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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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“While apoptotic bodies of hepatocytes are primarily eliminated by macrophages [32], HSCs can also engulf the apoptotic bodies, which can trigger fibrogenesis and promote HSC survival by increasing anti-apoptotic proteins such as myeloid cell leukemia-1 (Mcl-1) and Bcl-2-related protein A1 [33, 61].”
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“Enhanced apoptosis associated with hepatic IR, as we have shown herein, may lead to activation of hepatic stellate cells (HSC) either by the engulfment of apoptotic cells [40] or by a direct effect of Kupffer cells following phagocytosis of apoptotic bodies [41].”
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“Phagocytosis of an apoptotic body triggers a profi brogenic response with upregulation of TGF-β1 and procollagen α1(I) expression.(28) Phagocytosis of an apoptotic body by hepatic stellate cells is associated with liver fi brosis in vivo.”
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Self-citationHepatic Stellate Cells and Liver Fibrosis
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Self-citationThe Many Roles of Cell Adhesion Molecules in Hepatic Fibrosis
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Self-citationRole and Cellular Source of Nicotinamide Adenine Dinucleotide Phosphate Oxidase in Hepatic Fibrosis
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“Increased apoptosis and inflammation are also hallmarks of active hepatitis C infection, and the resulting release of hepatic microvesicles/apoptotic bodies triggers inflammation and fibrosis upon phagocytosis by Kupffer cells and hepatic stellate cells.(25,26) HCV infection results in death receptor–mediated mitochon…”
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Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC
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“Activated hepatic stellate cells can also engulf apoptotic hepatocytes, which in turn lead to increases in tumor growth factor-β (TGF-β) secretion (7).”
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“Inflammationmediated hepatocyte cell death and its engulfment by HSC result in a profibrogenic response and also activate Kupffer cells [8, 9].”
BackgroundAlpha-1 antitrypsin Z protein (PiZ) increases hepatic fibrosis in a murine model of cholestasis
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“response, and apoptotic bodies can activate HSCs and promote their transition to myofibroblasts, which enhance fibrogenesis (Canbay et al., 2003).”
BackgroundCD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in mice
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“In particular, non-phagocytic NOX components as well as phagocytic NOX are upregulated in activated HSCs compared to quiescent HSCs.42 Wild-type HSCs express the mRNAs for both phagocytic NOX2 and non-phagocytic NOX including NOX1 and NOX4.”
BackgroundInfluentialMonitoring fibrogenic progression in the liver
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“It was shown that pro-fibrogenic response was dependent upon apoptotic body engulfment, since nocodazole, a microtubule-inhibiting agent, blocked both the engulfment and the increase of TGF-β1 and collagen alpha1(I) mRNA (Canbay et al. 2003a, b).”
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“[16] [17] In addition to the classical modes of cell death, such as apoptosis and necrosis (oncosis), other forms of hepatic cell death have been more recently described in preclinical models and patients with NASH, including autophagic cell death, pyroptosis, and necroptosis.”
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Glycochenodeoxycholate Promotes Liver Fibrosis in Mice with Hepatocellular Cholestasis
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Mitochondrial DNA and the STING pathway are required for hepatic stellate cell activation
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“Phagocytosis of the hepatocyte-derived apoptotic bodies directly induces HSC activation and matrix deposition as it up-regulates TGF-β1 and induces collagen α1(I) through PI3K and p38MAPK pathways [46, 48, 49].”
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“These cells may become activated by the phagocytosis of apoptotic bodies resulting from hepatocyte death (234).”
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“Engulfment of apoptotic bodies by hepatic stellate cells (HSCs) stimulates fibrogenic activity [20]; and theDNA from apoptotic hepatocytes can act as an important mediator of HSC activation and differentiation [21].”
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BackgroundIn Vitro and In Vivo Protection of Stellate Cells from Apoptosis by Leptin
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“Several studies have proposed that the phagocytosis of apoptotic bodies by HSCs links cell death to HSC activation, showing increased HSC activation and survival after the phagocytosis of apoptotic bodies in vitro (33-35).”
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“Firstly, ethanol metabolism activates and upregulates TGF-beta, while subsequent ethanol-induced apoptosis of hepatocytes primes Kupffer cells and HSCs to upregulate TGF-beta (22-24).”
BackgroundTherapeutic modulation of the liver immune microenvironment
Tilg, H., Adolph, T. E., & Tacke, F. (2023) · Hepatology · doi:10.1097/hep.0000000000000386 · Cited by 32
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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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