Apoptotic Body Engulfment by a Human Stellate Cell Line Is Profibrogenic
Open accessAbstract
Hepatocyte apoptosis and stellate cell activation are both features of chronic liver diseases, but a relationship between these events has not been explored. In macrophages, engulfment of apoptotic bodies induces expression of transforming growth factor-beta (TGF-beta), a profibrogenic cytokine. We examined whether a similar response occurs in stellate cells. Fluorescently labeled hepatocyte apoptotic bodies were added to cultures of primary and immortalized human stellate cells. Stellate cells, but not hepatocytes, readily engulfed apoptotic bodies in a time-dependent manner as assessed by confocal microscopy. The activation of primary and immortalized human stellate cells after incubation with apoptotic bodies, as well as their fibrogenic activity, was indicated by an increase in alpha-smooth muscle actin (primary cells), TGF-beta1, and collagen alpha1(I) mRNA (primary and immortalized cells). The profibrogenic response was dependent upon apoptotic body engulfment, because nocodazole, a microtubule-inhibiting agent, blocked both the engulfment and the increase of TGF-beta1 and collagen alpha1(I) mRNA. As described in primary rodent stellate cells, up-regulation of collagen alpha1(I) mRNA was inhibited by a PI-3K inhibitor (LY294002) and a p38 mitogen-activated protein kinase inhibitor (SB203580) in LX-1 cells. In conclusion, these data support a model in which engulfment of hepatocyte apoptotic bodies by stellate cells leads to a fibrogenic response by eliciting a kinase-signaling pathway.
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HSC line LX-1 can engulf apoptotic bodies of hepatocytes, inducing pro-fibrogenic activation in vitro via NADPH oxidase and PI3K/p38 MAPK-dependent mechanisms.
“Earlier in vitro studies reported that HSC line LX-1 is able to engulf apoptotic bodies of hepatocytes, which induced pro-fibrogenic activation in vitro via a nicotinamide adenine dinucleotide phosphate oxidase20 and phosphoinositide 3-kinase/p38 mitogen-activated protein kinase-dependent manner21.”
From Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis (2020) · cites this paper as [21]
Dying or damaged hepatocytes release damage-associated molecular patterns, including HMGB1, SPP1, P2Y14 ligands, apoptotic bodies, miRNA, and DNA, which can be taken up by HSCs and activate them into collagen-producing myofibroblasts.
“Dying or damaged hepatocytes secrete damage-associated molecular patterns including high mobility group box 1 protein (HMGB1), osteopontin (SPP1), purinoceptor 14 (P2Y14) ligands, apoptotic bodies, microRNA (miRNA), and DNA that can be packaged into microvesicles and directly taken up by HSCs, leading to their activation into collagen-producing myofibroblasts (see “Cellular plasticity”, below) (23”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [24]
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Cites
Fadok, V. A., Bratton, D. L., Konowal, A., Freed, P. W., Westcott, J. Y., & Henson, P. M. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1112 · Cited by 3,166 · cited 3× · see citing works
“Current concepts derived from developmental biology suggest that apoptosis and clearance of apoptotic bodies are evolutionary conserved processes to limit or even prevent inflammatory responses (Fadok et al, 1998; Savill, 2000).”
BackgroundMechanisms of phagocytosis in macrophages
Aderem, A., & Underhill, D. M. (1999) · Annual Review of Immunology · doi:10.1146/annurev.immunol.17.1.593 · Cited by 2,854 · see citing works
Role of Transforming Growth Factor β in Human Disease
Blobe, G. C., Schiemann, W. P., & Lodish, H. F. (2000) · New England Journal of Medicine · doi:10.1056/nejm200005043421807 · Cited by 2,430 · 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
Self-citationProduct Differentiation by Analysis of DNA Melting Curves during the Polymerase Chain Reaction
Ririe, K. M., Rasmussen, R. P., & Wittwer, C. T. (1997) · Analytical Biochemistry · doi:10.1006/abio.1996.9916 · Cited by 1,663 · see citing works
Corpse clearance defines the meaning of cell death
Savill, J., & Fadok, V. A. (2000) · Nature · doi:10.1038/35037722 · Cited by 1,535 · see citing works
Hepatic lipocytes: the principal collagen-producing cells of normal rat liver.
Friedman, S. L., Roll, F. J., Boyles, J., & Bissell, D. M. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.24.8681 · Cited by 859 · see citing works
Self-citationHistory, Heterogeneity, Developmental Biology, and Functions of Quiescent Hepatic Stellate Cells
Geerts, A. (2001) · Seminars in Liver Disease · doi:10.1055/s-2001-17550 · Cited by 740 · see citing works
Fadok, V., de Cathelineau, A., Daleke, D. L., Henson, P., & Bratton, D. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m003649200 · Cited by 689 · see citing works
Transport and Storage of Vitamin A
Blomhoff, R., Green, M. H., Berg, T., & Norum, K. R. (1990) · Science · doi:10.1126/science.2218545 · Cited by 609 · see citing works
Hoffmann, P. R., deCathelineau, A. M., Ogden, C. A., Leverrier, Y., Bratton, D. L., Daleke, D. L., Ridley, A. J., Fadok, V. A., & Henson, P. M. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.200108080 · Cited by 541 · see citing works
Cytokine Receptors and Signaling in Hepatic Stellate Cells
Pinzani, M., & Marra, F. (2001) · Seminars in Liver Disease · doi:10.1055/s-2001-17554 · Cited by 432 · see citing works
The role of TGFβ1 in initiating hepatic stellate cell activation in vivo
Hellerbrand, C., Stefanovic, B., Giordano, F., Burchardt, E. R., & Brenner, D. A. (1999) · Journal of Hepatology · doi:10.1016/s0168-8278(99)80010-5 · Cited by 393 · see citing works
Recognizing death: the phagocytosis of apoptotic cells
Platt, N., da Silva, R. P., & Gordon, S. (1998) · Trends in Cell Biology · doi:10.1016/s0962-8924(98)01329-4 · Cited by 375 · see citing works
Friedman, S. L. (1999) · Seminars in Liver Disease · doi:10.1055/s-2007-1007105 · Cited by 350 · see citing works
Self-citationVitamin A-containing lipocytes and formation of type III collagen in liver injury.
