ArticleStem cell research & therapy2022
Notch-activated mesenchymal stromal/stem cells enhance the protective effect against acetaminophen-induced acute liver injury by activating AMPK/SIRT1 pathway.
Article in Stem cell research & therapy, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 26 citations in OpenAlex.
- [Mechanisms by which interleukin-18 binding protein regulates the NLRP3 inflammasome in Kawasaki disease-related coronary artery lesions].Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics · 2026Review
- MSCs overexpressing FGF21 alleviate acetaminophen-induced acute liver injury by eliciting macrophage-mediated phagocytosis.Hepatology communications · 2026Article
- Human umbilical cord-derived mesenchymal stem cell exosomes ameliorate hepatocyte ferroptosis and sepsis-associated liver injury by restoring iron homeostasis in hepatocytes.Journal of nanobiotechnology · 2026Article
- Harnessing MSCs plasticity: mechanisms and determinants of bidirectional immune regulation in stem-cell-based immunotherapy.Stem cell research & therapy · 2026Review
- Mesenchymal Stromal/Stem Cell-Based Therapies for Liver Regeneration: Current Status and Future Directions.International journal of molecular sciences · 2026Review
- Notch signaling in liver diseases: mechanistic insights and therapeutic implications.Frontiers in cell and developmental biology · 2026Review
- Adipose-derived mesenchymal stem cell therapy modulates mitochondrial function to attenuate acetaminophen-induced liver injury by DDIT4/PGC-1α axis.Stem cell research & therapy · 2025Article
- Hepatocyte cellular repressor of E1A-stimulated genes 1 protects against acetaminophen-induced liver injury by promoting autophagy.Acta pharmacologica Sinica · 2025Article
- Exosomes derived from human umbilical cord mesenchymal stem cells inhibit hepatocyte pyroptosis via miR-423-5p/ZBP1 in acute liver failure.Human cell · 2025Article
- Conserved spatial subtypes and cellular neighborhoods of cancer-associated fibroblasts revealed by single-cell spatial multi-omics.Cancer cell · 2025Article
- Roles of X-box binding protein 1 in liver pathogenesis.Clinical and molecular hepatology · 2025Review
- Exendin-4 Reduces Senescence of Inflammation-Induced Periodontal Ligament Stem Cells Through SIRT1/Notch1 Signaling.Stem cells international · 2025Article
- [MiR-139-5p regulates the Notch/RBP-J/Hes1 axis to promote homing of bone mesenchymal stem cells in bronchial asthma].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2024Article
- Mesenchymal stem cells-derived exosomes alleviate liver fibrosis by targeting Hedgehog/SMO signaling.Hepatology international · 2024Article
- Mesenchymal stromal cells alleviate APAP-induced liver injury via extracellular vesicle-mediated regulation of the miR-186-5p/CXCL1 axis.Stem cell research & therapy · 2024Article
- Metabolic mechanisms orchestrated by Sirtuin family to modulate inflammatory responses.Frontiers in immunology · 2024Review
- Ethanol Extract ofMolecules (Basel, Switzerland) · 2023Article
- Isolation, culture, and delivery considerations for the use of mesenchymal stem cells in potential therapies for acute liver failure.Frontiers in immunology · 2023Review
- Advances in Mesenchymal stem cells regulating macrophage polarization and treatment of sepsis-induced liver injury.Frontiers in immunology · 2023Review
- The sirtuin family in health and disease.Signal transduction and targeted therapy · 2022Review
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundNotch signaling plays important roles in regulating innate immunity. However, little is known about the role of Notch in mesenchymal stromal/stem cell (MSC)-mediated immunomodulation during liver inflammatory response.
methodsNotch activation in human umbilical cord-derived MSCs was performed by a tissue culture plate coated with Notch ligand, recombinant human Jagged1 (JAG1). Mice were given intravenous injection of Notch-activated MSCs after acetaminophen (APAP)-induced acute liver injury. Liver tissues were collected and analyzed by histology and immunohistochemistry.
resultsMSC administration reduced APAP-induced hepatocellular damage, as manifested by decreased serum ALT levels, intrahepatic macrophage/neutrophil infiltration, hepatocellular apoptosis and proinflammatory mediators. The anti-inflammatory activity and therapeutic effects of MSCs were greatly enhanced by Notch activation via its ligand JAG1. However, Notch2 disruption in MSCs markedly diminished the protective effect of MSCs against APAP-induced acute liver injury, even in the presence of JAG1 pretreatment. Strikingly, Notch-activated MSCs promoted AMP-activated protein kinase (AMPKα) phosphorylation, increased the sirtuins 1 (SIRT1) deacetylase expression, but downregulated spliced X-box-binding protein 1 (XBP1s) expression and consequently reduced NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation. Furthermore, SIRT1 disruption or XBP1s overexpression in macrophages exacerbated APAP-triggered liver inflammation and augmented NLRP3/caspase-1 activity in MSC-administrated mice. Mechanistic studies further demonstrated that JAG1-pretreated MSCs activated Notch2/COX2/PGE2 signaling, which in turn induced macrophage AMPK/SIRT1 activation, leading to XBP1s deacetylation and inhibition of NLRP3 activity.
conclusionsActivation of Notch2 is required for the ability of MSCs to reduce the severity of APAP-induced liver damage in mice. Our findings underscore a novel molecular insights into MSCs-mediated immunomodulation by activating Notch2/COX2/AMPK/SIRT1 pathway and thus provide a new strategy for the treatment of liver inflammatory diseases.
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