Hepatic Stellate Cell–Macrophage Crosstalk in Liver Fibrosis and Carcinogenesis

AbstractChronic liver injury due to viral hepatitis, alcohol abuse, and metabolic disorders is a worldwide health concern. Insufficient treatment of chronic liver injury leads to fibrosis, causing liver dysfunction and carcinogenesis. Most cases of hepatocellular carcinoma (HCC) develop in the fibrotic liver. Pathological features of liver fibrosis include extracellular matrix (ECM) accumulation, mesenchymal cell activation, immune deregulation, and angiogenesis, all of which contribute to the precancerous environment, supporting tumor development. Among liver cells, hepatic stellate cells (HSCs) and macrophages play critical roles in fibrosis and HCC. These two cell types interplay and remodel the ECM and immune microenvironment in the fibrotic liver. Once HCC develops, HCC-derived factors influence HSCs and macrophages to switch to protumorigenic cell populations, cancer-associated fibroblasts and tumor-associated macrophages, respectively. This review aims to summarize currently available data on the roles of HSCs and macrophages in liver fibrosis and HCC, with a focus on their interaction.

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3D hESC exosomes enriched with miR-6766-3p ameliorates liver fibrosis by attenuating activated stellate cells through targeting the TGFβRII-SMADS pathway

10.21203/rs.3.rs-736691/v1 ◽

2021 ◽

Author(s):

Ning Wang ◽

Xiajing Li ◽

Zhiyong Zhong ◽

Yaqi Qiu ◽

Shoupei Liu ◽

...

Keyword(s):

Stem Cells ◽

Liver Fibrosis ◽

Liver Injury ◽

Cell Activation ◽

Therapeutic Potential ◽

Stellate Cell ◽

Embryonic Stem ◽

Luciferase Reporter ◽

Fibrotic Liver

Abstract BackgroundExosomes secreted from stem cells exerted salutary effects on the fibrotic liver. Herein, the roles of exosomes derived from human embryonic stem cell (hESC) in anti-fibrosis were extensively investigated. Compared with two-dimensional (2D) culture, the clinical and biological relevance of three-dimensional (3D) cell spheroids were greater because of their higher regeneration potential since they behave more like cells in vivo. In our study, exosomes derived from 3D human embryonic stem cells (hESC) spheroids and the monolayer (2D) hESCs were collected and compared the therapeutic potential for fibrotic liver in vitro and in vivo. ResultsIn vitro, PKH26 labled-hESC-Exosomes were shown to be internalized and integrated into TGFβ-activated-LX2 cells, and reduced the expression of profibrogenic markers, thereby regulating cellular phenotypes. TPEF imaging indicated that PKH26-labled-3D-hESC-Exsomes possessed an enhanced capacity to accumulate in the livers and exhibited more dramatic therapeutic potential in the injured livers of fibrosis mouse model. 3D-hESC-Exosomes decreased profibrogenic markers and liver injury markers, and improved the level of liver functioning proteins, eventually restoring liver function of fibrosis mice. miRNA array revealed a significant enrichment of miR-6766-3p in 3D-hESC-Exosomes, moreover, bioinformatics and dual luciferase reporter assay identified and confirmed the TGFβRII gene as the target of miR-6766-3p. Furthermore, the delivery of miR-6766-3p into activated-LX2 cells decreased cell proliferation, chemotaxis and profibrotic effects, and further investigation demonstrated that the expression of target gene TGFβRII and its downstream SMADs proteins, especially phosphorylated protein p-SMAD2/3 was also notably down-regulated by miR-6766-3p. These findings unveiled that miR-6766-3p in 3D-hESC-Exosomes inactivated SMADs signaling by inhibiting TGFβRII expression, consequently attenuating stellate cell activation and suppressing liver fibrosis. ConclusionsOur results showed that miR-6766-3p in the 3D-hESC-Exosomes inactivates smads signaling by restraining TGFβRII expression, attenuated LX2 cell activation and suppressed liver fibrosis, suggesting that 3D-hESC-Exosome enriched-miR6766-3p is a novel anti-fibrotic therapeutics for treating chronic liver disease. These results also proposed a significant strategy that 3D-Exo could be used as natural nanoparticles to rescue liver injury via delivering antifibrotic miR-6766-3p.

