Replicative Senescence of Activated Human Hepatic Stellate Cells Is Accompanied by A Pronounced Inflammatory But Less Fibrogenic Phenotype
Open accessAbstract
Limited proliferative capacity is a characteristic of most normal human cells and results in a growth–arrested state, called replicative senescence . Functional expression of the telomerase catalytic subunit (human telomerase reverse transcriptase; hTERT) in human activated hepatic stellate cells (HSCs) rescues them from death with immortalization and maintains an activated HSC phenotype. The aim of this study was to evaluate alterations in gene and protein expression of in vitro aged human activated HSCs and to define the pathway by which senescent–activated HSCs are eliminated in culture. Altered patterns of gene expression in senescent human HSCs were assessed using DNA microarray analysis and compared with early passage HSCs or hTERT immortalized HSCs. Senescent HSCs showed higher expression of inflammation and stress–associated genes as compared with early passage HSCs. Senescent HSCs expressed reduced levels of extracellular matrix proteins, including collagens, tenascin, and fibronectin. TUNEL staining of senescent HSCs showed approximately 21% positive cells, indicating DNA fragmentation and apoptosis. Apoptosis involved the mitochondrial pathway with decreased levels of Bcl–2 and Bcl–x L protein, release of cytochrome c, and increased caspase–3 activity. In contrast, 4% to 5% of early activated HSCs or telomerase positive HSCs were TUNEL positive. In conclusion, cultured human HSCs undergo a switch from a fibrogenic to an inflammatory phenotype, suggesting that senescent human HSCs might modulate chronic wound healing processes. Maintenance of telomere length represents an important survival factor for activated human HSCs.
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These results provide a causal explanation for earlier findings showing that presence of senescent hepatic stellate cells correlates with increased inflammation but reduced fibrosis.
“These results provide a causal explanation for earlier findings showing that the presence of senescent hepatic stellate cells correlates with increased inflammation but reduced fibrosis (148).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [148]
The Results and Discussion report that senescent hepatic stellate cells in culture have a more inflammatory, less fibrogenic phenotype. They do not show that the presence of these cells in the liver correlates with increased inflammation and reduced fibrosis; the Discussion describes its comparison of human livers as preliminary gene-expression evidence, not that correlation. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn response to liver injury, hepatic stellate cells proliferate and produce extracellular matrixes for tissue repair before undergoing cellular senescence to prevent fibrosis.
“In response to liver injury, hepatic stellate cells (HSC) began to proliferate and produce extracellular matrixes for tissue repair before undergoing cellular senescence to prevent fibrosis.38, 39”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [38]
The paper’s introductory passage says that HSCs proliferate and secrete extracellular-matrix proteins following liver injury. The Discussion reports that activated human HSCs later become senescent in culture, and the Results show reduced collagen and fibronectin secretion in those cells. It does not establish that HSCs undergo senescence in injured livers to prevent fibrosis, or that their matrix production is specifically for tissue repair. (LLM, conf=0.88)
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Cites
WAF1, a potential mediator of p53 tumor suppression
El-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W., & Vogelstein, B. (1993) · Cell · doi:10.1016/0092-8674(93)90500-p · Cited by 8,321 · see citing works
A biomarker that identifies senescent human cells in culture and in aging skin in vivo.
Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., & Pereira-Smith, O. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.20.9363 · Cited by 7,477 · see citing works
Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death
Oltval, Z. N., Milliman, C. L., & Korsmeyer, S. J. (1993) · Cell · doi:10.1016/0092-8674(93)90509-o · Cited by 6,003 · see citing works
Prevention of Apoptosis by Bcl-2: Release of Cytochrome c from Mitochondria Blocked
Yang, J., Liu, X., Bhalla, K. N., Kim, C. N., Ibrado, A. M., Cai, J., Peng, T.-I., Jones, D. P., & Wang, X. (1997) · Science · doi:10.1126/science.275.5303.1129 · Cited by 4,913 · see citing works
Tumor suppressor p53 is a direct transcriptional activator of the human bax gene
Toshiyuki, M., & Reed, J. C. (1995) · Cell · doi:10.1016/0092-8674(95)90412-3 · Cited by 4,063 · see citing works
Telomere length predicts replicative capacity of human fibroblasts.
Allsopp, R. C., Vaziri, H., Patterson, C., Goldstein, S., Younglai, E. V., Futcher, A. B., Greider, C. W., & Harley, C. B. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.21.10114 · Cited by 2,200 · see citing works
Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo.
