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Special Issue "Liver Constituent Cells: Their Niche, Close Intercellular Relationship and Crosstalk with the Extracellular Environment—Current and Future Perspectives"

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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: closed (20 April 2023) | Viewed by 6524

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Special Issue Editors

Dr. Marco Fidaleo

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Guest Editor

1. Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, 00185 Rome, Italy
2. Research Center for Nanotechnology for Engineering of Sapienza (CNIS), Sapienza University of Rome, 00185 Rome, Italy
Interests: nutrients; nutrition; neurogenesis; neurodegeneration; aging; nutraceuticals; rare diseases; brain homeostasis; microbiome; gut–brain axis
Special Issues, Collections and Topics in MDPI journals

Dr. Fausto Andreola

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Guest Editor

Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
Interests: cirrhosis and liver failure; apoptosis; liver cancer; retinoids; hepatic stellate cells; clinical and public health nutrition; inflammation

Special Issue Information

Dear Colleagues,

The liver is complex anatomy-wise and comprises different specialised cell types. Within the hepatic parenchyma, mainly formed by hepatocytes, it is possible to identify a liver microcirculatory milieu composed of liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs) and resident macrophages (Kupffer cells). Also present in the hepatic parenchyma are biliary ductules made up by cholangiocytes. Sinusoids, hepatocytes and biliary ductules are anatomically similar, and the extracellular matrix takes part not only in spatial arrangement, but also in cellular crosstalk. The 3D structure, together with the composition of the extracellular matrix and the cell behaviour, is strictly involved in the liver physiological and pathophysiological processes. For example, the cause-and-effect relationships between the different liver cells and the exact timing that leads to CLDs still remain unclear. The capillarisation observed in the pathophysiology of non-alcoholic steatohepatitis was previously thought to follow the onset of hepatic inflammation; however, the current view holds that it occurs prior to inflammation. Furthermore, changes in the sinusoids and the perisinusoidal space (also known as the Disse space) in chronic liver diseases (CLDs) prevent drug delivery to the hepatic parenchyma, highlighting the urgent need to develop new effective pharmaceutical formulations.

This Special Issue aims to both report the most recent findings and current opinions on the biological constituents of the liver, their niche and the close intercellular relationship and crosstalk at anatomical and cell molecular levels in both health and disease. Priority will be given to research on the biological barriers formed during liver disease, their description and the therapeutic approaches to overcome them.

We welcome research and review articles, as well as short communications.

Dr. Marco Fidaleo
Dr. Fausto Andreola
Guest Editors

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 2400 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.

Keywords

chronic liver diseases
liver microcirculatory milieu
liver sinusoidal endothelial cells (LSECs)
hepatic stellate cells (HSCs)
Kupffer cells
hepatocytes
cholangiocytes
sinusoid capillarization
Disse space

Published Papers (6 papers)

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Research

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Open AccessArticle

Autophagy Inhibitor Chloroquine Downmodulates Hepatic Stellate Cell Activation and Liver Damage in Bile-Duct-Ligated Mice

and

Cells 2023, 12(7), 1025; https://doi.org/10.3390/cells12071025 - 27 Mar 2023

Viewed by 757

Abstract

Hepatic stellate cell (HSC) activation via the autophagy pathway is a critical factor in liver fibrogenesis. This study tests the hypothesis that chloroquine (CQ) treatment can prevent autophagy and HSC activation in vitro and in vivo in bile-duct-ligated (BDL) mice. Sham-operated and BDL mice were treated with either PBS or CQ in two 60 mg/kg doses the day (D) before and after surgery. On day 2 (2D), HSCs were isolated, and their biological activities were evaluated by measuring intracellular lipid content, α-sma/collagen, and expression of autophagy lc3, sqstm1/p62 markers. The treatment efficacy on liver function was evaluated with serum albumin, transaminases (AST/ALT), and hepatic histology. Primary HSCs were treated in vitro for 24 h with CQ at 0, 2.5, 5, 10, 30, and 50 µM. Autophagy and HSC activation were assessed after 2D of treatment. CQ treatment improved serum AST/ALT, albumin, and bile duct proliferation in 2D BDL mice. This is associated with a suppression of HSC activation, shown by higher HSC lipid content and collagen I staining, along with the blockage of HSC autophagy indicated by an increase in p62 level and reduction in lc3 staining. CQ 5 µM inhibited autophagy in primary HSCs in vitro by increasing p62 and lc3 accumulation, thereby suppressing their in vitro activation. The autophagy inhibitor CQ reduced HSC activation in vitro and in vivo. CQ improved liver function and reduced liver injury in BDL mice. Full article

