The DOI matches its Crossref record; 40 of the 42 references it cites were found in a registry or an index.
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
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“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
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Corpse clearance defines the meaning of cell death
Savill, J., & Fadok, V. A. (2000) · Nature · doi:10.1038/35037722 · Cited by 1,572
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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
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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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