Kent, G., Gay, S., Inouye, T., Bahu, R. M., Minick, O. T., & Pópper, H. (1976) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.73.10.3719 · Cited by 347 · see citing works
Schmitt-Gräff, A., Krüger, S., Bochard, F., Gabbiani, G., & Denk, H. (1991) · PubMed Central · Cited by 331 · see citing works
Purified Rat Liver Fat-Storing Cells in Culture Divide and Contain Collagen
Leeuw, A. D. M., McCarthy, S. P., Geerts, A. E., & Knook, D. L. (1984) · Hepatology · doi:10.1002/hep.1840040307 · Cited by 325 · see citing works
The phosphatidylserine receptor: a crucial molecular switch?
Henson, P. M., Bratton, D. L., & Fadok, V. A. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35085094 · Cited by 321 · see citing works
George, J., Roulot, D. M., Koteliansky, V., & Bissell, D. M. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.22.12719 · Cited by 320 · see citing works
Fas enhances fibrogenesis in the bile duct ligated mouse: A link between apoptosis and fibrosis
Canbay, A. E., Higuchi, H., Bronk, S. F., Taniai, M., Sebo, T. J., & Gores, G. J. (2002) · Gastroenterology · doi:10.1053/gast.2002.35953 · Cited by 300 · see citing works
Self-citationReif, S. S., Lang, A., Lindquist, J. N., Yata, Y., Gäbele, E., Scanga, A. E., Brenner, D. A., & Rippe, R. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212927200 · Cited by 298 · see citing works
Friedman, S. L., Rockey, D. C., McGuire, R. F., Maher, J. J., Boyles, J. K., & Yamasaki, G. (1992) · Hepatology · doi:10.1002/hep.1840150211 · Cited by 284 · see citing works
Self-citationRamadori, G. P., Veit, T., Schwögler, S., Dienes, H. P., Knittel, T. E., Rieder, H., & Büschenfelde, K. H. M. Z. (1990) · Virchows Archiv B Cell Pathology Including Molecular Pathology · doi:10.1007/bf02899424 · Cited by 277 · see citing works
Fibrogenesis I. New insights into hepatic stellate cell activation: the simple becomes complex
Eng, F. J., & Friedman, S. L. (2000) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.2000.279.1.g7 · Cited by 222 · see citing works
Self-citationDifferences between the clearance of apoptotic cells by professional and non-professional phagocytes
Parnaik, R., RAFF, M. C., & Scholes, J. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00598-4 · Cited by 216 · see citing works
Krahling, S., Callahan, M. K., Williamson, P., & Schlegel, R. (1999) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400473 · Cited by 211 · see citing works
Dooley, S., Delvoux, B., Streckert, M., Bonzel, L., Stopa, M., ten Dijke, P., & Gressner, A. M. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)02656-4 · Cited by 197 · see citing works
Actin dynamics during phagocytosis
Castellano, F., Chavrier, P., & Caron, E. (2001) · Seminars in Immunology · doi:10.1006/smim.2001.0331 · Cited by 181 · see citing works
Rust, C., & Gores, G. J. (2000) · The American Journal of Medicine · doi:10.1016/s0002-9343(00)00370-3 · Cited by 180 · see citing works
Self-citationThe phagocytosis of apoptotic cells
Fadok, V. A., & Chimini, G. (2001) · Seminars in Immunology · doi:10.1006/smim.2001.0333 · Cited by 166 · see citing works
Mitogenic signals for platelet-derived growth factor isoforms in liver fat-storing cells
Pinzani, M., Knauss, T. C., Pierce, G. F., Hsieh, P., Kenney, W. C., Dubyak, G., & Abboud, H. E. (1991) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1991.260.3.c485 · Cited by 108 · see citing works
Effects of nocodazole on structures of calf brain tubulin
Lee, J. C., Field, D. J., & Lee, L. L. Y. (1980) · Biochemistry · doi:10.1021/bi00567a041 · Cited by 103 · see citing works
Varela‐Rey, M., Montiel‐Duarte, C., Osés-Prieto, J. A., López-Zabalza, M. J., Jaffrézou, J., Rojkind, M., & Iraburu, M. J. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)03276-3 · Cited by 92 · see citing works
The Werner syndrome protein: an update
Oshima, J. (2000) · BioEssays · doi:10.1002/1521-1878(200010)22:10 · Cited by 80 · see citing works
Hepatocytes in the bile duct-ligated rat express Bcl-2
Kurosawa, H., Que, F. G., Roberts, L. R., Fesmier, P. J., & Gores, G. J. (1997) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.1997.272.6.g1587 · Cited by 76 · see citing works
Self-citationDLPC decreases TGF-β1-induced collagen mRNA by inhibiting p38 MAPK in hepatic stellate cells
Cao, Q., Mak, K. M., & Lieber, C. S. (2002) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00128.2002 · Cited by 72 · see citing works
Apoptosis in resolution of inflammation.