Miyashita, T., Krajewski, S., Krajewska, M., Wang, H., Lin, H., Liebermann, D. A., Hoffman‐Liebermann, B., & Reed, J. C. (1994) · PubMed · Cited by 2,143 · see citing works
Telomere Shortening and Tumor Formation by Mouse Cells Lacking Telomerase RNA
Blasco, M. A., Lee, H.-W., Hande, M. P., Samper, E., Lansdorp, P. M., DePinho, R. A., & Greider, C. W. (1997) · Cell · doi:10.1016/s0092-8674(01)80006-4 · Cited by 2,108 · see citing works
Bad, a heterodimeric partner for Bcl-xL and Bcl-2, displaces bax and promotes cell death
Yang, E., Zha, J., Jockel, J., Boise, L., Thompson, C. B., & Korsmeyer, S. J. (1995) · Cell · doi:10.1016/0092-8674(95)90411-5 · Cited by 2,101 · see citing works
Molecular Regulation of Hepatic Fibrosis, an Integrated Cellular Response to Tissue Injury
Friedman, S. L. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.4.2247 · Cited by 2,090 · see citing works
A novel form of Epstein-Barr virus latency in normal B cells in vivo
Miyashita, E. M., Yang, B., Lam, K. M. C., Crawford, D., & Thorley‐Lawson, D. A. (1995) · Cell · doi:10.1016/0092-8674(95)90513-8 · Cited by 1,591 · see citing works
Bax directly induces release of cytochrome c from isolated mitochondria
Jürgensmeier, J. M., Xie, Z., Deveraux, Q. L., Ellerby, L., Bredesen, D. E., & Reed, J. C. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.9.4997 · Cited by 1,523 · see citing works
Iredale, J. P., Benyon, R. C., Pickering, J., McCullen, M., Northrop, M., Pawley, S., Hovell, C., & Arthur, M. J. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1018 · Cited by 1,075 · see citing works
Chin, L., Artandi, S. E., Shen, Q., Tam, A., Lee, S.-L., Gottlieb, G. J., Greider, C. W., & DePinho, R. A. (1999) · Cell · doi:10.1016/s0092-8674(00)80762-x · Cited by 979 · see citing works
Narita, M., Shimizu, S., Ito, T., Chittenden, T., Lutz, R. J., Matsuda, H., & Tsujimoto, Y. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.25.14681 · Cited by 933 · see citing works
Structure and variability of human chromosome ends.
de Lange, T., Shiue, L., Myers, R. M., Cox, D. R., Naylor, S. L., Killery, A. M., & Varmus, H. E. (1990) · Molecular and Cellular Biology · doi:10.1128/mcb.10.2.518 · Cited by 848 · see citing works
Microarray analysis of replicative senescence
Shelton, D. N., Chang, E., Whittier, P. S., Choi, D., & Funk, W. D. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80420-5 · Cited by 764 · see citing works
Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts
von Zglinicki, T., Pilger, R., & Sitte, N. (2000) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(99)00207-5 · Cited by 546 · see citing works
Extracellular Matrix Degradation and the Role of Hepatic Stellate Cells
Benyon, R. C., & Arthur, M. J. P. (2001) · Seminars in Liver Disease · doi:10.1055/s-2001-17552 · Cited by 489 · see citing works
Maher, J. J., & McGuire, R. F. (1990) · Journal of Clinical Investigation · doi:10.1172/jci114886 · Cited by 426 · see citing works
Genes involved in senescence and immortalization
Lundberg, A. S., Hahn, W. C., Gupta, P., & Weinberg, R. A. (2000) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00155-1 · Cited by 313 · see citing works
Increased toxin-induced liver injury and fibrosis in interleukin-6-deficient mice
Kovalovich, K., DeAngelis, R. A., Li, W., Furth, E. E., Ciliberto, G., & Taub, R. (2000) · Hepatology · doi:10.1002/hep.510310123 · Cited by 298 · see citing works
Reversibility of Hepatic Fibrosis in Autoimmune Hepatitis
Dufour, J., DeLellis, R., & Kaplan, M. M. (1997) · Annals of Internal Medicine · doi:10.7326/0003-4819-127-11-199712010-00006 · Cited by 292 · see citing works
Leukocyte transendothelial migration: orchestrating the underlying molecular machinery
Worthylake, R. A., & Burridge, K. (2001) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00253-2 · Cited by 281 · see citing works
The Role of Smad3 in Mediating Mouse Hepatic Stellate Cell Activation
Schnabl, B., Kweon, Y. O., Frederick, J. P., Wang, X.-F., Rippe, R. A., & Brenner, D. A. (2001) · Hepatology · doi:10.1053/jhep.2001.25349 · Cited by 258 · see citing works
Self-citationSheron, N., Bird, G. L. A., Koskinas, J. S., Portmann, B. C., Ceska, M., Lindley, I., & William, R. (1993) · Hepatology · doi:10.1002/hep.1840180108 · Cited by 211 · see citing works
Posttranscriptional Regulation of Collagen α1(I) mRNA in Hepatic Stellate Cells
Stefanovic, B., Hellerbrand, C., Holčı́k, M., Briendl, M., Aliebhaber, S., & Brenner, D. A. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.9.5201 · Cited by 204 · see citing works
Self-citationTrim, N., Morgan, S., Evans, M. L., Issa, R., Fine, D. R., Afford, S. C., Wilkins, B. S., & Iredale, J. P. (2000) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64994-2 · Cited by 187 · see citing works
Saile, B., Knittel, T. E., Matthes, N., Schott, P., & Ramadori, G. P. (1997) · Europe PMC (PubMed Central) · Cited by 177 · see citing works
Greenwel, P., Rubin, J. B., Schwartz, M., Hertzberg, E. L., & Rojkind, M. (1993) · PubMed · Cited by 173 · see citing works
