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Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis III

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Tissues and Organs".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 12175

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Special Issue Editor

Prof. Dr. Ralf Weiskirchen

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Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany
Interests: liver diseases, biomakrer, cellular signaling, cytokines, chemokines; food products, vitamin A, weight loss, diet, fats, carbohydrates; supplements
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Dear Colleagues,

The hallmark of hepatic fibrosis is the formation and deposition of excess fibrous connective tissue, leading to progressive architectural tissue remodeling. Irrespective of the underlying pathogenic cause (e.g., genetic disorders, viruses, alcohol, autoimmune attacks, metabolic disorders, cholestasis, venous obstruction, parasites), tissue damage induces an inflammatory response involving the local vascular system and the immune system and a systemic mobilization of endocrine and neurological mediators, ultimately leading to the activation of matrix-producing cell populations. In addition, excess fat and other lipotoxic mediators provoking endoplasmic reticulum stress, the alteration of mitochondrial function, oxidative stress, and modifications in the microbiota are associated with non-alcoholic fatty liver disease and, subsequently, the initiation and/or progression of hepatic fibrosis.

In this Special Issue of Cells, I invite you to contribute original research articles, reviews, or shorter perspective articles on all aspects related to the theme of “Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis”. Expert articles describing mechanistic, functional, cellular, biochemical, or general aspects of hepatic fibrogenesis are highly welcome. Relevant topics include but are not limited to:

Cytokine signaling;
Chemokine function;
In vitro and in vivo models;
Immunology in hepatic fibrosis;
Extracellular matrix;
Inflammation;
Fibrosis;
NASH/NAFLD;
Alcohol;
Hepatitis;
Microbiota;
Bioimaging;
Big data on liver fibrosis;
Translational medicine.

Prof. Dr. Ralf Weiskirchen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Related Special Issues

Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis in Cells (49 articles)
Cellular and Molecular Mechanisms underlying the Pathogenesis of Hepatic Fibrosis II in Cells (22 articles)

Published Papers (6 papers)

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Research

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22 pages, 7873 KiB

Open AccessArticle

Genetic Characterization of Rat Hepatic Stellate Cell Line PAV-1

by Kiara Gäberlein, Sarah K. Schröder, Indrajit Nanda, Claus Steinlein, Thomas Haaf, Eva M. Buhl, Patrick Sauvant, Vincent Sapin, Armand Abergel and Ralf Weiskirchen

Cells 2023, 12(12), 1603; https://doi.org/10.3390/cells12121603 - 11 Jun 2023

Viewed by 1533

Abstract

The rat hepatic stellate cell line PAV-1 was established two decades ago and proposed as a cellular model to study aspects of hepatic retinoic acid metabolism. This cell line exhibits a myofibroblast-like phenotype but also has the ability to store retinyl esters and synthesize retinoic acid from its precursor retinol. Importantly, when cultured with palmitic acid alone or in combination with retinol, the cells switch to a deactivated phenotype in which the proliferation and expression of profibrogenic marker genes are suppressed. Despite these interesting characteristics, the cell line has somehow fallen into oblivion. However, based on the fact that working with in vivo models is becoming increasingly complicated, genetically characterized established cell lines that mimic aspects of hepatic stellate cell biology are of fundamental value for biomedical research. To genetically characterize PAV-1 cells, we performed karyotype analysis using conventional chromosome analysis and multicolor spectral karyotyping (SKY), which allowed us to identify numerical and specific chromosomal alteration in PAV-1 cells. In addition, we used a panel of 31 species-specific allelic variant sites to define a unique short tandem repeat (STR) profile for this cell line and performed bulk mRNA-sequencing, showing that PAV-1 cells express an abundance of genes specific for the proposed myofibroblastic phenotype. Finally, we used Rhodamine-Phalloidin staining and electron microscopy analysis, which showed that PAV-1 cells contain a robust intracellular network of filamentous actin and process typical ultrastructural features of hepatic stellate cells. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis III)

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13 pages, 3151 KiB

Open AccessArticle

12-O-tetradecanoylphorbol-13-acetate Reduces Activation of Hepatic Stellate Cells by Inhibiting the Hippo Pathway Transcriptional Coactivator YAP

by Chang Wan Kim, Yongdae Yoon, Moon Young Kim, Soon Koo Baik, Hoon Ryu, Il Hwan Park and Young Woo Eom