Savill, J. (2000) · PubMed · Cited by 57 · see citing works
Almasio, P. L., Floreani, A., Chiaramonte, M., Provenzano, G., Battezzati, P. M., Crosignani, A., Podda, M., Todros, L., Rosina, F., Saccoccio, G., et al. (2000) · Alimentary Pharmacology & Therapeutics · doi:10.1046/j.1365-2036.2000.00869.x · Cited by 53 · see citing works
The role of perisinusoidal cells in experimental hepatic fibrogenesis.
McGee, J. O., & Patrick, R. S. (1972) · PubMed · Cited by 9 · see citing works
Flagged first, then by citations
2 of the 42 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Mechanisms of hepatic stellate cell activation
Tsuchida, T., & Friedman, S. L. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2017.38 · Cited by 2,909 · see citing works
Self-citationHepatic 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
Self-citationMechanisms and disease consequences of nonalcoholic fatty liver disease
Loomba, R., Friedman, S. L., & Shulman, G. I. (2021) · Cell · doi:10.1016/j.cell.2021.04.015 · Cited by 2,002 · see citing works
“Apoptosis of hepatocytes, in part through lipotoxicity, is a critical feature of NASH histopathology, and apoptotic bodies are fibrogenic toward hepatic stellate cells (Canbay et al., 2003).”
BackgroundSelf-citationHepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis
Feldstein, A. E., Canbay, A., Angulo, P., Taniai, M., Burgart, L. J., Lindor, K. D., & Gores, G. J. (2003) · Gastroenterology · doi:10.1016/s0016-5085(03)00907-7 · Cited by 1,085 · see citing works
Self-citationA position statement on NAFLD/NASH based on the EASL 2009 special conference
Ratziu, V., Bellentani, S., Cortez‐Pinto, H., Day, C., & Marchesini, G. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.04.008 · Cited by 1,059 · see citing works
“Both HSC and KCs engulf apoptotic cells to generate pro-fibrotic signals [151], with therapeutic prospects for anti-apoptotic agents [152].”
BackgroundLiver 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
Hepatic inflammation and fibrosis: Functional links and key pathways
Seki, E., & Schwabe, R. F. (2015) · Hepatology · doi:10.1002/hep.27332 · Cited by 972 · see citing works
“As such, apoptotic hepatocyte bodies have been demonstrated to promote secretion of proinflammatory and fibrogenic cytokines from macrophages and directly promote HSC activation.(5,17,18) Moreover, it has been suggested that damage-associated molecular patterns (DAMPs) released from dying hepatocytes may also directly…”
BackgroundTriggering and resolution of inflammation in NASH
Schuster, S., Cabrera, D., Arrese, M., & Feldstein, A. E. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0009-6 · Cited by 943 · see citing works
Nonalcoholic Fatty Liver Disease: Pathology and Pathogenesis
Tiniakos, D. G., Vos, M. B., & Brunt, E. M. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102132 · Cited by 870 · see citing works
“Phagocytosis of apoptotic hepatocytes results in activation of Kupffer cells (143).”
BackgroundModels of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ
Iredale, J. P. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30542 · Cited by 866 · see citing works
Cell Death and Cell Death Responses in Liver Disease: Mechanisms and Clinical Relevance
Luedde, T., Kaplowitz, N., & Schwabe, R. F. (2014) · Gastroenterology · doi:10.1053/j.gastro.2014.07.018 · Cited by 760 · 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
Self-citationCytokeratin-18 Fragment Levels as Noninvasive Biomarkers for Nonalcoholic Steatohepatitis
Feldstein, A. E., Wieckowska, A., López, R., Liu, Y., Zein, N. N., & McCullough, A. J. (2009) · Hepatology · doi:10.1002/hep.23050 · Cited by 711 · see citing works
Apoptosis and Necrosis in the Liver: A Tale of Two Deaths?
Malhi, H., Gores, G. J., & Lemasters, J. J. (2006) · Hepatology · doi:10.1002/hep.21062 · Cited by 688 · see citing works
Self-citationMechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis
Schwabe, R. F., Tabas, I., & Pajvani, U. B. (2020) · Gastroenterology · doi:10.1053/j.gastro.2019.11.311 · Cited by 671 · see citing works
Wieckowska, A., Zein, N. N., Yerian, L. M., López, R., McCullough, A. J., & Feldstein, A. E. (2006) · Hepatology · doi:10.1002/hep.21223 · Cited by 668 · see citing works
Ricchi, M., Odoardi, M. R., Carulli, L., Anzivino, C., Ballestri, S., Pinetti, A., Fantoni, L. I., Marra, F., Bertolotti, M., Banni, S., et al. (2009) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2008.05733.x · Cited by 652 · see citing works
From NAFLD to NASH to cirrhosis—new insights into disease mechanisms
Wree, A., Broderick, L., Canbay, A. E., Hoffman, H. M., & Feldstein, A. E. (2013) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2013.149 · Cited by 608 · see citing works
Self-citationApoptosis and necroptosis in the liver: a matter of life and death
Schwabe, R. F., & Luedde, T. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0065-y · Cited by 582 · see citing works
Cellular and Molecular Mechanisms of Liver Injury
Malhi, H., & Gores, G. J. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.03.002 · Cited by 559 · see citing works
Self-citationApoptosis: 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
Self-citationApoptosis: a mechanism of acute and chronic liver injury
Guicciardi, M. E., & Gores, G. J. (2005) · Gut · doi:10.1136/gut.2004.053850 · Cited by 509 · see citing works
Self-citationMechanisms of Disease: mechanisms of hepatic fibrosis and therapeutic implications
Friedman, S. L. (2004) · Nature Clinical Practice Gastroenterology & Hepatology · doi:10.1038/ncpgasthep0055 · Cited by 499 · see citing works
Self-citationLiver sinusoidal endothelial cells in hepatic fibrosis
DeLeve, L. D. (2015) · Hepatology · doi:10.1002/hep.27376 · Cited by 482 · see citing works
“During resolution of fibrosis, the decline in activated HSC is due to both reversion to quiescence and apoptosis (28, 50).”
