SECs (Sinusoidal Endothelial Cells), Liver Microenvironment, and Fibrosis

Liver fibrosis is a wound-healing response to chronic liver injury such as alcoholic/nonalcoholic fatty liver disease and viral hepatitis with no FDA-approved treatments. Liver fibrosis results in a continual accumulation of extracellular matrix (ECM) proteins and paves the way for replacement of parenchyma with nonfunctional scar tissue. The fibrotic condition results in drastic changes in the local mechanical, chemical, and biological microenvironment of the tissue. Liver parenchyma is supported by an efficient network of vasculature lined by liver sinusoidal endothelial cells (LSECs). These nonparenchymal cells are highly specialized resident endothelial cell type with characteristic morphological and functional features. Alterations in LSECs phenotype including lack of LSEC fenestration, capillarization, and formation of an organized basement membrane have been shown to precede fibrosis and promote hepatic stellate cell activation. Here, we review the interplay of LSECs with the dynamic changes in the fibrotic liver microenvironment such as matrix rigidity, altered ECM protein profile, and cell-cell interactions to provide insight into the pivotal changes in LSEC physiology and the extent to which it mediates the progression of liver fibrosis. Establishing the molecular aspects of LSECs in the light of fibrotic microenvironment is valuable towards development of novel therapeutic and diagnostic targets of liver fibrosis.

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The mechanism of increased intestinal palmitic acid absorption and its impact on hepatic stellate cell activation in nonalcoholic steatohepatitis

Scientific Reports ◽

10.1038/s41598-021-92790-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Masakazu Hanayama ◽

Yasunori Yamamoto ◽

Hiroki Utsunomiya ◽

Osamu Yoshida ◽

Shuang Liu ◽

...

Keyword(s):

Liver Fibrosis ◽

Portal Vein ◽

Palmitic Acid ◽

Intestinal Absorption ◽

Nonalcoholic Steatohepatitis ◽

Cell Activation ◽

Stellate Cell ◽

Mrna Levels ◽

Nonalcoholic Fatty Liver ◽

Chylomicron Formation

AbstractDietary palmitic acid (PA) promotes liver fibrosis in patients with nonalcoholic steatohepatitis (NASH). Herein, we clarified the intestinal absorption kinetics of dietary PA and effect of trans-portal PA on the activation of hepatic stellate cells (HSCs) involved in liver fibrosis in NASH. Blood PA levels after meals were significantly increased in patients with NASH compared to those in the control. Expression of genes associated with fat absorption and chylomicron formation, such as CD36 and MTP, was significantly increased in the intestine of NASH model rats compared with that in the controls. Plasma levels of glucagon-like peptide-2, involved in the upregulation of CD36 expression, were elevated in NASH rats compared with those in the controls. Furthermore, portal PA levels after meals in NASH rats were significantly higher than those in control and nonalcoholic fatty liver rats. Moreover, PA injection into the portal vein to the liver in control rats increased the mRNA levels associated with the activation of HSCs. Increased intestinal absorption of diet-derived PA was observed in NASH. Thus, the rapid increase in PA levels via the portal vein to the liver may activate HSCs and affect the development of liver fibrosis in NASH.

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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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Liver Sinusoidal Endothelial Cells Contribute to Hepatic Antigen-Presenting Cell Function and Th17 Expansion in Cirrhosis

Cells ◽

10.3390/cells9051227 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1227

Author(s):

Esther Caparrós ◽

Oriol Juanola ◽

Isabel Gómez-Hurtado ◽

Amaya Puig-Kroger ◽

Paula Piñero ◽

...

Keyword(s):

Endothelial Cells ◽

T Cell ◽

Bile Duct ◽

T Cell Activation ◽

Cell Activation ◽

Experimental Models ◽

Cd4 T Cell ◽

Liver Sinusoidal Endothelial Cells ◽

Sinusoidal Endothelial Cells ◽

Bacterial Peritonitis

Hepatic immune function is compromised during cirrhosis. This study investigated the immune features of liver sinusoidal endothelial cells (LSECs) in two experimental models of cirrhosis. Dendritic cells, hepatic macrophages, and LSECs were isolated from carbon tetrachloride and bile duct-ligated rats. Gene expression of innate receptors, bacterial internalization, co-stimulatory molecules induction, and CD4+ T cell activation and differentiation were evaluated. Induced bacterial peritonitis and norfloxacin protocols on cirrhotic rats were also carried out. LSECs demonstrated an active immunosurveillance profile, as shown by transcriptional modulation of different scavenger and cell-adhesion genes, and their contribution to bacterial internalization. LSECs significantly increased their expression of CD40 and CD80 and stimulated CD4+ T cell activation marker CD71 in both models. The pro-inflammatory Th17 subset was expanded in CCl4-derived LSECs co-cultures. In the bile duct ligation (BDL) model, CD4+ T cell differentiation only occurred under induced bacterial peritonitis conditions. Differentiated pro-inflammatory Th cells by LSECs in both experimental models were significantly reduced with norfloxacin treatment, whereas Foxp3 tolerogenic Th CD4+ cells were expanded. Conclusion: LSECs’ participation in the innate-adaptive immune progression, their ability to stimulate pro-inflammatory CD4+ T cells expansion during liver damage, and their target role in norfloxacin-induced immunomodulation granted a specific competence to this cell population in cirrhosis.