Cells 2023, 12(1), 91; https://doi.org/10.3390/cells12010091 - 26 Dec 2022

Cited by 3 | Viewed by 1714

Abstract

Although protein kinase C (PKC) regulates various biological activities, including cell proliferation, differentiation, migration, tissue remodeling, gene expression, and cell death, the antifibrotic effect of PKC in myofibroblasts is not fully understood. We investigated whether 12-O-tetradecanoylphorbol-13-acetate (TPA), a PKC activator, reduced the activation of hepatic stellate cells (HSCs) and explored the involvement of the Hippo pathway transcriptional coactivator YAP. We analyzed the effect of TPA on the proliferation and expression of α-smooth muscle actin (SMA) in the LX-2 HSC line. We also analyzed the phosphorylation of the Hippo pathway molecules YAP and LATS1 and investigated YAP nuclear translocation. We examined whether Gö 6983, a pan-PKC inhibitor, restored the TPA-inhibited activities of HSCs. Administration of TPA decreased the growth rate of LX-2 cells and inhibited the expression of α-SMA and collagen type I alpha 1 (COL1A1). In addition, TPA induced phosphorylation of PKCδ, LATS1, and YAP and inhibited the nuclear translocation of YAP compared with the control. These TPA-induced phenomena were mostly ameliorated by Gö 6983. Our results indicate that PKCδ exerts an antifibrotic effect by inhibiting the Hippo pathway in HSCs. Therefore, PKCδ and YAP can be used as therapeutic targets for the treatment of fibrotic diseases. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis III)

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19 pages, 8059 KiB

Open AccessArticle

Adipose-Derived Stem Cells (ADSCs) Supplemented with Hepatocyte Growth Factor (HGF) Attenuate Hepatic Stellate Cell Activation and Liver Fibrosis by Inhibiting the TGF-β/Smad Signaling Pathway in Chemical-Induced Liver Fibrosis Associated with Diabetes

by Sami Gharbia, Simona-Rebeca Nazarie, Sorina Dinescu, Cornel Balta, Hildegard Herman, Victor Eduard Peteu, Mihaela Gherghiceanu, Anca Hermenean and Marieta Costache

Cells 2022, 11(21), 3338; https://doi.org/10.3390/cells11213338 - 22 Oct 2022

Cited by 15 | Viewed by 2071

Abstract

Liver fibrosis can develop on the background of hyperglycemia in diabetes mellitus. However, xenobiotic-related factors may accelerate diabetes-associated liver fibrosis. In this study, we aimed to assess the antfibrotic effect of ADSC and HGF therapy and to establish the cellular and molecular mechanisms through in vitro and in vivo experiments. In vitro, TGF-β1-activated hepatic stellate cells (HSCs) were cocultured with ADSCs or HGF, and the expression of several fibrosis markers was investigated. The antifibrotic effect of the ADSCs, HGF, and ADSCs supplemented with HGF was further assessed in vivo on diabetic mice with liver fibrosis experimentally induced. In vitro results showed the inhibition of HSC proliferation and decrease in fibrogenesis markers. Coadministration of ADSCs and HGF on diabetic mice with liver fibrosis enhanced antifibrotic effects confirmed by the downregulation of Col I, α-SMA, TGF-β1, and Smad2, while Smad7 was upregulated. Moreover, stem cell therapy supplemented with HGF considerably attenuated inflammation and microvesicular steatosis, decreased collagen deposits, and alleviated liver fibrosis. In conclusion, the HGF-based ADSC therapy might be of interest for the treatment of liver fibrosis in diabetic patients, consecutive aggression exerts by different environmental factors. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis III)

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19 pages, 4749 KiB

Open AccessArticle

Rat Hepatic Stellate Cell Line CFSC-2G: Genetic Markers and Short Tandem Repeat Profile Useful for Cell Line Authentication

by Indrajit Nanda, Sarah K. Schröder, Claus Steinlein, Thomas Haaf, Eva M. Buhl, Domink G. Grimm and Ralf Weiskirchen

