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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]
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“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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“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…”
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“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
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TNF-Receptor-1 inhibition reduces liver steatosis, hepatocellular injury and fibrosis in NAFLD mice
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Succinate is a paracrine signal for liver damage
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“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].”
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BackgroundSteatosis and liver cell apoptosis in chronic hepatitis C: A mechanism for increased liver injury
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“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?
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BackgroundAmelioration of hepatic fibrosis by NK cell activation
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“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.”
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“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.”
BackgroundApoptosis and Cytokines in Non-Alcoholic Steatohepatitis
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“In a similar fashion, engulfment of apoptotic bodies by primary or immortalized HSC was shown to trigger their own activation and promote fibrosis (48).”
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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