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Possible Therapeutic Uses of Extracellular Vesicles for Reversion of Activated Hepatic Stellate Cells: Context and Future Perspectives

Current Molecular Medicine ◽

10.2174/1566524021666210218113928 ◽

2021 ◽

Vol 21 ◽

Author(s):

Fahim Rejanur Tasin ◽

Debasish Halder ◽

Chanchal Mandal

Keyword(s):

Liver Fibrosis ◽

Extracellular Vesicles ◽

Hepatic Stellate Cells ◽

Cell Activation ◽

Stellate Cell ◽

Stellate Cells ◽

Target Cells ◽

Fibrotic Liver ◽

Paracrine Effects ◽

Cell Therapies

: Liver fibrosis is one of the leading causes for cirrhotic liver disease and the lack of therapies to treat fibrotic liver is a major concern. Liver fibrosis is mainly occurred by activation of hepatic stellate cells and some stem cell therapies had previously reported for treatment. However, due to some problems with cell-based treatment, a safe therapeutic agent is vehemently sought by the researchers. Extracellular vesicles are cell-derived nanoparticles that are employed in several therapeutic approaches, including fibrosis, for their ability to transfer specific molecules in the target cells. In this review the possibilities of extracellular vesicles to inactivate stellate cells are summarized and discussed. According to several studies, extracellular vesicles from different sources can either put beneficial or detrimental effects by regulating the activation of stellate cells. Therefore, targeting extracellular vesicles for maximizing or inhibiting their production is a potential approach for fibrotic liver treatment. Extracellular vesicles from different cells can also inactivate stellate cells by carrying out the paracrine effects of those cells, working as the agents. They are also implicated as smart carrier of anti-fibrotic molecules when their respective parent cells are engineered to produce specific stellate cell-regulating substances. A number of studies showed stellate cell activation can be regulated by up/downregulation of specific proteins, and extracellular vesicle-based therapies can be an effective move to exploit these mechanisms. In conclusion, EVs are advantageous nano-carriers with the potential to treat fibrotic liver by inactivating activated stellate cells by various mechanisms.

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CD248/endosialin critically regulates hepatic stellate cell proliferation during chronic liver injury via a PDGF-regulated mechanism

Gut ◽

10.1136/gutjnl-2014-308325 ◽

2015 ◽

Vol 65 (7) ◽

pp. 1175-1185 ◽

Cited By ~ 32

Author(s):

Annika Wilhelm ◽

Victoria Aldridge ◽

Debashis Haldar ◽

Amy J Naylor ◽

Christopher J Weston ◽

...

Keyword(s):

Cell Proliferation ◽

Liver Injury ◽

Hepatic Stellate Cell ◽

Stellate Cell ◽

Chronic Liver ◽

Chronic Liver Injury

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Cellular Mechanisms of Tissue Fibrosis. 5. Novel insights into liver fibrosis

AJP Cell Physiology ◽

10.1152/ajpcell.00230.2013 ◽

2013 ◽

Vol 305 (8) ◽

pp. C789-C799 ◽

Cited By ~ 137

Author(s):

Ariane Mallat ◽

Sophie Lotersztajn

Keyword(s):