Hellerbrand, C., Jobin, C., Iimuro, Y., Licato, L. L., Sartor, R. B., & Brenner, D. A. (1998) · Hepatology · doi:10.1002/hep.510270514 · Cited by 170 · see citing works
Self-citationKweon, Y.-O., Goodman, Z. D., Dienstag, J. L., Schiff, E. R., Brown, N. A., Burkhardt, E., Schoonhoven, R., Brenner, D. A., & Fried, M. W. (2001) · Journal of Hepatology · doi:10.1016/s0168-8278(01)00218-5 · Cited by 168 · see citing works
Self-citationRegulation and function of the CXC chemokine ENA-78 in monocytes and its role in disease
Walz, A., Schmutz, P., Mueller, C., & Schnyder‐Candrian, S. (1997) · Journal of Leukocyte Biology · doi:10.1002/jlb.62.5.604 · Cited by 158 · see citing works
Schwabe, R. F., Schnabl, B., Kweon, Y. O., & Brenner, D. A. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.11.6812 · Cited by 155 · see citing works
Self-citationFunk, W. D., Wang, C. K., Shelton, D. N., Harley, C. B., Pagon, G. D., & Hoeffler, W. K. (2000) · Experimental Cell Research · doi:10.1006/excr.2000.4945 · Cited by 154 · see citing works
Expression of Intracellular Adhesion Molecule 1 by Activated Hepatic Stellate Cells
Hellerbrand, C., Wang, S. C., Tsukamoto, H., Brenner, D. A., & Rippe, R. A. (1996) · Hepatology · doi:10.1002/hep.510240333 · Cited by 152 · see citing works
Self-citationKaplan, M. M., DeLellis, R. A., & Wolfe, H. J. (1997) · Annals of Internal Medicine · doi:10.7326/0003-4819-126-9-199705010-00002 · Cited by 132 · see citing works
TAK1/JNK and p38 have opposite effects on rat hepatic stellate cells
Schnabl, B., Bradham, C. A., Bennett, B. L., Manning, A. M., Stefanovic, B., & Brenner, D. A. (2001) · Hepatology · doi:10.1053/jhep.2001.28790 · Cited by 129 · see citing works
Self-citationReversibility of hepatic fibrosis in experimentally induced cholestasis in rat.
Abdelaziz, G., Lebeau, G., Rescan, P., Clément, B., Rissel, M., Deugnier, Y., Campion, J. P., & Guillouzo, A. (1990) · Europe PMC (PubMed Central) · Cited by 124 · see citing works
Expression and Regulation of Cell Adhesion Molecules by Hepatic Stellate Cells (HSC) of Rat Liver
Knittel, T. E., Dinter, C., Kobold, D., Neubauer, K., Mehde, M., Eichhorst, S. T., & Ramadori, G. P. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65262-5 · Cited by 124 · see citing works
Natsume, M., Tsuji, H., Harada, A., Akiyama, M., Yano, T., Ishikura, H., Nakanishi, I., Matsushima, K., Kaneko, S., & Mukaida, N. (1999) · Journal of Leukocyte Biology · doi:10.1002/jlb.66.4.601 · Cited by 119 · see citing works
Immortal Activated Human Hepatic Stellate Cells Generated by Ectopic Telomerase Expression
Schnabl, B., Choi, Y. H., Olsen, J. C., Hagedorn, C. H., & Brenner, D. A. (2002) · Laboratory Investigation · doi:10.1038/labinvest.3780426 · Cited by 119 · see citing works
Self-citationResistance to apoptosis in human cells conferred by telomerase function and telomere stability
Holt, S. E., Glinsky, V. V., Ivanova, A. B., & Glinsky, G. V. (1999) · Molecular Carcinogenesis · doi:10.1002/(sici)1098-2744(199908)25:4 · Cited by 118 · see citing works
Regression of Hepatic Fibrosis in Hepatitis C with Long-Term Interferon Treatment
Dufour, J., Delellis, R., & Kaplan, M. M. (1998) · Digestive Diseases and Sciences · doi:10.1023/a:1026601904609 · Cited by 114 · see citing works
A novel role for α3β1 integrins in extracellular matrix assembly
Wu, C., Chung, A. E., & McDonald, J. A. (1995) · Journal of Cell Science · doi:10.1242/jcs.108.6.2511 · Cited by 102 · see citing works
Gong, W., Pecci, A., Roth, S., Lahme, B., Beato, M., & Gressner, A. M. (1998) · Hepatology · doi:10.1002/hep.510280229 · Cited by 99 · see citing works
Regulatory Role of the Conserved Stem-Loop Structure at the 5′ End of Collagen α1(I) mRNA
Stefanovic, B., Hellerbrand, C., & Brenner, D. A. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.6.4334 · Cited by 97 · see citing works
Self-citationMaher, J. J., Lozier, J. S., & Scott, M. K. (1998) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.1998.275.4.g847 · Cited by 82 · see citing works
Iwamoto, H., Sakai, H., Tada, S., Nakamuta, M., & Nawata, H. (1999) · Journal of Laboratory and Clinical Medicine · doi:10.1016/s0022-2143(99)90057-4 · Cited by 59 · see citing works
Senoo, H., Imai, K., SATO, M., Kojima, N., Miura, M., & Hata, R. (1996) · Cell Biology International · doi:10.1006/cbir.1996.0065 · Cited by 53 · see citing works
Inhibition of Collagen α1(I) Expression by the 5′ Stem-Loop as a Molecular Decoy
Stefanovic, B., Schnabl, B., & Brenner, D. A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m108065200 · Cited by 49 · see citing works
Self-citationStefanovic, B., & Brenner, D. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209175200 · Cited by 42 · see citing works
Self-citationZhang, J., Gruber, B. L., Marchese, M. J., Zucker, S., Schwartz, L. B., & Kew, R. R. (1999) · Journal of Cellular Physiology · doi:10.1002/(sici)1097-4652(199911)181:2 · Cited by 16 · see citing works
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- [30]30. Burns TF, El-Deiry WS. The p53 pathway and apoptosis. J Cell Physiol 1999;181:231-239.