Hepatocyte Death: A Clear and Present Danger
Malhi, H., Guicciardi, M. E., & Gores, G. J. (2010) · Physiological Reviews · doi:10.1152/physrev.00061.2009 · Cited by 477 · see citing works
“In the liver, both stellate cells and Kupffer cells, the resident macrophages of the liver, can phagocytose apoptotic bodies (31, 33, 124).”
Self-citationKupffer Cell Engulfment of Apoptotic Bodies Stimulates Death Ligand and Cytokine Expression
Canbay, A. E., Feldstein, A. E., Higuchi, H., Werneburg, N., Grambihler, A., Bronk, S. F., & Gores, G. J. (2003) · Hepatology · doi:10.1053/jhep.2003.50472 · Cited by 469 · see citing works
Self-citationPessayre, D., & Fromenty, B. (2005) · Journal of Hepatology · doi:10.1016/j.jhep.2005.03.004 · Cited by 441 · see citing works
“[115] Canbay A, Taimr P, Torok N, Higuchi H, Friedman S, Gores GJ.”
BackgroundHepatic fibrosis 2022: Unmet needs and a blueprint for the future
Friedman, S. L., & Pinzani, M. (2022) · Hepatology · doi:10.1002/hep.32285 · Cited by 430 · see citing works
“These include (1) disruption of the normal ECM of the space of Disse as a consequence of hepatocyte damage and inflammatory infiltration[12,13]; (2) release of reactive oxygen species and other fibrogenic/proinflammatory mediators[14,15]; and (3) recruitment of immune cells, which in turn sustain HSC activation.”
BackgroundSelf-citationRedox mechanisms in hepatic chronic wound healing and fibrogenesis
Novo, E., & Parola, M. (2008) · Fibrogenesis & Tissue Repair · doi:10.1186/1755-1536-1-5 · Cited by 406 · see citing works
“hepatocyte apoptosis represents an effective pro-fibrogenic stimulus [97,98].”
BackgroundResultInfluentialCellular and molecular mechanisms in the pathogenesis of liver fibrosis: An update
Elpek, G. Ö. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i23.7260 · Cited by 384 · 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
“Engulfment of apoptotic bodies has been shown to increase HSC activation in vitro and leads to the increased production of TGFβ—a potent pro-fibrogenic cytokine[120].”
BackgroundApoptosis and Necrosis in the Liver
Guicciardi, M. E., Malhi, H., Mott, J. L., & Gores, G. J. (2013) · Comprehensive physiology · doi:10.1002/cphy.c120020 · Cited by 387 · see citing works
Self-citationFriedman, S. L. (2008) · Toxicology · doi:10.1016/j.tox.2008.06.013 · Cited by 350 · see citing works
Self-citationTGF-β in Renal Injury and Disease
Böttinger, E. P. (2007) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2007.02.009 · Cited by 339 · see citing works
An, P., Wei, L.-L., Zhao, S., Sverdlov, D. Y., Vaid, K. A., Miyamoto, M., Kuramitsu, K., Lai, M., & Popov, Y. V. (2020) · Nature Communications · doi:10.1038/s41467-020-16092-0 · Cited by 319 · see citing works
The Role of Insulin Resistance and Diabetes in Nonalcoholic Fatty Liver Disease
Fujii, H., Kawada, N., & Japan Study Group of NAFLD (JSG-NAFLD) (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21113863 · Cited by 300 · see citing works
“This may be through the release of profibrogenic damageassociated molecular patterns [36,37] or other profibrogenic mediators such as Hh ligands and osteopontin (OPN) [19], or via apoptotic bodies [38,39] that may directly act on HSCs.”