Liver Fibrosis ◽

Liver Injury ◽

Cell Injury ◽

Parenchymal Cell ◽

Chronic Liver ◽

Special Focus ◽

Chronic Liver Injury ◽

Cellular Mechanisms ◽

Extracellular Matrix Components ◽

Liver Fibrogenesis

Liver fibrosis is the common scarring reaction associated with chronic liver injury that results from prolonged parenchymal cell injury and/or inflammation. The fibrogenic response is characterized by progressive accumulation of extracellular matrix components enriched in fibrillar collagens and a failure of matrix turnover. This process is driven by a heterogeneous population of hepatic myofibroblasts, which mainly derive from hepatic stellate cells and portal fibroblasts. Regression of fibrosis can be achieved by the successful control of chronic liver injury, owing to termination of the fibrogenic reaction following clearance of hepatic myofibroblasts and restoration of fibrolytic pathways. Understanding of the complex network underlying liver fibrogenesis has allowed the identification of a large number of antifibrotic targets, but no antifibrotic drug has as yet been approved. This review will highlight recent advances regarding the mechanisms that regulate liver fibrogenesis and fibrosis regression, with special focus on novel signaling pathways and the role of inflammatory cells. Translation of these findings to therapies will require continued efforts to develop multitarget therapeutic approaches that will improve the grim prognosis of liver cirrhosis.

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Baihe Wuyao decoction ameliorates CCl4-induced chronic liver injury and liver fibrosis in mice through blocking TGF-β1/Smad2/3 signaling, anti-inflammation and anti-oxidation effects

Journal of Ethnopharmacology ◽

10.1016/j.jep.2020.113227 ◽

2020 ◽

Vol 263 ◽

pp. 113227

Author(s):

Yajing Chen ◽

Ruofei Li ◽

Nan Hu ◽

Chunping Yu ◽

Hongyu Song ◽

...

Keyword(s):

Liver Fibrosis ◽

Liver Injury ◽

Chronic Liver ◽

Chronic Liver Injury ◽

Anti Inflammation ◽

Tgf Β1

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Liver fibrosis is driven by protease‐activated receptor‐1 expressed by hepatic stellate cells in experimental chronic liver injury

Research and Practice in Thrombosis and Haemostasis ◽

10.1002/rth2.12403 ◽

2020 ◽

Vol 4 (5) ◽

pp. 906-917

Author(s):

Lauren G. Poole ◽

Asmita Pant ◽

Holly M. Cline‐Fedewa ◽

Kurt J. Williams ◽

Bryan L. Copple ◽

...

Keyword(s):

Liver Fibrosis ◽

Liver Injury ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Chronic Liver ◽

Chronic Liver Injury ◽

Protease Activated Receptor 1

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LC3-associated phagocytosis protects against inflammation and liver fibrosis via immunoreceptor inhibitory signaling

Science Translational Medicine ◽

10.1126/scitranslmed.aaw8523 ◽

2020 ◽

Vol 12 (539) ◽

pp. eaaw8523 ◽

Cited By ~ 4

Author(s):

JingHong Wan ◽

Emmanuel Weiss ◽

Sanae Ben Mkaddem ◽

Morgane Mabire ◽

Pierre-Marie Choinier ◽

...

Keyword(s):