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Hepatocellular Carcinoma: Epidemiology and Molecular Carcinogenesis
El‐Serag, H. B., & Rudolph, K. L. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.04.061 · Cited by 5,401 · see citing works
The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206 · see citing works
Aging, Cellular Senescence, and Cancer
Campisi, J. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-030212-183653 · Cited by 2,954 · see citing works
Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver
Friedman, S. L. (2008) · Physiological Reviews · doi:10.1152/physrev.00013.2007 · Cited by 2,842 · see citing works
Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome
Yoshimoto, S., Loo, T. M., Atarashi, K., Kanda, H., Sato, S., Oyadomari, S., Iwakura, Y., Oshima, K., Morita, H., Hattori, M., et al. (2013) · Nature · doi:10.1038/nature12347 · Cited by 2,219 · see citing works
Oncogene-Induced Senescence Relayed by an Interleukin-Dependent Inflammatory Network
Kuilman, T., Michaloglou, C., Vredeveld, L. C. W., Douma, S., van Doorn, R., Desmet, C. J., Aarden, L. A., Mooi, W. J., & Peeper, D. S. (2008) · Cell · doi:10.1016/j.cell.2008.03.039 · Cited by 2,086 · see citing works
“This is consistent with previous reports on expression of interleukins, including IL-6 and IL-8, being increased in senescent cells (Mason et al., 2004; Schnabl et al., 2003), and these reports also indicate that this is seen for different cell types and for oncogenes in addition to BRAF.”
ResultSenescence of activated stellate cells limits liver fibrosis
Krizhanovsky, V., Yon, M., Dickins, R. A., Hearn, S., Simon, J., Miething, C., Yee, H., Zender, L., & Lowe, S. W. (2008) · Cell · doi:10.1016/j.cell.2008.06.049 · Cited by 2,029 · see citing works
Molecular and cellular mechanisms of liver fibrosis and its regression
Kisseleva, T., & Brenner, D. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-00372-7 · Cited by 2,024 · see citing works
Self-citationSenescence of Activated Stellate Cells Limits Liver Fibrosis
Krizhanovsky, V., Yon, M., Dickins, R. A., Hearn, S., Simon, J., Miething, C., Yee, H., Zender, L., & Lowe, S. W. (2008) · Cell · doi:10.1016/j.cell.2008.09.015 · Cited by 2,027
Hepatic stellate cells as key target in liver fibrosis
Higashi, T., Friedman, S. L., & Hoshida, Y. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.05.007 · Cited by 1,485 · see citing works
Senolytic CAR T cells reverse senescence-associated pathologies
Amor, C., Feucht, J., Leibold, J., Ho, Y.-J., Zhu, C., Alonso-Curbelo, D., Mansilla-Soto, J., Boyer, J. A., Li, X., Giavridis, T., et al. (2020) · Nature · doi:10.1038/s41586-020-2403-9 · Cited by 1,098 · see citing works
Hepatic Stellate Cells and Liver Fibrosis
Puche, J. E., Saiman, Y., & Friedman, S. L. (2013) · Comprehensive physiology · doi:10.1002/cphy.c120035 · Cited by 736 · see citing works
Apoptosis: The nexus of liver injury and fibrosis
Canbay, A. E., Friedman, S. L., & Gores, G. J. (2004) · Hepatology · doi:10.1002/hep.20051 · Cited by 529 · see citing works
Strategies for targeting senescent cells in human disease
Gasek, N. S., Kuchel, G. A., Kirkland, J. L., & Xu, M. (2021) · Nature Aging · doi:10.1038/s43587-021-00121-8 · Cited by 501 · see citing works
Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice
Kong, X., Feng, D., Wang, H., Hong, F., Bertola, A., Wang, F.-S., & Gao, B. (2012) · Hepatology · doi:10.1002/hep.25744 · Cited by 448 · see citing works
Mechanisms of liver fibrosis and its role in liver cancer
Dhar, D., Baglieri, J., Kisseleva, T., & Brenner, D. A. (2020) · Experimental Biology and Medicine · doi:10.1177/1535370219898141 · Cited by 440 · see citing works
Self-citationAydin, M. M., & Akçalı, K. C. (2018) · The Turkish Journal of Gastroenterology · doi:10.5152/tjg.2018.17330 · Cited by 388 · see citing works
Evolving Concepts in the Pathogenesis of NASH: Beyond Steatosis and Inflammation
Peverill, W., Powell, L. W., & Skoien, R. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms15058591 · Cited by 380 · see citing works
Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases
Gao, B., Radaeva, S., & Park, O. (2009) · Journal of Leukocyte Biology · doi:10.1189/jlb.0309135 · Cited by 380 · see citing works
Salminen, A., Ojala, J., Kaarniranta, K., Haapasalo, A., Hiltunen, M., & Soininen, H. (2011) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2011.07738.x · Cited by 333 · see citing works
Recent advancement of molecular mechanisms of liver fibrosis
Seki, E., & Brenner, D. A. (2015) · Journal of Hepato-Biliary-Pancreatic Sciences · doi:10.1002/jhbp.245 · Cited by 299 · see citing works
Self-citationHepatic stellate cells and the reversal of fibrosis