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The Endothelium as a Driver of Liver Fibrosis and Regeneration

Cells ◽

10.3390/cells9040929 ◽

2020 ◽

Vol 9 (4) ◽

pp. 929 ◽

Cited By ~ 7

Author(s):

Erica Lafoz ◽

Maria Ruart ◽

Aina Anton ◽

Anna Oncins ◽

Virginia Hernández-Gea

Keyword(s):

Endothelial Cells ◽

Liver Fibrosis ◽

Liver Injury ◽

Stellate Cell ◽

Public Health Problem ◽

Cell Types ◽

Regenerative Process ◽

Research Field ◽

Major Public Health Problem ◽

Liver Sinusoidal Endothelial Cells

Liver fibrosis is a common feature of sustained liver injury and represents a major public health problem worldwide. Fibrosis is an active research field and discoveries in the last years have contributed to the development of new antifibrotic drugs, although none of them have been approved yet. Liver sinusoidal endothelial cells (LSEC) are highly specialized endothelial cells localized at the interface between the blood and other liver cell types. They lack a basement membrane and display open channels (fenestrae), making them exceptionally permeable. LSEC are the first cells affected by any kind of liver injury orchestrating the liver response to damage. LSEC govern the regenerative process initiation, but aberrant LSEC activation in chronic liver injury induces fibrosis. LSEC are also main players in fibrosis resolution. They maintain liver homeostasis and keep hepatic stellate cell and Kupffer cell quiescence. After sustained hepatic injury, they lose their phenotype and protective properties, promoting angiogenesis and vasoconstriction and contributing to inflammation and fibrosis. Therefore, improving LSEC phenotype is a promising strategy to prevent liver injury progression and complications. This review focuses on changes occurring in LSEC after liver injury and their consequences on fibrosis progression, liver regeneration, and resolution. Finally, a synopsis of the available strategies for LSEC-specific targeting is provided.

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Hepatic Stellate Cell–Macrophage Crosstalk in Liver Fibrosis and Carcinogenesis

Seminars in Liver Disease ◽

10.1055/s-0040-1708876 ◽

2020 ◽

Vol 40 (03) ◽

pp. 307-320

Author(s):

Michitaka Matsuda ◽

Ekihiro Seki

Keyword(s):

Liver Fibrosis ◽

Liver Injury ◽

Cell Activation ◽

Stellate Cell ◽

Tumor Development ◽

Mesenchymal Cell ◽

Chronic Liver ◽

Health Concern ◽

Chronic Liver Injury ◽

Fibrotic Liver

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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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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Inhibition of liver sinusoidal endothelial cells in rats with hepatic fibrosis by injection of VEGF 165 via the inferior vena cava

10.21203/rs.3.rs-200465/v1 ◽

2021 ◽

Author(s):

Zhigang Sun ◽

Tianyi Dong ◽

Zhun Zhang ◽

Tiantian Wang ◽

Chenyu Zhang ◽

...

Keyword(s):

Electron Microscopy ◽

Transmission Electron Microscopy ◽

Endothelial Cells ◽

Liver Fibrosis ◽

Serum Level ◽

Basement Membranes ◽

Liver Sinusoidal Endothelial Cells ◽

Sinusoidal Endothelial Cells ◽

Transmission Electron

Abstract Background Although VEGF can maintain the normal phenotype of liver sinusoidal endothelial cells (LSECs), it has also been reported that VEGF exacerbates cirrhosis. The role of VEGF in the progression and recovery of cirrhosis has still remained controversial.Methods We established a cirrhotic rat model by thioacetamide that was used as drinking water; besides, 0, 1, 2, and 4 μg VEGF165 were then continuously injected into the rats. The serum level of hyaluronic acid was measured by ELISA at 0, 1, and 4 weeks, separately. Serum levels of ALT, AST, direct bilirubin, indirect bilirubin, and ALB were detected by an automatic biochemical analyzer. In addition, the levels of VEGF165, CD44, MMP9, MMP2, HIF-1α, and endothelin were detected by Western blotting. The expression level of CD44 in LSECs was detected by immunohistochemistry. Changes of fenestrations of LSECs and basement membranes of blood vessels were observed by transmission electron microscopy. Results With the increase of dosage and duration of VEGF treatment, the levels of liver function markers in the serum, the levels of CD44, HIF-1α, hydroxyproline and endothelin were significantly improved. With determination of the serum level of hydroxyproline in the blood, it was disclosed that the mentioned level was markedly decreased. In the Sirius Red staining, the stained red area was gradually reduced. Images captured by transmission electron microscopy also confirmed that the ultrastructure of LSECs tended to be normal.Conclusion VEGF165 can accelerate the resolution of liver fibrosis by promoting fenestration structure formation in LSECs, as well as promoting material exchange between sinusoids and hepatocytes. Our findings may provide a new insight for the study of the role of VEGF in liver fibrosis.

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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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