(This article belongs to the Special Issue Liver Constituent Cells: Their Niche, Close Intercellular Relationship and Crosstalk with the Extracellular Environment—Current and Future Perspectives)

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Open AccessArticle

Cirrhotic Liver Sustains In Situ Regeneration of Acellular Liver Scaffolds after Transplantation into G-CSF-Treated Animals

Marlon Lemos Dias

Inês Julia Ribas Wajsenzon

Gabriel Bastos Naves Alves

Bruno Andrade Paranhos

Cherley Borba Vieira Andrade

Victoria Regina Siqueira Monteiro

Raysa Maria Reis de Sousa

Evelyn Nunes Goulart da Silva Pereira

Karine Lino Rodrigues

Anissa Daliry

Debora Bastos Mello

and

Regina Coeli dos Santos Goldenberg

Cells 2023, 12(7), 976; https://doi.org/10.3390/cells12070976 - 23 Mar 2023

Viewed by 684

Abstract

Acellular liver scaffolds (ALS) produced by decellularization have been successfully explored for distinct regenerative purposes. To date, it is unknown whether transplanted ALSs are affected by cirrhotic livers, either becoming cirrhotic themselves or instead remaining as a robust template for healthy cell growth after transplantation into cirrhotic rats. Moreover, little is known about the clinical course of recipient cirrhotic livers after ALS transplantation. To address these questions, we transplanted ALSs into cirrhotic rats previously treated with the granulocyte colony-stimulating factor. Here, we report successful cellular engraftment within the transplanted ALSs at 7, 15, and 30 days after transplantation. Recellularization was orchestrated by liver tissue cell activation, resident hepatocytes and bile duct proliferation, and an immune response mediated by the granulocyte components. Furthermore, we showed that transplanted ALSs ensured a pro-regenerative and anti-inflammatory microenvironment, attracted vessels from the host cirrhotic tissue, and promoted progenitor cell recruitment. ALS transplantation induced cirrhotic liver regeneration and extracellular matrix remodeling. Moreover, the transplanted ALS sustained blood circulation and attenuated alterations in the ultrasonographic and biochemical parameters in cirrhotic rats. Taken together, our results confirm that transplanted ALSs are not affected by cirrhotic livers and remain a robust template for healthy cell growth and stimulated cirrhotic liver regeneration. Full article

(This article belongs to the Special Issue Liver Constituent Cells: Their Niche, Close Intercellular Relationship and Crosstalk with the Extracellular Environment—Current and Future Perspectives)

