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

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 21888

Special Issue Editors

Dr. Marco Fidaleo

E-Mail Website
Guest Editor
1. Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, Rome, Italy
2. Research Center for Nanotechnology for Engineering of Sapienza (CNIS), Sapienza University of Rome, Rome, Italy
Interests: nutrients; nutrition; neurogenesis; neurodegeneration; aging; nutraceuticals; rare diseases; brain homeostasis; microbione; gut–brain axis
Special Issues, Collections and Topics in MDPI journals
Dr. Fausto Andreola

E-Mail Website
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 Issues, Collections and Topics in MDPI journals

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 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.

Keywords

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

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Published Papers (10 papers)

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Research

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26 pages, 17639 KiB  
Article
Improvements in Maturity and Stability of 3D iPSC-Derived Hepatocyte-like Cell Cultures
by Siiri Suominen, Tinja Hyypijev, Mari Venäläinen, Alma Yrjänäinen, Hanna Vuorenpää, Mari Lehti-Polojärvi, Mikko Räsänen, Aku Seppänen, Jari Hyttinen, Susanna Miettinen, Katriina Aalto-Setälä and Leena E. Viiri
Cells 2023, 12(19), 2368; https://doi.org/10.3390/cells12192368 - 27 Sep 2023
Viewed by 1727
Abstract
Induced pluripotent stem cell (iPSC) technology enables differentiation of human hepatocytes or hepatocyte-like cells (iPSC-HLCs). Advances in 3D culturing platforms enable the development of more in vivo-like liver models that recapitulate the complex liver architecture and functionality better than traditional 2D monocultures. Moreover, [...] Read more.
Induced pluripotent stem cell (iPSC) technology enables differentiation of human hepatocytes or hepatocyte-like cells (iPSC-HLCs). Advances in 3D culturing platforms enable the development of more in vivo-like liver models that recapitulate the complex liver architecture and functionality better than traditional 2D monocultures. Moreover, within the liver, non-parenchymal cells (NPCs) are critically involved in the regulation and maintenance of hepatocyte metabolic function. Thus, models combining 3D culture and co-culturing of various cell types potentially create more functional in vitro liver models than 2D monocultures. Here, we report the establishment of 3D cultures of iPSC-HLCs alone and in co-culture with human umbilical vein endothelial cells (HUVECs) and adipose tissue-derived mesenchymal stem/stromal cells (hASCs). The 3D cultures were performed as spheroids or on microfluidic chips utilizing various biomaterials. Our results show that both 3D spheroid and on-chip culture enhance the expression of mature liver marker genes and proteins compared to 2D. Among the spheroid models, we saw the best functionality in iPSC-HLC monoculture spheroids. On the contrary, in the chip system, the multilineage model outperformed the monoculture chip model. Additionally, the optical projection tomography (OPT) and electrical impedance tomography (EIT) system revealed changes in spheroid size and electrical conductivity during spheroid culture, suggesting changes in cell–cell connections. Altogether, the present study demonstrates that iPSC-HLCs can successfully be cultured in 3D as spheroids and on microfluidic chips, and co-culturing iPSC-HLCs with NPCs enhances their functionality. These 3D in vitro liver systems are promising human-derived platforms usable in various liver-related studies, specifically when using patient-specific iPSCs. 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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14 pages, 4669 KiB  
Article
Circadian Disruption Primes Myofibroblasts for Accelerated Activation as a Mechanism Underpinning Fibrotic Progression in Non-Alcoholic Fatty Liver Disease
by Elliot Jokl, Jessica Llewellyn, Kara Simpson, Oluwatobi Adegboye, James Pritchett, Leo Zeef, Ian Donaldson, Varinder S. Athwal, Huw Purssell, Oliver Street, Lucy Bennett, Indra Neil Guha, Neil A. Hanley, Qing-Jun Meng and Karen Piper Hanley
Cells 2023, 12(12), 1582; https://doi.org/10.3390/cells12121582 - 08 Jun 2023
Viewed by 1689
Abstract
Circadian rhythm governs many aspects of liver physiology and its disruption exacerbates chronic disease. CLOCKΔ19 mice disrupted circadian rhythm and spontaneously developed obesity and metabolic syndrome, a phenotype that parallels the progression of non-alcoholic fatty liver disease (NAFLD). NAFLD represents an increasing health [...] Read more.