BackgroundBarreyro, F. J., Holod, S., Finocchietto, P. V., Camino, A. M., Aquino, J. B., Avagnina, A., Carreras, M. C., Poderoso, J. J., & Gores, G. J. (2014) · Liver International · doi:10.1111/liv.12570 · Cited by 295 · see citing works
“We demonstrate that prolonged pharmacological inhibition of caspases has a beneficial effect in NASH Liver International (2015) © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 959 by reducing hepatocyte apoptosis and decreasing liver injury, hepatic inflammation and markedly reducing HSC activation an…”
BackgroundInfluentialSelf-citationTrauner, M., Arrese, M. A., & Wagner, M. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2009.10.007 · Cited by 291 · see citing works
Zhan, S.-S., Jiang, J. X., Wu, J., Halsted, C., Friedman, S. L., Zern, M. A., & Torok, N. J. (2006) · Hepatology · doi:10.1002/hep.21093 · Cited by 284 · see citing works
Self-citationRole of mitochondria in non‐alcoholic fatty liver disease
Pessayre, D. (2007) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2006.04640.x · Cited by 280 · see citing works
Cellular and Molecular Mechanisms Underlying Liver Fibrosis Regression
Caligiuri, A., Gentilini, A., Pastore, M., Gitto, S., & Marra, F. (2021) · Cells · doi:10.3390/cells10102759 · Cited by 273 · see citing works
Pathogenesis and management issues for non-alcoholic fatty liver disease
Duvnjak, M. (2007) · World Journal of Gastroenterology · doi:10.3748/wjg.v13.i34.4539 · Cited by 265 · see citing works
Weiskirchen, R., & Tacke, F. (2014) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2304-3881.2014.11.03 · Cited by 269 · see citing works
“HSC can phagocytose hepatocyte-derived apoptotic bodies, which results in the activation of HSC (146).”
BackgroundApoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9
Watanabe, A., Hashmi, A., Gomes, D. A., Town, T., Badou, A., Flavell, R. A., & Mehal, W. Z. (2007) · Hepatology · doi:10.1002/hep.21867 · Cited by 262 · see citing works
Apoptosis in nonalcoholic fatty liver disease: diagnostic and therapeutic implications
Alkhouri, N., Carter-Kent, C. A., & Feldstein, A. E. (2011) · Expert Review of Gastroenterology & Hepatology · doi:10.1586/egh.11.6 · Cited by 255 · see citing works
Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis #
Witek, R. P., Stone, C. W., Karaca, G., Syn, W., Pereira, T. A., Agboola, K. M., Omenetti, A., Jung, Y., Teaberry, V. S., Choi, S. S., et al. (2009) · Hepatology · doi:10.1002/hep.23167 · Cited by 252 · see citing works
Pathogenesis and treatment of non-alcoholic steatohepatitis and its fibrosis
Lee, K., Wu, P.-S., & Lin, H. (2022) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2022.0237 · Cited by 260 · see citing works
Principles of Liver Regeneration and Growth Homeostasis
Michalopoulos, G. K. (2012) · Comprehensive physiology · doi:10.1002/cphy.c120014 · Cited by 267 · see citing works
Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis
Khomich, O. A., Ivanov, A. V., & Bartosch, B. (2019) · Cells · doi:10.3390/cells9010024 · Cited by 227 · see citing works
Non-Alcoholic Steatohepatitis: A Review of Its Mechanism, Models and Medical Treatments
Peng, C. Y., Stewart, A. G., Woodman, O. L., Ritchie, R. H., & Qin, C. X. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.603926 · Cited by 230 · see citing works
Takehara, T., Tatsumi, T., Suzuki, T., Rucker, E. B., Hennighausen, L. G., Jinushi, M., Miyagi, T., Kanazawa, Y., & Hayashi, N. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.07.019 · Cited by 223 · see citing works
Apotopes and the biliary specificity of primary biliary cirrhosis†
Lleo, A., Selmi, C., Invernizzi, P., Podda, M., Coppel, R. L., Mackay, I. R., Gores, G. J., Ansari, A. A., Van de Water, J., & Gershwin, M. E. (2009) · Hepatology · doi:10.1002/hep.22736 · Cited by 222 · see citing works
Self-citationDiabetes mellitus in patients with cirrhosis: clinical implications and management
Elkrief, L., Rautou, P., Sarin, S. K., Valla, D. C., Paradis, V., & Moreau, R. (2016) · Liver International · doi:10.1111/liv.13115 · Cited by 222 · see citing works
“Engulfment of apoptotic bodies by hepatic stellate cells stimulates their fibrogenic activity and may be one mechanism by which hepatocyte apoptosis promotes fibrosis (19).”
BackgroundImmunological mechanisms and therapeutic targets of fatty liver diseases
Wang, H., Mehal, W. Z., Nagy, L. E., & Rotman, Y. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-00579-3 · Cited by 222 · see citing works
Liver fibrosis in NAFLD/NASH: from pathophysiology towards diagnostic and therapeutic strategies
Parola, M., & Pinzani, M. (2023) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2023.101231 · Cited by 226 · see citing works
Role of NADPH Oxidases in Liver Fibrosis
Paik, Y., Kim, J., Aoyama, T., de Minicis, S., Bataller, R., & Brenner, D. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5619 · Cited by 214 · see citing works
“Furthermore, NOX2 is involved in the activation of HSCs by phagocytosis of apoptotic hepatocytes (33, 203).”
BackgroundDisassembly of the Dying: Mechanisms and Functions
Atkin‐Smith, G. K., & Poon, I. K. H. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.08.011 · Cited by 214 · see citing works
Biomarkers of liver cell death
Eguchi, A., Wree, A., & Feldstein, A. E. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2013.12.026 · Cited by 220 · see citing works
“Sustained hepatocyte cell death has also been implicated in the development of hepatic fibrosis [6,7].”
