Hepatic stellate cell senescence in liver fibrosis: Characteristics, mechanisms and perspectives. (October 2021)

• Record Type: Journal Article
• Authors: Zhang, Mengfan; Serna-Salas, Sandra; Damba, Turtushikh; Borghesan, Michaela; Demaria, Marco; Moshage, Han
• Is Part Of: Mechanisms of ageing and development. Volume 199(2021)
• Publication Date: 2021-10
• Subjects: ECM extracellular matrix -- MSC mesenchymal stromal cell -- HSC hepatic stellate cell -- qHSC quiescent hepatic stellate cell -- aHSC activated hepatic stellate cell -- iHSC inactivated hepatic stellate cell -- PF portal fibroblast -- PDGFRβ platelet-derived growth factor receptor-β -- LRAT lecithin retinol acyltransferase -- GFAP glial fibrillary acidic protein -- ACAT2 alpha smooth muscle actin 2 -- COL1A1 collagen type 1 alpha 1 -- PPARG proliferator-activated receptor gamma -- TIMP1 metallopeptidase inhibitor 1 -- DDR DNA damage response -- SA-β-Gal senescence-associated β galactosidase -- SAHF Senescence-associated heterochromatin foci -- CDKI cyclin-dependent kinase inhibitors -- CDKN1A cyclin dependent kinase inhibitor 1a -- CDKN2A cyclin dependent kinase inhibitor 2a -- PCNA proliferating cell nuclear antigen -- SASP senescence-associated secretory phenotype -- PAI-1 plasminogen activator inhibitor 1 -- GFBP7 insulin-like growth factor-binding protein 7 -- IL-8 interleukin-8 -- CXCL1 C-X-C Motif Chemokine Ligand 1 -- IL-6 interleukin-6 -- H3K4me3 histone 3 lysine 4 trimethylation -- LAD lamin-associated domain -- UPR unfolded protein response -- ROS reactive oxygen species -- SSB single-strand DNA break -- DSB double-strand DNA break -- MRN complex Mre11-Rad50-Nbs1 complex -- ATM Ataxia-Telangiectasia Mutated kinase -- ATR Ataxia-Telangiectasia Rad3-related kinase -- CHK1 check point kinase 1 -- CHK2 check point kinase 2 -- PARP poly-(ADP)ribose polymerase -- NF-κB nuclear factor-kappa B -- C/EBPβ CCAAT/enhancer binding protein β -- IKK IκB kinase -- NIK NF-κB-inducing kinase -- PI3K phosphatidylinositol-3-kinase -- GSK3 Glycogen Synthase Kinase 3 -- FOXO Forkhead box O family -- TSC2 Tuberous Sclerosis Complex 2 -- SOD2 Superoxide dismutase 2 -- mTOR mammalian target of rapamycin -- mTORC1 mTOR complex 1 -- mTORC2 mTOR complex 2 -- S6K1 p70S6 Kinase 1 -- 4EBP eIF4E Binding Protein -- PGC1α Peroxisome proliferator-activated receptor gamma coactivator 1-alpha -- NAD nicotinamide adenine dinucleotide -- CMA chaperone-mediated autophagy -- HSC70 heat shock cognate protein 71 kDa -- LAMP2A lysosome-associated membrane protein type 2a -- NEF2L2 Nuclear Factor, Erythroid 2 Like 2 -- PLP pyridoxal-5'-phosphate -- CBS cystathionine β-synthase -- CTH cystathionine γ-lyase -- KEAP1 kelch like ECH associated protein 1 -- STAT3 signal transducers and activators of transcription 3 -- G-CSF granulocyte colony-stimulating factor -- EIF2AK2 eukaryotic translation initiation factor 2 alpha kinase 2 -- SOSC3 suppressor of cytokine signaling 3 -- AR adrenergic receptor -- CaM Calmodulin -- CCl4 carbon tetrachloride -- NAFLD non-alcoholic fatty liver disease -- LSEC liver sinusoidal endothelial cell -- uPAR urokinase-type plasminogen activator receptor -- CAR chimeric antigen receptor -- cGAS cyclic GMP-AMP synthase -- STING stimulator of interferon genes protein -- CCF cytoplasmic chromatin fragments; Liver fibrosis -- Hepatic stellate cells -- Senescence -- Oxidative stress; Aging -- Periodicals; Developmental biology -- Periodicals; Aging -- Periodicals; Developmental Biology -- Periodicals; Vieillissement -- Périodiques; Biologie du développement -- Périodiques; Aging; Developmental biology; Periodicals; 612.67
• DOI: 10.1016/j.mad.2021.111572
• Languages: English
• ISSNs: 0047-6374

Abstract

Highlights: This review discusses the basic mechanism of cell senescence, in particular hepatic stellate cells. The role of hepatic stellate cell senescence in liver fibrosis is discussed in detail. Discussion of the potential of inducing stellate cell senescence for therapeutic intervention. Abstract: Myofibroblasts play an important role in fibrogenesis. Hepatic stellate cells are the main precursors of myofibroblasts. Cellular senescence is the terminal cell fate in which proliferating cells undergo irreversible cell cycle arrest. Senescent hepatic stellate cells were identified in liver fibrosis. Senescent hepatic stellate cells display decreased collagen production and proliferation. Therefore, induction of senescence could be a protective mechanism against progression of liver fibrosis and the concept of therapy-induced senescence has been proposed to treat liver fibrosis. In this review, characteristics of senescent hepatic stellate cells and the essential signaling pathways involved in senescence are reviewed. Furthermore, the potential impact of senescent hepatic stellate cells on other liver cell types are discussed. Senescent cells are cleared by the immune system. The persistence of senescent cells can remodel the microenvironment and interact with inflammatory cells to induce aging-related dysfunction. Therefore, senolytics, a class of compounds that selectively induce death of senescent cells, were introduced as treatment to remove senescent cells and consequently decrease the disadvantageous effects of persisting senescent cells. The effects of senescent hepatic stellate cells in liver fibrosis need further investigation.