TGFb1 secreted by macrophages was largely increased with LPS/DGalN injection (Figure 7A).”
BackgroundResultInfluentialBeyond Tumor Suppression: Senescence in Cancer Stemness and Tumor Dormancy
Triana-Martínez, F., Loza, M. I., & Domínguez, E. (2020) · Cells · doi:10.3390/cells9020346 · Cited by 96 · see citing works
Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer
Gay, D. M., Ridgway, R. A., Müller, M., Hodder, M. C., Hedley, A., Clark, W. A., Leach, J. D. G., Jackstadt, R., Nixon, C., Huels, D. J., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-08586-3 · Cited by 94 · see citing works
Self-citationEngelmann, C., Habtesion, A., Hassan, M., Kerbert, A. J. C., Hammerich, L., Novelli, S., Fidaleo, M., Philips, A., Davies, N. A., Ferreira-González, S., et al. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.07.006 · Cited by 92 · see citing works
Self-citationTGFβ-Directed Therapeutics: 2020
Teicher, B. A. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107666 · Cited by 92 · see citing works
“TGFβR1 inhibition reduced hepatic senescence and enhanced liver regeneration (87).”
BackgroundSenescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2
Cheng, N., Kim, K.-H., & Lau, L. F. (2022) · JCI Insight · doi:10.1172/jci.insight.158207 · Cited by 87 · see citing works
“Indeed, senescence induced by cell type–specific deletion of Mdm2 in hepatocytes or cholangiocytes resulted in impaired regeneration (19, 20).”
Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ
Kiourtis, C., Terradas-Terradas, M., Gee, L., May, S., Γεωργακοπούλου, Α., Collins, A., O'Sullivan, E. D., Baird, D., Hassan, M., Shaw, R., et al. (2024) · Nature Cell Biology · doi:10.1038/s41556-024-01543-3 · Cited by 85 · see citing works
Self-citationEarly SRC activation skews cell fate from apoptosis to senescence
Anerillas, C., Herman, A. B., Rossi, M., Munk, R., Lehrmann, E., Martindale, J. L., Cui, C.-Y., Abdelmohsen, K., De, S., & Gorospe, M. (2022) · Science Advances · doi:10.1126/sciadv.abm0756 · Cited by 71 · see citing works
Evaluating causality of cellular senescence in non-alcoholic fatty liver disease
Meijnikman, A. S., Herrema, H., Scheithauer, T. P. M., Kroon, J., Nieuwdorp, M., & Groen, A. K. (2021) · JHEP Reports · doi:10.1016/j.jhepr.2021.100301 · Cited by 77 · see citing works
“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-”
BackgroundMolecular pathogenesis of acetaminophen-induced liver injury and its treatment options
Cai, X., Cai, H., Wang, J., Yang, Q., Guan, J., Deng, J., & Chen, Z. (2022) · Journal of Zhejiang University SCIENCE B · doi:10.1631/jzus.b2100977 · Cited by 78 · see citing works
“An improvement in the regen‐ eration and survival rate of hepatocytes in AILI mice is observed in the presence of TGF-β inhibi‐ tors or TGF-β receptor inhibitors (Bird et al., 2018).”
BackgroundRhoifolin ameliorates osteoarthritis via the Nrf2/NF-κB axis: in vitro and in vivo experiments.
Chen, H., Qin, J., Shi, H.-S., Li, Q., Zhou, S.-Q., & Chen, L.-B. (2022) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2022.01.009 · Cited by 66 · see citing works
Kiourtis, C., Wilczynska, A., Nixon, C., Clark, W. A., May, S., & Bird, T. G. (2021) · Biology Open · doi:10.1242/bio.058678 · Cited by 69 · see citing works
Self-citationA spatiotemporal atlas of cholestatic injury and repair in mice
Wu, B., Shentu, X., Nan, H., Guo, P., Hao, S., Xu, J., Shangguan, S., Cui, L., Cen, J., Deng, Q., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01687-w · Cited by 65 · see citing works
Yang, S., Liu, C., Jiang, M., Liu, X., Geng, L., Zhang, Y., Sun, S., Wang, K., Yin, J. B., Ma, S., et al. (2023) · Protein & Cell · doi:10.1093/procel/pwad039 · Cited by 64 · see citing works
“These senescent cells arise in the liver under pathological conditions that adversely affect liver function and tissue regeneration (Aravinthan et al., 2013; He and Sharpless, 2017; Bird et al., 2018; Sun et al., 2022).”