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Open AccessArticle

Impact of Liver Inflammation on Bile Acid Side Chain Shortening and Amidation

Marta Alonso-Peña

Ricardo Espinosa-Escudero

Jose C. Fernandez-Checa

and

Cells 2022, 11(24), 3983; https://doi.org/10.3390/cells11243983 - 09 Dec 2022

Viewed by 1204

Abstract

Bile acid (BA) synthesis from cholesterol by hepatocytes is inhibited by inflammatory cytokines. Whether liver inflammation also affects BA side chain shortening and conjugation was investigated. In human liver cell lines (IHH, HepG2, and HepaRG), agonists of nuclear receptors including the farnesoid X receptor (FXR), liver X receptor (LXR), and peroxisome proliferator-activated receptors (PPARs) did not affect the expression of BA-related peroxisomal enzymes. In contrast, hepatocyte nuclear factor 4α (HNF4α) inhibition down-regulated acyl-CoA oxidase 2 (ACOX2). ACOX2 was repressed by fibroblast growth factor 19 (FGF19), which was prevented by extracellular signal-regulated kinase (ERK) pathway inhibition. These changes were paralleled by altered BA synthesis (HPLC-MS/MS). Cytokines able to down-regulate cholesterol-7α-hydroxylase (CYP7A1) had little effect on peroxisomal enzymes involved in BA synthesis except for ACOX2 and bile acid-CoA:amino acid N-acyltransferase (BAAT), which were down-regulated, mainly by oncostatin M (OSM). This effect was prevented by Janus kinase (JAK) inhibition, which restored BA side chain shortening and conjugation. The binding of OSM to the extracellular matrix accounted for a persistent effect after culture medium replacement. In silico analysis of four databases (n = 201) and a validation cohort (n = 90) revealed an inverse relationship between liver inflammation and ACOX2/BAAT expression which was associated with changes in HNF4α levels. In conclusion, BA side chain shortening and conjugation are inhibited by inflammatory effectors. However, other mechanisms involved in BA homeostasis counterbalance any significant impact on the serum BA profile. Full article

(This article belongs to the Special Issue Liver Constituent Cells: Their Niche, Close Intercellular Relationship and Crosstalk with the Extracellular Environment—Current and Future Perspectives)

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Open AccessCommunication

Scalable Production of Size-Controlled Cholangiocyte and Cholangiocarcinoma Organoids within Liver Extracellular Matrix-Containing Microcapsules

Gilles S. van Tienderen

Jorke Willemse

Bas van Loo

Eline V. A. van Hengel

Jeroen de Jonge

Luc J. W. van der Laan

Jeroen Leijten

and

Monique M. A. Verstegen

Cells 2022, 11(22), 3657; https://doi.org/10.3390/cells11223657 - 18 Nov 2022

Viewed by 1750

Abstract

Advances in biomaterials, particularly in combination with encapsulation strategies, have provided excellent opportunities to increase reproducibility and standardization for cell culture applications. Herein, hybrid microcapsules are produced in a flow-focusing microfluidic droplet generator combined with enzymatic outside-in crosslinking of dextran-tyramine, enriched with human liver extracellular matrix (ECM). The microcapsules provide a physiologically relevant microenvironment for the culture of intrahepatic cholangiocyte organoids (ICO) and patient-derived cholangiocarcinoma organoids (CCAO). Micro-encapsulation allowed for the scalable and size-standardized production of organoids with sustained proliferation for at least 21 days in vitro. Healthy ICO (n = 5) expressed cholangiocyte markers, including KRT7 and KRT19, similar to standard basement membrane extract cultures. The CCAO microcapsules (n = 3) showed retention of stem cell phenotype and expressed LGR5 and PROM1. Furthermore, ITGB1 was upregulated, indicative of increased cell adhesion to ECM in microcapsules. Encapsulated CCAO were amendable to drug screening assays, showing a dose-response response to the clinically relevant anti-cancer drugs gemcitabine and cisplatin. High-throughput drug testing identified both pan-effective drugs as well as patient-specific resistance patterns. The results described herein show the feasibility of this one-step encapsulation approach to create size-standardized organoids for scalable production. The liver extracellular matrix-containing microcapsules can provide a powerful platform to build mini healthy and tumor tissues for potential future transplantation or personalized medicine applications. Full article

(This article belongs to the Special Issue Liver Constituent Cells: Their Niche, Close Intercellular Relationship and Crosstalk with the Extracellular Environment—Current and Future Perspectives)