Kisseleva, T., & Brenner, D. A. (2006) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2006.04584.x · Cited by 280 · see citing works
Self-citationWidjaja, A. A., Singh, B. K., Adami, E., Viswanathan, S., Dong, J., D’Agostino, G. A., Ng, B., Lim, W., Tan, J., Paleja, B. S., et al. (2019) · Gastroenterology · doi:10.1053/j.gastro.2019.05.002 · Cited by 276 · see citing works
Guo, C., Pan, Q., Li, D., Sun, H., & Liu, B. (2009) · Journal of Hepatology · doi:10.1016/j.jhep.2008.11.025 · Cited by 279 · see citing works
Tanwar, S., Rhodes, F., Srivastava, A., Trembling, P. M., & Rosenberg, W. M. (2020) · World Journal of Gastroenterology · doi:10.3748/wjg.v26.i2.109 · Cited by 253 · see citing works
Ramakrishna, G., Rastogi, A., Trehanpati, N., Sen, B., Khosla, R., & Sarin, S. K. (2013) · Liver Cancer · doi:10.1159/000343852 · Cited by 237 · see citing works
Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells
Wobser, H., Dorn, C., Weiß, T. S., Amann, T., Bollheimer, C., Büttner, R., Schölmerich, J., & Hellerbrand, C. (2009) · Cell Research · doi:10.1038/cr.2009.73 · Cited by 235 · see citing works
Cellular Senescence: Molecular Mechanisms, In Vivo Significance, and Redox Considerations
Müller, M. K. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2008.2104 · Cited by 237 · see citing works
Loo, T. M., Miyata, K., Tanaka, Y., & Takahashi, A. (2020) · Cancer Science · doi:10.1111/cas.14266 · Cited by 232 · see citing works
The ECM path of senescence in aging: components and modifiers
Levi, N., Papismadov, N., Solomonov, I., Sagi, I., & Krizhanovsky, V. (2020) · FEBS Journal · doi:10.1111/febs.15282 · Cited by 221 · see citing works
Severino, V, Alessio, N., Farina, A., Sandomenico, A., Cipollaro, M., Peluso, G., Galderisi, U., & Chambery, A. (2013) · Cell Death & Disease · doi:10.1038/cddis.2013.445 · Cited by 214 · see citing works
Li, F., Huangyang, P., Burrows, M., Guo, K., Riscal, R., Godfrey, J. T., Lee, K. E., Lin, N., Lee, P., Blair, I. A., et al. (2020) · Nature Cell Biology · doi:10.1038/s41556-020-0511-2 · Cited by 211 · see citing works
Immunosurveillance of senescent cells: the bright side of the senescence program
Sagiv, A., & Krizhanovsky, V. (2013) · Biogerontology · doi:10.1007/s10522-013-9473-0 · Cited by 208 · see citing works
Hepatic fibrosis: It is time to go with hepatic stellate cell-specific therapeutic targets
Ezhilarasan, D., Sokal, E., & Najimi, M. (2018) · Hepatobiliary & Pancreatic Diseases International · doi:10.1016/j.hbpd.2018.04.003 · Cited by 204 · see citing works
Akkız, H., Gieseler, R. K., & Canbay, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25147873 · Cited by 191 · see citing works
Cellular and molecular mechanisms in liver fibrogenesis
Novo, E., Cannito, S., Paternostro, C., Bocca, C., Miglietta, A., & Parola, M. (2014) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2014.02.015 · Cited by 190 · see citing works
Astrocyte senescence promotes glutamate toxicity in cortical neurons
Limbad, C., Oron, T. R., Alimirah, F., Davalos, A. R., Tracy, T. E., Gan, L., Desprez, P.-Y., & Campisi, J. (2020) · PLOS ONE · doi:10.1371/journal.pone.0227887 · Cited by 183 · see citing works
Adachi, M., & Brenner, D. A. (2008) · Hepatology · doi:10.1002/hep.21991 · Cited by 182 · see citing works
Self-citationHepatic 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
Carloni, V., Luong, T. V., & Rombouts, K. (2014) · Liver International · doi:10.1111/liv.12465 · Cited by 174 · see citing works
Valdes, A. M., Richards, J. B., Gardner, J. P., Swaminathan, R., Kimura, M., Xiaobin, L., Aviv, A., & Spector, T. D. (2007) · Osteoporosis International · doi:10.1007/s00198-007-0357-5 · Cited by 164 · see citing works
Novo, E., Marra, F., Zamara, E., di Bonzo, L. V., Monitillo, L., Cannito, S., Petrai, I., Mazzocca, A., Bonacchi, A., Franco, R. S. M. D., et al. (2006) · Gut · doi:10.1136/gut.2005.082701 · Cited by 167 · see citing works
Natural killer and natural killer T cells in liver fibrosis
Gao, B., & Radaeva, S. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2012.09.008 · Cited by 158 · see citing works
Fibrosis Regression After Eradication of Hepatitis C Virus: From Bench to Bedside
Rockey, D. C., & Friedman, S. L. (2021) · Gastroenterology · doi:10.1053/j.gastro.2020.09.065 · Cited by 155 · see citing works
Adachi, M., Osawa, Y., Uchinami, H., Kitamura, T., Accili, D., & Brenner, D. A. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.01.033 · Cited by 155 · see citing works
Self-citationFriend or foe? The elusive role of hepatic stellate cells in liver cancer
Cogliati, B., Yashaswini, C. N., Wang, S., Sia, D., & Friedman, S. L. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00821-z · Cited by 157 · see citing works
Inflammatory signaling and cellular senescence