BackgroundThe Caspase Inhibitor IDN-6556 Attenuates Hepatic Injury and Fibrosis in the Bile Duct Ligated Mouse
Canbay, A. E., Feldstein, A. E., Baskin-Bey, E. S., Bronk, S. F., & Gores, G. J. (2004) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.060129 · Cited by 213 · see citing works
Self-citationImmunopathogenesis of hepatitis B virus infection
Chang, J. J., & Lewin, S. R. (2006) · Immunology and Cell Biology · doi:10.1038/sj.icb.7100009 · Cited by 212 · see citing works
CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury
Tamaki, N., Hatano, E., Taura, K., Tada, M., Kodama, Y., Nitta, T., Iwaisako, K., Seo, S., Nakajima, A., Ikai, I., et al. (2008) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00482.2007 · Cited by 207 · see citing works
“TGF- 1 is secreted by Kupffer cells, HSCs, and hepatocytes in the liver, and its secretion is stimulated upon engulfment of dead hepatocytes (2, 5, 35).”
BackgroundApoptosis in alcoholic and nonalcoholic steatohepatitis
Ariel, E. F. (2005) · Frontiers in bioscience · doi:10.2741/1765 · Cited by 203 · see citing works
“Engulfment of apoptotic bodies by hepatic stellate cells stimulates the fibrogenic activity of these cells and may be one mechanism by which hepatocyte apoptosis promotes fibrosis (25).”
BackgroundDeath Receptor-Mediated Cell Death and Proinflammatory Signaling in Nonalcoholic Steatohepatitis
Hirsova, P., & Gores, G. (2014) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2014.11.005 · Cited by 184 · see citing works
“We have demonstrated that engulfment of hepatocyte apoptotic bodies by HSC increases expression of profibrogenic genes, suggesting that the cells underwent profibrogenic activation.(77) A similar effect was also observed when HSC were incubated with isolated microvesicles released from lipotoxic hepatocytes.”
BackgroundSelf-citationHCV and HIV co-infection: mechanisms and management
Chen, J. Y., Feeney, E. R., & Chung, R. T. (2014) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2014.17 · Cited by 196 · see citing works
Non-alcoholic steatohepatitis: From cell biology to clinical practice
Cortez‐Pinto, H., de Moura, M. C., & Day, C. P. (2005) · Journal of Hepatology · doi:10.1016/j.jhep.2005.09.002 · Cited by 193 · see citing works
“Hepatocyte apoptosis leads to fibrogenesis following the ingestion of apoptosing hepatocytes by Kupffer cells and HSC themselves which subsequently release TGFb capable of activating HSC [91,92].”
BackgroundCathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis
Canbay, A. E., Guicciardi, M. E., Higuchi, H., Feldstein, A. E., Bronk, S. F., Rydzewski, R. M., Taniai, M., & Gores, G. J. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17740 · Cited by 193 · see citing works
“Alternatively, engulfment of hepatocyte apoptotic bodies directly by stellate cells may also promote activation of these cells as has been observed in vitro (35).”
Self-citationThe epidemiology, pathogenesis and histopathology of fatty liver disease
Levene, A., & Goldin, R. D. (2012) · Histopathology · doi:10.1111/j.1365-2559.2011.04145.x · Cited by 192 · see citing works
“Hepatic stellate cells engulf apoptotic bodies and stimulate their fibrogenic activity, which may be a mechanism via which hepatocyte apoptosis promotes fibrosis.(63) As hepatocyte apoptosis is a prominent feature of NASH, biomarkers of hepatocyte apoptosis are being used as potential diagnostic tools for NASH.”
BackgroundAkkız, H., Gieseler, R. K., & Canbay, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25147873 · Cited by 191 · see citing works
Self-citationCathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis
Canbay, A. E., Guicciardi, M. E., Higuchi, H., Feldstein, A. E., Bronk, S. F., Rydzewski, R. M., Taniai, M., & Gores, G. J. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200317740 · Cited by 188 · see citing works
Self-citationBiliary bile acids in hepatobiliary injury – What is the link?
Fickert, P., & Wagner, M. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.04.026 · Cited by 187 · see citing works
Joka, D., Wahl, K., Moeller, S., Schlué, J., Vaske, B., Bahr, M. J., Manns, M. P., Schulze‐Osthoff, K., & Bantel, H. (2011) · Hepatology · doi:10.1002/hep.24734 · Cited by 182 · see citing works
“For instance, engulfment of apoptotic bodies by hepatic stellate cells stimulates their fibrogenic activity, whereas attenuation of hepatocyte apoptosis was shown to reduce fibrogenesis in experimental cholestasis.(35,36) In this study we analyzed sera from patients with chronic liver diseases (n 1⁄4 121) and differen…”
BackgroundApoptosis as a Mechanism for Liver Disease Progression
Guicciardi, M. E., & Gores, G. (2010) · Seminars in Liver Disease · doi:10.1055/s-0030-1267540 · Cited by 185 · see citing works
“Whatever their lineage, activated myofibroblasts are phagocytic and capable of engulfing apoptotic bodies.(44,45,58,59) When activated myofibroblast cell lines engulf apoptotic bodies derived from hepatocytes, they produce profibrogenic cytokines (such as TGFb) and type I collagen.”
BackgroundSelf-citationLiver fibrosis and inflammation. A review
Stalnikowitz, D. K., & Weissbrod, A. B. (2003) · Annals of Hepatology · doi:10.1016/s1665-2681(19)32127-1 · Cited by 183 · see citing works
“Apoptotic body engulfment by SC has also recently been reported to trigger activation and collagen expression by this profibrogenetic cell type.(23) Hepatic neutrophil infiltration is a frequent occurrence in alcoholic hepatitis.”
BackgroundBöttcher, K., & Pinzani, M. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.05.016 · Cited by 183 · see citing works
“mediators [24, 25] and recruitment of immune cells, which in turn mediate HSC activation and stimulate collagen secretion through release of cytokines and chemokines [26, 27].”