Liver Fibrosis ◽

Liver Injury ◽

Systemic Inflammation ◽

Multiorgan Failure ◽

Chronic Liver ◽

Human Monocytes ◽

Macrophage Phenotype ◽

Chronic Liver Injury ◽

Inflammatory Profile ◽

Inhibitory Signaling

Sustained hepatic and systemic inflammation, particularly originating from monocytes/macrophages, is a driving force for fibrosis progression to end-stage cirrhosis and underlies the development of multiorgan failure. Reprogramming monocyte/macrophage phenotype has emerged as a strategy to limit inflammation during chronic liver injury. Here, we report that LC3-associated phagocytosis (LAP), a noncanonical form of autophagy, protects against hepatic and systemic inflammation during chronic liver injury in rodents, with beneficial antifibrogenic effects. LAP is enhanced in blood and liver monocytes from patients with fibrosis and cirrhosis. Pharmacological inhibition of LAP components in human monocytes from patients with cirrhosis or genetic disruption of LAP in mice with chronic liver injury exacerbates both the inflammatory signature in isolated human monocytes and the hepatic inflammatory profile in mice, resulting in enhanced liver fibrosis. Mechanistically, patients with cirrhosis showed increased monocyte expression of Fc fragment of IgG receptor IIA (FcγRIIA) and enhanced engulfment of immunoglobulin G in LC3+ phagosomes that triggers an FcγRIIA/Src homology region 2 domain–containing phosphatase-1 (SHP-1) inhibitory immunoreceptor tyrosine-based activation motif (ITAMi) anti-inflammatory pathway. Mice overexpressing human FcγRIIA in myeloid cells show enhanced LAP in response to chronic liver injury and resistance to inflammation and liver fibrosis. Activation of LAP is lost in monocytes from patients with multiorgan failure and restored by specifically targeting ITAMi signaling with anti-FcγRIIA F(ab′)2 fragments, or with intravenous immunoglobulin (IVIg). These data suggest the existence of an ITAMi-mediated mechanism by which LAP might protect against inflammation. Sustaining LAP may open therapeutic perspectives for patients with chronic liver disease.

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Aspirin induces autophagy and alleviates liver fibrosis by reducing oxidative stress and inflammation in mice model of chronic liver injury

Journal of Hepatology ◽

10.1016/s0168-8278(20)31532-4 ◽

2020 ◽

Vol 73 ◽

pp. S527

Author(s):

Adil Bhat ◽

Sudrishti Chaudhary ◽

Gaurav Yadav ◽

Anupama Parasar ◽

Chhagan Bihari ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Fibrosis ◽

Liver Injury ◽

Chronic Liver ◽

Mice Model ◽

Chronic Liver Injury

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PTPRO-Associated Hepatic Stellate Cell Activation Plays a Critical Role in Liver Fibrosis

Cellular Physiology and Biochemistry ◽

10.1159/000369746 ◽

2015 ◽

Vol 35 (3) ◽

pp. 885-898 ◽

Cited By ~ 4

Author(s):

Xudong Zhang ◽

Zhongming Tan ◽

Youjing Wang ◽

Junwei Tang ◽

Runjiu Jiang ◽

...

Keyword(s):

Liver Fibrosis ◽

Cell Activation ◽

Ischemia Reperfusion Injury ◽

Stellate Cell ◽

Ischemia Reperfusion ◽

Critical Role ◽

Inflammatory Factors ◽

Hepatic Ischemia ◽

Fibrotic Liver ◽

Duct Ligation

Background/Aims: PTPRO (protein tyrosine phosphatase, receptor type O) is implicated in diverse physiological and pathological processes in cancer and hepatic ischemia/reperfusion injury, although little is known about its role in hepatic fibrosis. Methods: Here, by using genetically deficient mice, we reported that PTPRO knockout (PTPRO-/-) significantly attenuated liver injury, release of inflammatory factors, tissue remodeling, and liver fibrosis in two experimental mouse models of fibrogenesis induced by bile-duct ligation or carbon tetrachloride administration. Results: However, we proved that PTPRO expression was strongly downregulated in clinical and experimental liver fibrosis specimens. Further investigations revealed that stimulation of primary hepatic stellate cells (HSCs) and hepatocytes with specific activator platelet-derived growth factor (PDGF)-BB increased PTPRO transcription in HSCs but had the opposite effect in primary hepatocytes. More importantly, synthetic short hairpin RNA targeting PTPRO significantly neutralized PDGF-BB-induced HSC proliferation and myofibroblast marker expression through downregulated phosphorylation of extracellular signal-regulated kinase (ERK) and AKT. Conclusion: These observations confirm that PTPRO plays a critical role in liver fibrogenesis by affecting PDGF signaling in HSC activation and might be developed into a feasible therapeutic approach for the treatment of chronic fibrotic liver diseases.

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