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Review

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Open AccessReview

Microphysiological Models for Mechanistic-Based Prediction of Idiosyncratic DILI

Sydney Stern

Hongbing Wang

and

Nakissa Sadrieh

Cells 2023, 12(11), 1476; https://doi.org/10.3390/cells12111476 - 25 May 2023

Viewed by 414

Abstract

Drug-induced liver injury (DILI) is a major contributor to high attrition rates among candidate and market drugs and a key regulatory, industry, and global health concern. While acute and dose-dependent DILI, namely, intrinsic DILI, is predictable and often reproducible in preclinical models, the nature of idiosyncratic DILI (iDILI) limits its mechanistic understanding due to the complex disease pathogenesis, and recapitulation using in vitro and in vivo models is extremely challenging. However, hepatic inflammation is a key feature of iDILI primarily orchestrated by the innate and adaptive immune system. This review summarizes the in vitro co-culture models that exploit the role of the immune system to investigate iDILI. Particularly, this review focuses on advancements in human-based 3D multicellular models attempting to supplement in vivo models that often lack predictability and display interspecies variations. Exploiting the immune-mediated mechanisms of iDILI, the inclusion of non-parenchymal cells in these hepatoxicity models, namely, Kupffer cells, stellate cells, dendritic cells, and liver sinusoidal endothelial cells, introduces heterotypic cell–cell interactions and mimics the hepatic microenvironment. Additionally, drugs recalled from the market in the US between 1996–2010 that were studies in these various models highlight the necessity for further harmonization and comparison of model characteristics. Challenges regarding disease-related endpoints, mimicking 3D architecture with different cell–cell contact, cell source, and the underlying multi-cellular and multi-stage mechanisms are described. It is our belief that progressing our understanding of the underlying pathogenesis of iDILI will provide mechanistic clues and a method for drug safety screening to better predict liver injury in clinical trials and post-marketing. Full article

(This article belongs to the Special Issue Liver Constituent Cells: Their Niche, Close Intercellular Relationship and Crosstalk with the Extracellular Environment—Current and Future Perspectives)

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Open AccessReview

Role of Hepatocyte Growth Regulators in Liver Regeneration

Mitsutoshi Kimura

Hajime Moteki

and

Masahiko Ogihara

Cells 2023, 12(2), 208; https://doi.org/10.3390/cells12020208 - 04 Jan 2023

Cited by 2 | Viewed by 1084

Abstract

We have studied whether growth factors, cytokines, hormones, neurotransmitters, and local hormones (autacoids) promote the proliferation of hepatic parenchymal cells (i.e., hepatocytes) using in vitro primary cultured hepatocytes. The indicators used for this purpose include changes in DNA synthesis activity, nuclear number, cell number, cell cycle, and gene expression. In addition, the intracellular signaling pathways from the plasma membrane receptors to the nucleus have been examined in detail for representative growth-promoting factors that have been found to promote DNA synthesis and cell proliferation of hepatocytes. In examining intracellular signaling pathways, the effects of specific inhibitors of presumed signaling factors involved have been pharmacologically confirmed, and the phosphorylation activities of the signaling factors (e.g., RTK, ERK, mTOR, and p70 S6K) have been evaluated. As a result, it has been found that there are many factors that promote the proliferation of hepatocytes (e.g., HGF, EGF, TGF-α, IL-1β, TNF-α, insulin, growth hormone (GH), prostaglandin (PG)), and serotonin (5-HT)), while there are very few factors (e.g., TGF-β1 and glucocorticoids) that inhibit the effects of growth-promoting factors. We have also found that 5-HT and GH promote the proliferation of hepatocytes via different autocrine factors (e.g., TGF-α and IGF-I, respectively). Using primary cultured hepatocytes, it will be possible to further study the molecular and cellular aspects of liver regeneration. Full article

(This article belongs to the Special Issue Liver Constituent Cells: Their Niche, Close Intercellular Relationship and Crosstalk with the Extracellular Environment—Current and Future Perspectives)

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