BackgroundPatin, É., Kutalik, Z., Guergnon, J., Bibert, S., Nalpas, B., Jouanguy, E., Munteanu, M., Bousquet, L., Argiro, L., Halfon, P., et al. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.07.097 · Cited by 176 · see citing works
Choi, S. S., Syn, W., Karaca, G., Omenetti, A., Moylan, C. A., Witek, R. P., Agboola, K. M., Jung, Y., Michelotti, G. A., & Diehl, A. M. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.168542 · Cited by 174 · see citing works
Kodama, T., Takehara, T., Hikita, H., Shimizu, S., Shigekawa, M., Tsunematsu, H., Li, W. S., Miyagi, T., Hosui, A., Tatsumi, T., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44957 · Cited by 172 · see citing works
Molecular mechanism of hepatic stellate cell activation and antifibrotic therapeutic strategies
Li, J., Liao, Z., Ping, J., Xu, D., & Wang, H. (2008) · Journal of Gastroenterology · doi:10.1007/s00535-008-2180-y · Cited by 167 · see citing works
“Although apoptosis of activated HSCs may well be critical in fi brosis resolution, other work suggests that apoptosis of activated HSCs may stimulate activation, and thus could be detrimental with regard to fi brogenesis.(9) More recent studies combining in vitro and in vivo work have provided defi nitive evidence of…”
BackgroundIntercellular crosstalk of hepatic stellate cells in liver fibrosis: New insights into therapy
Cai, X., Wang, J., Wang, J., Zhou, Q., Yang, B., He, Q., & Weng, Q. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104720 · Cited by 167 · see citing works
Ratziu, V., Sheikh, M. Y., Sanyal, A. J., Lim, J. K., Conjeevaram, H. S., Chalasani, N., Abdelmalek, M. F., Bakken, A., Renou, C., Palmer, M., et al. (2011) · Hepatology · doi:10.1002/hep.24747 · Cited by 164 · see citing works
Minicis, S. D., & Brenner, D. A. (2007) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2007.04.016 · Cited by 161 · see citing works
Mitochondrial injury in steatohepatitis
Pessayre, D., Fromenty, B., & Mansouri, A. (2004) · European Journal of Gastroenterology & Hepatology · doi:10.1097/00042737-200411000-00003 · Cited by 162 · see citing works
Beilfuss, A., Sowa, J., Sydor, S., Beste, M., Bechmann, L. P., Schlattjan, M., Syn, W., Wedemeyer, I., Máthé, Z., Jochum, C., et al. (2014) · Gut · doi:10.1136/gutjnl-2014-307024 · Cited by 159 · see citing works
Self-citationFound in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH)
Wang, S., & Friedman, S. L. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.adi0759 · Cited by 158 · see citing works
Self-citationJiang, J. X., Mikami, K., Venugopal, S. K., Li, Y., & Torok, N. J. (2009) · Journal of Hepatology · doi:10.1016/j.jhep.2009.03.024 · Cited by 157 · see citing works
“To generate carboxytetramethyl rhodamine succinimidyl ester(TAMRA, Invitrogen, Carlsbad, CA) labeled AB, HepG2 cells were incubated with TAMRA (10 lM), then exposed to UV irradiation (100 mJ/cm(2), 142 s) as described previously [19].”
Self-citation3D in vitro models of liver fibrosis
van Grunsven, L. A. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.07.004 · Cited by 154 · see citing works
TNF-Receptor-1 inhibition reduces liver steatosis, hepatocellular injury and fibrosis in NAFLD mice
Wandrer, F., Liebig, S., Marhenke, S., Vogel, A., John, K., Manns, M. P., Teufel, A., Itzel, T., Longerich, T., Maier, O., et al. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2411-6 · Cited by 153 · see citing works
Manuelpillai, U., Tchongue, J., Lourensz, D., Vaghjiani, V., Samuel, C. S., Liu, A., Williams, E. D., & Sievert, W. (2010) · Cell Transplantation · doi:10.3727/096368910x504496 · Cited by 152 · see citing works
Succinate is a paracrine signal for liver damage
Correa, P. R. A. V., Kruglov, E. A., Thompson, M., Leite, M. F., Dranoff, J. A., & Nathanson, M. H. (2007) · Journal of Hepatology · doi:10.1016/j.jhep.2007.03.016 · Cited by 151 · see citing works
“Hepatic necrosis activates stellate cells in part through reactive oxygen intermediates and initiation of oxidant stress-related pathways [18,22], whereas apoptotic hepatocytes activate stellate cells via released apoptotic fragments [23] as well as Fas-related pathways [24].”
BackgroundAcute liver failure is associated with elevated liver stiffness and hepatic stellate cell activation
Dechêne, A., Sowa, J., Gieseler, R., Jochum, C., Bechmann, L., Fouly, A. E. E., Schlattjan, M., Saner, F., Baba, H., Paul, A., et al. (2010) · Hepatology · doi:10.1002/hep.23754 · Cited by 158 · see citing works
Self-citationMuhanna, N., Doron, S., Wald, O., Horani, A., Eid, A., Pappo, O., Friedman, S. L., & Safadi, R. (2008) · Hepatology · doi:10.1002/hep.22413 · Cited by 147 · see citing works
Self-citationNon-parenchymal TREM-2 protects the liver from immune-mediated hepatocellular damage
Perugorria, M. J., Esparza-Baquer, A., Oakley, F., Labiano, I., Korosec, A., Jais, A., Mann, J., Tiniakos, D., Santos-Laso, A., Arbelaiz, A., et al. (2019) · Gut · doi:10.1136/gutjnl-2017-314107 · Cited by 144 · see citing works
Effect of intracellular lipid accumulation in a new model of non-alcoholic fatty liver disease
Chávez-Tapia, N. C., Rosso, N., & Tiribelli, C. (2012) · BMC Gastroenterology · doi:10.1186/1471-230x-12-20 · Cited by 138 · see citing works
“produced by the hepatocyte in the activation of hepatic stellate cells [21].”