Circadian rhythm governs many aspects of liver physiology and its disruption exacerbates chronic disease. CLOCKΔ19 mice disrupted circadian rhythm and spontaneously developed obesity and metabolic syndrome, a phenotype that parallels the progression of non-alcoholic fatty liver disease (NAFLD). NAFLD represents an increasing health burden with an estimated incidence of around 25% and is associated with an increased risk of progression towards inflammation, fibrosis and carcinomas. Excessive extracellular matrix deposition (fibrosis) is the key driver of chronic disease progression. However, little attention was paid to the impact of disrupted circadian rhythm in hepatic stellate cells (HSCs) which are the primary mediator of fibrotic ECM deposition. Here, we showed in vitro and in vivo that liver fibrosis is significantly increased when circadian rhythm is disrupted by CLOCK mutation. Quiescent HSCs from CLOCKΔ19 mice showed higher expression of RhoGDI pathway components and accelerated activation. Genes altered in this primed CLOCKΔ19 qHSC state may provide biomarkers for early liver disease detection, and include AOC3, which correlated with disease severity in patient serum samples. Integration of CLOCKΔ19 microarray data with ATAC-seq data from WT qHSCs suggested a potential CLOCK regulome promoting a quiescent state and downregulating genes involved in cell projection assembly. CLOCKΔ19 mice showed higher baseline COL1 deposition and significantly worse fibrotic injury after CCl4 treatment. Our data demonstrate that disruption to circadian rhythm primes HSCs towards an accelerated fibrotic response which worsens liver disease. 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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15 pages, 5075 KiB  
Article
Autophagy Inhibitor Chloroquine Downmodulates Hepatic Stellate Cell Activation and Liver Damage in Bile-Duct-Ligated Mice
by Trinh Van Le, Hong-Thuy Phan-Thi, My-Xuan Huynh-Thi, Thanh Minh Dang, Ai Xuan Le Holterman, Gabriele Grassi, Thao-Uyen Nguyen-Luu and Nhung Hai Truong
Cells 2023, 12(7), 1025; https://doi.org/10.3390/cells12071025 - 27 Mar 2023
Cited by 2 | Viewed by 1798
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 [...] Read more.
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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29 pages, 7271 KiB  
Article
Cirrhotic Liver Sustains In Situ Regeneration of Acellular Liver Scaffolds after Transplantation into G-CSF-Treated Animals
by 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 1722
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 [...] Read more.
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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20 pages, 3782 KiB  
Article
Impact of Liver Inflammation on Bile Acid Side Chain Shortening and Amidation
by Marta Alonso-Peña, Ricardo Espinosa-Escudero, Heike M. Hermanns, Oscar Briz, Jose M. Herranz, Carmen Garcia-Ruiz, Jose C. Fernandez-Checa, Javier Juamperez, Matias Avila, Josepmaria Argemi, Ramon Bataller, Javier Crespo, Maria J. Monte, Andreas Geier, Elisa Herraez and Jose J. G. Marin
Cells 2022, 11(24), 3983; https://doi.org/10.3390/cells11243983 - 09 Dec 2022
Cited by 1 | Viewed by 2170
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 [...] Read more.
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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14 pages, 3253 KiB  
Communication
Scalable Production of Size-Controlled Cholangiocyte and Cholangiocarcinoma Organoids within Liver Extracellular Matrix-Containing Microcapsules
by 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
Cited by 3 | Viewed by 2951
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 [...] Read more.
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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32 pages, 5274 KiB  
Review
“Small Hepatocytes” in the Liver
by Toshihiro Mitaka, Norihisa Ichinohe and Naoki Tanimizu
Cells 2023, 12(23), 2718; https://doi.org/10.3390/cells12232718 - 27 Nov 2023
Viewed by 1670
Abstract
Mature hepatocytes (MHs) in an adult rodent liver are categorized into the following three subpopulations based on their proliferative capability: type I cells (MH-I), which are committed progenitor cells that possess a high growth capability and basal hepatocytic functions; type II cells (MH-II), [...] Read more.