The Potential Role of Cellular Senescence in Non-Alcoholic Fatty Liver Disease
Engelmann, C., & Tacke, F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23020652 · Cited by 61 · see citing works
Cellular Senescence and Senotherapies in the Kidney: Current Evidence and Future Directions
Docherty, M. H., Baird, D., Hughes, J., & Ferenbach, D. A. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00755 · Cited by 63 · see citing works
“…been shown to be effective in animal models of biliary disease Frontiers in Pharmacology | www.frontiersin.org 13 and acute liver injury by blocking paracrine senescence leading to subsequent hepatocyte proliferation and improved liver function (Bird et al., 2018; Ferreira-Gonzalez et al., 2018).”
BackgroundRing, N., Valdivieso, K., Grillari, J., Redl, H. R., & Ogrodnik, M. B. (2022) · Developmental Cell · doi:10.1016/j.devcel.2022.04.005 · Cited by 57 · see citing works
Cellular Senescence in Liver Disease and Regeneration
Ferreira-González, S., Rodrigo‐Torres, D., Gadd, V. L., & Forbes, S. J. (2021) · Seminars in Liver Disease · doi:10.1055/s-0040-1722262 · Cited by 58 · see citing works
Self-citationNew aspects of hepatic endothelial cells in physiology and nonalcoholic fatty liver disease
Sun, X., & Harris, E. N. (2020) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00062.2020 · Cited by 58 · see citing works
Hu, C., Zhao, L., Wu, Z., & Li, L. (2020) · Stem Cell Research & Therapy · doi:10.1186/s13287-020-01596-9 · Cited by 58 · see citing works
Rizvi, F., Lee, Y., Díaz‐Aragon, R., Bawa, P., So, J., Florentino, R. M., Wu, S. Y., Sarjoo, A., Truong, E., Smith, A. R., et al. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.10.008 · Cited by 59 · see citing works
Different roles of interleukin 6 and interleukin 11 in the liver: implications for therapy
Widjaja, A. A., Chothani, S. P., & Cook, S. A. (2020) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2020.1761203 · Cited by 54 · see citing works
“strategy for treating acute and chronic liver disease has been proposed.(59,60) However, systemic and long-term inhibition of”
BackgroundJin, Y., Zhang, J., Xu, Y., Yi, K., Li, F., Zhou, H., Wang, H., Chan, H. F., Lao, Y.-H., Lv, S., et al. (2023) · Bioactive Materials · doi:10.1016/j.bioactmat.2023.05.001 · Cited by 55 · see citing works
“As most cells can be removed by macrophages or phagocytes after intrasplenic transplantation [41,43], and an inflammatory environment in the liver also impairs the viability of transplanted cells [31,44], Cu NZs@PLGA nanofibers integrated with dECM hydrogels were applied for in situ delivery of HLCs.”
BackgroundZhuge, A., Li, B., Yin, Y., Lv, L., Li, Y., Wu, J., Yang, L., Bian, X., Wang, K., Wang, Q., et al. (2020) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-020-10749-y · Cited by 54 · see citing works
“TGF-β is involved in senescence induction and regenerative responses in liver injury (Bird et al. 2018).”
BackgroundPeriodontal Disease and Senescent Cells: New Players for an Old Oral Health Problem?
Aquino-Martínez, R., Khosla, S., Farr, J. N., & Monroe, D. G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207441 · Cited by 54 · see citing works
“In agreement with this finding, it has been reported that TGF-β inhibition accelerates liver regeneration by inhibiting paracrine senescence [48].”