BackgroundEvolving concepts of liver fibrogenesis provide new diagnostic and therapeutic options
Gressner, O. A., Weiskirchen, R., & Gressner, A. M. (2007) · Comparative Hepatology · doi:10.1186/1476-5926-6-7 · Cited by 137 · see citing works
“Additional functions of these cells were recently discovered: they seem to play a role as antigen presenting cells (APC) [19-21], as CD133+ progenitorcells with the ability to differentiate to progenitor endothelial cells and hepatocytes suggesting important roles in liver regeneration and repair [22], they are involv…”
BackgroundSteatosis and liver cell apoptosis in chronic hepatitis C: A mechanism for increased liver injury
Walsh, M. J., Vanags, D. M., Clouston, A. D., Richardson, M. M., Purdie, D. M., Jonsson, J. R., & Powell, E. E. (2004) · Hepatology · doi:10.1002/hep.20179 · Cited by 135 · see citing works
Lee, Y. A., & Friedman, S. L. (2014) · Antiviral Research · doi:10.1016/j.antiviral.2014.03.012 · Cited by 132 · see citing works
“Apart from directly promoting fibrosis resolution via production of MMPs, macrophages can mediate anti-inflammatory effects, for example by phagocytosing apoptotic hepatocytes which can activate HSCs (Canbay et al., 2003), and by differentiating into regulatory macrophages that produce suppressor cytokines locally.”
Self-citationPathophysiology and Treatment Options for Hepatic Fibrosis: Can It Be Completely Cured?
Khanam, A., Saleeb, P. G., & Kottilil, S. (2021) · Cells · doi:10.3390/cells10051097 · Cited by 132 · see citing works
“Evidence suggests that apoptotic fragments released from hepatocytes have fibrogenic potential towards cultured stellate cells, while lipid peroxidases produced from necrotic hepatocytes also induce HSC activation [56,57].”
BackgroundAmelioration of hepatic fibrosis by NK cell activation
Muhanna, N., Tair, L. A., Doron, S., Amer, J., Azzeh, M., Mahamid, M., Friedman, S., & Safadi, R. (2011) · Gut · doi:10.1136/gut.2010.211136 · Cited by 127 · see citing works
“Reduction of activation was achieved when LX2 cells were cultured to confluence in 6-well flasks (Nunc Brand Products, Roskilde, Denmark) with 1% fetal calf serum (FCS).(11) Healthy and HCVderived peripheral blood lymphocytes (PBLs) were co-cultured for 48 h with LX2 cells.”
MethodSelf-citationChojkier, M. (2005) · Hepatology · doi:10.1002/hep.20567 · Cited by 127 · see citing works
Popov, Y., Sverdlov, D. Y., Bhaskar, K. R., Sharma, A. K., Millonig, G., Patsenker, E., Krahenbuhl, S., Krahenbuhl, L., & Schuppan, D. (2010) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00394.2009 · Cited by 136 · see citing works
“Cholangiocyte apoptosis triggers recruitment of CD68 macrophages into scarred portal tracts to remove apoptotic cholangiocytes via phagocytosis (6) and to upregulate MMP-3, -8, and-9 to remodel the scar, leading to dissolution of fibrous septa and restoration of normal liver architecture.”
Background
- Authors
- Canbay, A., Taimr, P., Torok, N., Higuchi, H., Friedman, S., & Gores, G. J.
- Affiliations
- Mayo Clinic (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Gores, Gregory J
- Venue
- Laboratory Investigation
- Publisher
- Elsevier BV
- Published
- 2003-05
- Volume
- 83
- Issue
- 5
- Pages
- 655-663
- ISSN
- 0023-6837 (ISSN-L)
- OpenAlex
- W2089907961
- Cited by
- 417
- References
- 42
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 13 · 2023: 23 · 2022: 15 · 2021: 19 · 2020: 29 · 2019: 10 · 2018: 20 · 2017: 31 · 2016: 13 · 2015: 11 · 2014: 33 · 2013: 13 · 2012: 18
- FWCI
- 9.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Laboratory Investigation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Mayo Foundation for Medical Education and Research
- US-UK Fulbright Commission
- Deutscher Akademischer Austauschdienst
- National Institutes of Health (DK 41876, DK56621)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK37430, DK 56621, DK-41876)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- hepatic stellate cells, hepatocyte apoptosis, liver fibrosis, TGF-β1, stellate cell activation, PI3K signaling, p38 MAPK signaling, chronic liver disease
- MeSH terms
- Cell Line, Humans, Liver Cirrhosis, Microtubules, RNA, Messenger, Nocodazole, Transforming Growth Factor beta, Apoptosis, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinases, Hepatocytes, Collagen Type I, p38 Mitogen-Activated Protein Kinases, Transforming Growth Factor beta1
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