Cells 2022, 11(18), 2900; https://doi.org/10.3390/cells11182900 - 16 Sep 2022

Cited by 3 | Viewed by 1876

Abstract

Hepatic stellate cells (HSCs) are also known as lipocytes, fat-storing cells, perisinusoidal cells, or Ito cells. These liver-specific mesenchymal cells represent about 5% to 8% of all liver cells, playing a key role in maintaining the microenvironment of the hepatic sinusoid. Upon chronic liver injury or in primary culture, these cells become activated and transdifferentiate into a contractile phenotype, i.e., the myofibroblast, capable of producing and secreting large quantities of extracellular matrix compounds. Based on their central role in the initiation and progression of chronic liver diseases, cultured HSCs are valuable in vitro tools to study molecular and cellular aspects of liver diseases. However, the isolation of these cells requires special equipment, trained personnel, and in some cases needs approval from respective authorities. To overcome these limitations, several immortalized HSC lines were established. One of these cell lines is CFSC, which was originally established from cirrhotic rat livers induced by carbon tetrachloride. First introduced in 1991, this cell line and derivatives thereof (i.e., CFSC-2G, CFSC-3H, CFSC-5H, and CFSC-8B) are now used in many laboratories as an established in vitro HSC model. We here describe molecular features that are suitable for cell authentication. Importantly, chromosome banding and multicolor spectral karyotyping (SKY) analysis demonstrate that the CFSC-2G genome has accumulated extensive chromosome rearrangements and most chromosomes exist in multiple copies producing a pseudo-triploid karyotype. Furthermore, our study documents a defined short tandem repeat (STR) profile including 31 species-specific markers, and a list of genes expressed in CFSC-2G established by bulk mRNA next-generation sequencing (NGS). Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis III)

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14 pages, 6996 KiB

Open AccessArticle

Increased Levels of Phosphorylated ERK Induce CTGF Expression in Autophagy-Deficient Mouse Hepatocytes

by Hye-Young Seo, So-Hee Lee, Eugene Han, Jae Seok Hwang, Mi Kyung Kim and Byoung Kuk Jang

Cells 2022, 11(17), 2704; https://doi.org/10.3390/cells11172704 - 30 Aug 2022

Cited by 3 | Viewed by 1646

Abstract

Autophagy performs essential cell functions in the liver through an intracellular lysosomal degradation process. Several studies have reported that autophagy deficiency can lead to liver injury, including hepatic fibrosis; however, the mechanisms underlying the relationship between autophagy deficiency and liver pathology are unclear. In this study, we examined the expression levels of fibrosis-associated genes in hepatocyte-specific ATG7-deficient mice. The expression levels of the connective tissue growth factor (CTGF) and phosphorylated ERK (phospho-ERK) proteins were increased significantly in primary hepatocytes isolated from hepatocyte-specific ATG7-deficient mice compared to those isolated from control mice. In addition, the inhibition of autophagy in cultured mammalian hepatic AML12 and LX2 cells increased CTGF and phospho-ERK protein levels without altering CTGF mRNA expression. In addition, the autophagy deficiency-mediated enhancement of CTGF expression was attenuated when ERK was inhibited. Overall, these results suggest that the inhibition of autophagy in hepatocytes increases phospho-ERK expression, which in turn increases the expression of CTGF, a biomarker of fibrosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis III)

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Review

Jump to: Research

24 pages, 2023 KiB

Open AccessReview

Regulatory Functions and Mechanisms of Circular RNAs in Hepatic Stellate Cell Activation and Liver Fibrosis

by Archittapon Nokkeaw, Pannathon Thamjamrassri, Pisit Tangkijvanich and Chaiyaboot Ariyachet

Cells 2023, 12(3), 378; https://doi.org/10.3390/cells12030378 - 19 Jan 2023

Cited by 4 | Viewed by 2509

Abstract

Chronic liver injury induces the activation of hepatic stellate cells (HSCs) into myofibroblasts, which produce excessive amounts of extracellular matrix (ECM), resulting in tissue fibrosis. If the injury persists, these fibrous scars could be permanent and disrupt liver architecture and function. Currently, effective anti-fibrotic therapies are lacking; hence, understanding molecular mechanisms that control HSC activation could hold a key to the development of new treatments. Recently, emerging studies have revealed roles of circular RNAs (circRNAs), a class of non-coding RNAs that was initially assumed to be the result of splicing errors, as new regulators in HSC activation. These circRNAs can modulate the activity of microRNAs (miRNAs) and their interacting protein partners involved in regulating fibrogenic signaling cascades. In this review, we will summarize the current knowledge of this class of non-coding RNAs for their molecular function in HSC activation and liver fibrosis progression. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis III)

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