Ren, J., Pan, J., Lu, Y.-P., Sun, P., & Han, J. (2008) · Cellular Signalling · doi:10.1016/j.cellsig.2008.10.011 · Cited by 149 · see citing works
Hepatocellular carcinoma in nonalcoholic fatty liver: role of environmental and genetic factors
Dongiovanni, P. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i36.12945 · Cited by 145 · see citing works
Biomarkers to identify and isolate senescent cells
Matjusaitis, M., Chin, G., Sarnoski, E. A., & Stolzing, A. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.05.003 · Cited by 144 · see citing works
Jin, H., Lian, N., Zhang, F., Chen, L., Chen, Q., Lu, C., Bian, M., Shao, J., Wu, L., & Zheng, S. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.92 · Cited by 143 · see citing works
Liver Myofibroblasts Regulate Infiltration and Positioning of Lymphocytes in Human Liver
Holt, A. P., Shepherd, E. L., Lalor, P. F., Filer, A. D., Buckley, C. D., & Adams, D. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.10.020 · Cited by 140 · see citing works
Cellular senescence, ageing and disease
Burton, D. G. A. (2008) · AGE · doi:10.1007/s11357-008-9075-y · Cited by 135 · see citing works
Human hepatic stellate cell isolation and characterization
Shang, L., Hosseini, M., Liu, X., Kisseleva, T., & Brenner, D. A. (2017) · Journal of Gastroenterology · doi:10.1007/s00535-017-1404-4 · Cited by 126 · see citing works
Self-citationp53-Dependent ICAM-1 overexpression in senescent human cells identified in atherosclerotic lesions
Gorgoulis, V. G., Pratsinis, H., Zacharatos, P., Demoliou, C., Sigala, F., Asimacopoulos, P. J., Papavassiliou, A. G., & Kletsas, D. (2005) · Laboratory Investigation · doi:10.1038/labinvest.3700241 · Cited by 122 · see citing works
Stellate cells: A moving target in hepatic fibrogenesis†
Friedman, S. L. (2004) · Hepatology · doi:10.1002/hep.20476 · Cited by 120 · see citing works
Chimeric antigen receptor-modified macrophages ameliorate liver fibrosis in preclinical models
Dai, H., Zhu, C., Huai, Q., Xu, W., Zhu, J., Zhang, X., Zhang, X., Sun, B., Xu, H., Zheng, M., et al. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.01.034 · Cited by 114 · 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
Herrmann, J., Gressner, A. M., & Weiskirchen, R. (2007) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2007.00060.x · Cited by 113 · see citing works
Kong, X., Feng, D., Mathews, S., & Gao, B. (2013) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.12032 · Cited by 108 · see citing works
Liver organoid as a 3D in vitro model for drug validation and toxicity assessment
Brooks, A., Liang, X., Zhang, Y., Zhao, C., Roberts, M. S., Wang, H., Zhang, L., & Crawford, D. H. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105608 · Cited by 109 · see citing works
Immune Interactions in Hepatic Fibrosis
Holt, A. P., Salmon, M., Buckley, C. D., & Adams, D. (2008) · Clinics in Liver Disease · doi:10.1016/j.cld.2008.07.002 · Cited by 101 · see citing works
Lade, A. G., Noon, L. A., & Friedman, S. L. (2013) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000042 · Cited by 100 · see citing works
Prestigiacomo, V., Weston, A. A., Messner, S., Lampart, F. L., & Suter‐Dick, L. (2017) · PLoS ONE · doi:10.1371/journal.pone.0179995 · Cited by 100 · see citing works
The phenotypic fate and functional role for bone marrow-derived stem cells in liver fibrosis
Kisseleva, T., & Brenner, D. A. (2011) · Journal of Hepatology · doi:10.1016/j.jhep.2011.09.021 · Cited by 93 · see citing works
Self-citationNovo, E., Marra, F., Zamara, E., di Bonzo, L. V., Caligiuri, A., Cannito, S., Antonaci, C., Colombatto, S., Pinzani, M., & Parola, M. (2005) · Gut · doi:10.1136/gut.2005.069633 · Cited by 93 · see citing works
The role of senescence in cancer development
Mavrogonatou, E., Pratsinis, H., & Kletsas, D. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.06.018 · Cited by 92 · see citing works
Morgillo, F., Dallio, M., Corte, C. M. D., Gravina, A. G., Viscardi, G., Loguercio, C., Ciardiello, F., & Federico, A. (2018) · Neoplasia · doi:10.1016/j.neo.2018.05.002 · Cited by 94 · see citing works
Hepatic Stellate Cells and Liver Fibrosis
Puche, J. E., Saiman, Y., & Friedman, S. L. (2013) · Comprehensive Physiology · doi:10.1002/j.2040-4603.2013.tb00529.x · Cited by 89 · see citing works
Defining therapeutic targets for liver fibrosis: Exploiting the biology of inflammation and repair
Iredale, J. P. (2008) · Pharmacological Research · doi:10.1016/j.phrs.2008.06.011 · Cited by 80 · see citing works
Paik, Y., Lee, K. S., Lee, H. J., Yang, K. M., Lee, S. J., Lee, D. K., Han, K., Chon, C. Y., Lee, S. I., Moon, Y. M., et al. (2006) · Laboratory Investigation · doi:10.1038/labinvest.3700422 · Cited by 80 · see citing works
Self-citationMetabolic Reprogramming of Liver Fibrosis