BackgroundLuo, J., Sun, T., Liu, Z., Liu, Y., Liu, J., Wang, S., Shi, X., & Zhou, H. (2025) · International Journal of Oral Science · doi:10.1038/s41368-025-00380-w · Cited by 56 · see citing works
Human Liver Regeneration: An Etiology Dependent Process
Haele, M. V., Snoeck, J., & Roskams, T. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092332 · Cited by 52 · see citing works
“illustrated that hepatocellular senescence was macrophage-derived transforming growth factor–β1 (TGFβ1) ligand-dependent and distributed through paracrine factors [33].”
BackgroundSelf-citationCellular senescence promotes progenitor cell expansion during axolotl limb regeneration
Yu, Q., Walters, H. E., Pasquini, G., Pal Singh, S., Lachnit, M., Oliveira, C. R., León-Periñán, D., Petzold, A., Kesavan, P., Subiran Adrados, C., et al. (2023) · Developmental Cell · doi:10.1016/j.devcel.2023.09.009 · Cited by 52 · see citing works
Barthet, V. J. A., Brucoli, M., Ladds, M. J. G. W., Nössing, C., Kiourtis, C., Baudot, A. D., O’Prey, J., Zunino, B., Müller, M., May, S., et al. (2021) · Science Advances · doi:10.1126/sciadv.abf9141 · Cited by 52 · see citing works
Self-citationTGF‐β signaling in liver metastasis
Marvin, D. L., Heijboer, R., ten Dijke, P., & Ritsma, L. (2020) · Clinical and Translational Medicine · doi:10.1002/ctm2.160 · Cited by 51 · see citing works
Polyploidy control in hepatic health and disease
Sladky, V. C., Eichin, F., Reiberger, T., & Villunger, A. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.06.030 · Cited by 49 · see citing works
NF‐κB/IKK activation by small extracellular vesicles within the SASP
Fafián‐Labora, J., & O’Loghlen, A. (2021) · Aging Cell · doi:10.1111/acel.13426 · Cited by 48 · see citing works
“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
Nakahara, Y., Hashimoto, N., Sakamoto, K., Enomoto, A., Adams, T. S., Yokoi, T., Omote, N., Poli, S., Ando, A., Wakahara, K., et al. (2021) · European Respiratory Journal · doi:10.1183/13993003.03397-2020 · Cited by 46 · see citing works
Signaling pathways of liver regeneration: Biological mechanisms and implications
Zhang, C., Sun, C., Zhao, Y., Ye, B., & Yu, G. (2023) · iScience · doi:10.1016/j.isci.2023.108683 · Cited by 48 · see citing works
“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 · see citing works
Spatial 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 · see citing works
“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 44 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
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 40 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
Self-citationEffects of senescence on the tumour microenvironment and response to therapy
Reynolds, L. E., Maallin, S., Haston, S., Martı́nez-Barberá, J. P., Hodivala‐Dilke, K., & Pedrosa, A. (2023) · FEBS Journal · doi:10.1111/febs.16984 · Cited by 40 · see citing works
“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 37 · see citing works
“(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…”
BackgroundSingle-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 · see citing works
“Senescent cells expressed typical SASP components as well as being enriched for transcripts of Notch and Tgf signalling pathways (Supplemental Figure 4) (21, 22).”
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 37 · see citing works
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 · see citing works
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 · see citing works
“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 39 · see citing works
Umbaugh, D. S., & Jaeschke, H. (2020) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2021.1857238 · Cited by 37 · see citing works
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 · see citing works
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 · see citing works
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 35 · see citing works
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 36 · see citing works
“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 · see citing works
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 32 · see citing works
“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 · see citing works
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 29 · see citing works
“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 30 · see citing works
“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 · see citing works
“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 26 · see citing works
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 · see citing works
Self-citationQian, Y., Zhao, J., Wu, H., & Kong, X. (2024) · Archives of Toxicology · doi:10.1007/s00204-024-03886-0 · Cited by 26 · see citing works
“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 27 · see citing works
“32 The severe acute hepatic necrosis present during ALF induces the spread of senescence to remaining viable hepatocytes, thus impairing hepatocyte-mediated regeneration.”
Background
- 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
- Health Sciences › Medicine › Physiology › 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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