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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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“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]
In the citing paper
“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×
“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
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 2,453
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 2,067
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
Corpse clearance defines the meaning of cell death
Savill, J., & Fadok, V. A. (2000) · Nature · doi:10.1038/35037722 · Cited by 1,572
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
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
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
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
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
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 434
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
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
Friedman, S. L. (1999) · Seminars in Liver Disease · doi:10.1055/s-2007-1007105 · Cited by 348
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
Schmitt-Gräff, A., Krüger, S., Bochard, F., Gabbiani, G., & Denk, H. (1991) · PubMed Central · Cited by 331
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
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
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
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 302
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
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
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
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
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
Krahling, S., Callahan, M. K., Williamson, P., & Schlegel, R. (1999) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400473 · Cited by 211
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
Actin dynamics during phagocytosis
Castellano, F., Chavrier, P., & Caron, E. (2001) · Seminars in Immunology · doi:10.1006/smim.2001.0331 · Cited by 181
Rust, C., & Gores, G. J. (2000) · The American Journal of Medicine · doi:10.1016/s0002-9343(00)00370-3 · Cited by 180
Self-citationThe phagocytosis of apoptotic cells
Fadok, V. A., & Chimini, G. (2001) · Seminars in Immunology · doi:10.1006/smim.2001.0333 · Cited by 166
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
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
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
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
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
Apoptosis in resolution of inflammation.
Savill, J. (2000) · PubMed · Cited by 57
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
Redox control and the evolution of multicellularity
Blackstone, N. W. (2000) · BioEssays · doi:10.1002/1521-1878(200010)22:10 · Cited by 47
The role of perisinusoidal cells in experimental hepatic fibrogenesis.
McGee, J. O., & Patrick, R. S. (1972) · PubMed · Cited by 9
Cited by
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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
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
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
“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
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 1,083
“Both HSC and KCs engulf apoptotic cells to generate pro-fibrotic signals [151], with therapeutic prospects for anti-apoptotic agents [152].”
Background
Metadata
- 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 › Hepatology › 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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