Delgado, M. E., Cárdenas, B., Farran, N., & Fernández, M. (2021) · Cells · doi:10.3390/cells10123604 · Cited by 73 · see citing works
M2 Kupffer Cells Promote Hepatocyte Senescence
Wan, J., Benkdane, M., Alons, E., Lotersztajn, S., & Pavoine, C. (2014) · American Journal Of Pathology · doi:10.1016/j.ajpath.2014.02.014 · Cited by 72 · see citing works
Sarkar, D., Lebedeva, I., Emdad, L., Kang, D., Baldwin, A., & Fisher, P. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1772 · Cited by 41 · see citing works
Cyclin D1 Activity Regulates Autophagy and Senescence in the Mammary Epithelium
Brown, N. E., Jeselsohn, R. M., Bihani, T., Hu, M. G., Foltopoulou, P. F., Kuperwasser, C., & Hinds, P. W. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-4139 · Cited by 72 · see citing works
Peroxisome proliferator-activated receptors in the pathogenesis and therapies of liver fibrosis
Han, X., Wu, Y., Yang, Q., & Cao, G. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107791 · Cited by 71 · see citing works
Obesity and Cancer: A Gut Microbial Connection
Ohtani, N., Yoshimoto, S., & Hara, E. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-3501 · Cited by 70 · see citing works
Premature aging/senescence in cancer cells facing therapy: good or bad?
Calvo, L., Ghadaouia, S., Martinez, A., & Rodier, F. (2015) · Biogerontology · doi:10.1007/s10522-015-9593-9 · Cited by 71 · see citing works
The immune landscape in nonalcoholic steatohepatitis
Narayanan, S., Surette, F. A., & Hahn, Y. S. (2016) · Immune Network · doi:10.4110/in.2016.16.3.147 · Cited by 64 · see citing works
Telomeres, NAFLD and Chronic Liver Disease
Donati, B., & Valenti, L. V. C. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17030383 · Cited by 68 · see citing works
Wang, F., Li, Z., Chen, L., Yang, T., Liang, B.-Y., Zhang, Z.-L., Shao, J.-J., Xu, X., Yin, G., Wang, S., et al. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.03.014 · Cited by 64 · see citing works
Bosselut, N., Housset, C., Marcelo, P., Rey, C., Burmester, T., Vinh, J., Vaubourdolle, M., Cadoret, A., & Baudin, B. (2010) · PROTEOMICS · doi:10.1002/pmic.200900257 · Cited by 66 · see citing works
Regulation of Hepatic Stellate Cell Phenotypes in Metabolic Dysfunction–Associated Steatohepatitis
Kisseleva, T., Ganguly, S., Murad, R., Wang, A., & Brenner, D. A. (2025) · Gastroenterology · doi:10.1053/j.gastro.2025.03.010 · Cited by 72 · see citing works
Self-citationZhang, F., Lu, Y., & Zheng, S. (2011) · Cellular Signalling · doi:10.1016/j.cellsig.2011.11.008 · Cited by 64 · see citing works
Tacke, F., Gäbele, E., Bataille, F., Schwabe, R. F., Hellerbrand, C., Klebl, F. H., Straub, R. H., Luedde, T., Manns, M. P., Trautwein, C., et al. (2007) · Digestive Diseases and Sciences · doi:10.1007/s10620-007-9758-8 · Cited by 64 · see citing works
Self-citationNon-alcoholic Fatty Liver Disease and Liver Fibrosis during Aging
Li, Y., Adeniji, N., Fan, W., Kunimoto, K., & Torok, N. J. (2022) · Aging and Disease · doi:10.14336/ad.2022.0318 · Cited by 64 · see citing works
The Origin and Fate of Liver Myofibroblasts
Kim, H. Y., Sakane, S., Eguileor, A., Carvalho Gontijo Weber, R., Lee, W., Liu, X., Lam, K., Ishizuka, K., Rosenthal, S. B., Diggle, K., et al. (2024) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2023.09.008 · Cited by 63 · see citing works
Self-citationFormation of vitamin A lipid droplets in pancreatic stellate cells requires albumin
Kim, N., Yoo, W., Lee, J., Kim, H., Lee, H. S., Kim, Y.-S., Kim, D.-U., & Oh, J. (2009) · Gut · doi:10.1136/gut.2008.170233 · Cited by 61 · see citing works
Luo, X., Jiang, X., Li, J., Bai, Y., Li, Z., Wei, P., Sun, S., Liang, Y., Han, S., Li, X., et al. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1670-6 · Cited by 60 · see citing works
Nrf2 protects stellate cells from Smad-dependent cell activation
Prestigiacomo, V., & Suter‐Dick, L. (2018) · PLoS ONE · doi:10.1371/journal.pone.0201044 · Cited by 57 · see citing works
Activated Hepatic Stellate Cells Mediate the Differentiation of Macrophages
Chang, J., Hisamatsu, T., Shimamura, K., Yoneno, K., Adachi, M., Naruse, H., Igarashi, T., Higuchi, H., Matsuoka, K., Kitazume, M. T., et al. (2013) · Hepatology Research · doi:10.1111/j.1872-034x.2012.01111.x · Cited by 56 · see citing works
Hongo, A., Okumura, N., Nakahara, M., Kay, E. P., & Koizumi, N. (2017) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.16-21170 · Cited by 53 · see citing works
Role of the Extracellular Matrix in Cancer: Insights into Tumor Progression and Therapy
Desai, N., Sahel, D. K., Sawant, B. K. S., Postwala, H. I., Shah, Y. B., Chavda, V. P., Fernandes, C., Khatri, D. K., & Vora, L. K. (2025) · Advanced Therapeutics · doi:10.1002/adtp.202400370 · Cited by 53 · see citing works
Reversal of Fibrosis: No Longer a Pipe Dream?