Mature hepatocytes (MHs) in an adult rodent liver are categorized into the following three subpopulations based on their proliferative capability: type I cells (MH-I), which are committed progenitor cells that possess a high growth capability and basal hepatocytic functions; type II cells (MH-II), which possess a limited proliferative capability; and type III cells (MH-III), which lose the ability to divide (replicative senescence) and reach the final differentiated state. These subpopulations may explain the liver’s development and growth after birth. Generally, small-sized hepatocytes emerge in mammal livers. The cells are characterized by being morphologically identical to hepatocytes except for their size, which is substantially smaller than that of ordinary MHs. We initially discovered small hepatocytes (SHs) in the primary culture of rat hepatocytes. We believe that SHs are derived from MH-I and play a role as hepatocytic progenitors to supply MHs. The population of MH-I (SHs) is distributed in the whole lobules, a part of which possesses a self-renewal capability, and decreases with age. Conversely, injured livers of experimental models and clinical cases showed the emergence of SHs. Studies demonstrate the involvement of SHs in liver regeneration. SHs that appeared in the injured livers are not a pure population but a mixture of two distinct origins, MH-derived and hepatic-stem-cell-derived cells. The predominant cell-derived SHs depend on the proliferative capability of the remaining MHs after the injury. This review will focus on the SHs that appeared in the liver and discuss the significance of SHs in 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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24 pages, 1033 KiB  
Review
Microvascular Thrombosis and Liver Fibrosis Progression: Mechanisms and Clinical Applications
by Carlo Airola, Maria Pallozzi, Lucia Cerrito, Francesco Santopaolo, Leonardo Stella, Antonio Gasbarrini and Francesca Romana Ponziani
Cells 2023, 12(13), 1712; https://doi.org/10.3390/cells12131712 - 24 Jun 2023
Cited by 2 | Viewed by 1898
Abstract
Fibrosis is an unavoidable consequence of chronic inflammation. Extracellular matrix deposition by fibroblasts, stimulated by multiple pathways, is the first step in the onset of chronic liver disease, and its propagation promotes liver dysfunction. At the same time, chronic liver disease is characterized [...] Read more.
Fibrosis is an unavoidable consequence of chronic inflammation. Extracellular matrix deposition by fibroblasts, stimulated by multiple pathways, is the first step in the onset of chronic liver disease, and its propagation promotes liver dysfunction. At the same time, chronic liver disease is characterized by alterations in primary and secondary hemostasis but unlike previously thought, these changes are not associated with an increased risk of bleeding complications. In recent years, the role of coagulation imbalance has been postulated as one of the main mechanisms promoting hepatic fibrogenesis. In this review, we aim to investigate the function of microvascular thrombosis in the progression of liver disease and highlight the molecular and cellular networks linking hemostasis to fibrosis in this context. We analyze the predictive and prognostic role of coagulation products as biomarkers of liver decompensation (ascites, variceal hemorrhage, and hepatic encephalopathy) and liver-related mortality. Finally, we evaluate the current evidence on the application of antiplatelet and anticoagulant therapies for prophylaxis of hepatic decompensation or prevention of the progression of liver fibrosis. 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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27 pages, 1789 KiB  
Review
Microphysiological Models for Mechanistic-Based Prediction of Idiosyncratic DILI
by Sydney Stern, Hongbing Wang and Nakissa Sadrieh
Cells 2023, 12(11), 1476; https://doi.org/10.3390/cells12111476 - 25 May 2023
Cited by 2 | Viewed by 2001
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 [...] Read more.
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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13 pages, 1731 KiB  
Review
Role of Hepatocyte Growth Regulators in Liver Regeneration
by Mitsutoshi Kimura, Hajime Moteki and Masahiko Ogihara
Cells 2023, 12(2), 208; https://doi.org/10.3390/cells12020208 - 04 Jan 2023
Cited by 8 | Viewed by 3314
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 [...] Read more.
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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