Fallowfield, J. A., Kendall, T. J., & Iredale, J. P. (2006) · Clinics in Liver Disease · doi:10.1016/j.cld.2006.08.022 · Cited by 53 · see citing works
Chronic lung inflammation in aging mice
Aoshiba, K., & Nagai, A. (2007) · FEBS Letters · doi:10.1016/j.febslet.2007.06.075 · Cited by 52 · see citing works
Sato, R., Maesawa, C., Fujisawa, K., Wada, K., Oikawa, K., Takikawa, Y., Suzuki, K., Oikawa, H., Ishikawa, K., & Masuda, T. (2004) · Gut · doi:10.1136/gut.2003.027516 · Cited by 52 · see citing works
Liu, P., Tang, Q., Chen, M., Chen, W., Lu, Y., Liu, Z., & He, Z. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.589908 · Cited by 49 · see citing works
Expression of TIMP-1 and TIMP-2 in rats with hepatic fibrosis
Nie, Q., Duan, G.-R., Luo, X.-D., Xie, Y.-M., Luo, H., Zhou, Y., & Pan, B.-R. (2004) · World Journal of Gastroenterology · doi:10.3748/wjg.v10.i1.86 · Cited by 50 · see citing works
Tacke, F., Trautwein, C., Yagmur, E., Hellerbrand, C., Wiest, R., Brenner, D. A., & Schnabl, B. (2006) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2006.04621.x · Cited by 48 · see citing works
Self-citationTranscriptional regulation of stellate cell activation
Friedman, S. L. (2006) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2006.04585.x · Cited by 47 · see citing works
Antifibrotic therapies for metabolic dysfunction-associated steatotic liver disease
Schwabe, R. F., Tacke, F., Sugimoto, A., & Friedman, S. L. (2025) · JHEP Reports · doi:10.1016/j.jhepr.2025.101421 · Cited by 50 · see citing works
- Authors
- Schnabl, B., Purbeck, C. A., Choi, Y. H., Hagedorn, C. H., & Brenner, D.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Emory University (US)
- Corresponding author
- Brenner, David
- Venue
- Hepatology
- Published
- 2003-03
- Volume
- 37
- Issue
- 3
- Pages
- 653-664
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2020573317
- Cited by
- 224
- References
- 53
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 13 · 2023: 11 · 2022: 13 · 2021: 12 · 2020: 14 · 2019: 8 · 2018: 10 · 2017: 10 · 2016: 8 · 2015: 10 · 2014: 6 · 2013: 12 · 2012: 12
- FWCI
- 5.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DK-34987, AA-11605)
- National Institute on Alcohol Abuse and Alcoholism (AA 11605)
- National Institute of General Medical Sciences (GM41804, R01GM041804)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 34987, P30DK034987)
- Center for Gastrointestinal Biology and Disease, School of Medicine, University of North Carolina at Chapel Hill
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- replicative senescence, hepatic stellate cells, telomerase reverse transcriptase, hTERT, apoptosis, mitochondrial apoptosis, Bcl-2, Bcl-xL, caspase-3, cytochrome c release, extracellular matrix proteins, inflammation, liver fibrosis, telomere length, gene expression profiling, chronic wound healing
- MeSH terms
- beta-Galactosidase, Cell Cycle, Cell Division, Cell Survival, Cytoskeletal Proteins, DNA-Binding Proteins, Hepatitis, Humans, Liver, Phenotype, RNA, Messenger, Gene Expression, Cytokines, Cellular Senescence, Reactive Oxygen Species, Intercellular Adhesion Molecule-1, Chemokines, Vascular Cell Adhesion Molecule-1, Telomerase, Caspases, In Situ Nick-End Labeling, Oligonucleotide Array Sequence Analysis, Caspase 3
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