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Cell and Molecular Biology of Hepatocytes
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Cell and Molecular Biology of Hepatocytes

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 22403

Special Issue Editor

Dr. Francisco Lázaro-Diéguez

E-Mail Website
Guest Editor
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Interests: Golgi apparatus; post-Golgi trafficking; actin cytoskeleton; RhoA; cell adhesion; cell polarity; cell division
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hepatocytes—the most abundant cell type in the liver—are organized in branched cords, with a luminal/bile canalicular network between neighboring cells formed by their apical surfaces, and their basal membranes facing sinusoidal endothelial cells. The polarization of hepatocytes is crucial for their functions, and the loss of polarity is a hallmark of numerous hepatic diseases; therefore, the study of the molecular mechanisms that govern hepatocyte polarization is essential for understanding both liver cell biology and the pathogenesis of liver diseases.

This Special Issue will focus on basic research on cellular and animal models and will collect reviews and original research articles that expand knowledge in the field. Potential topics include, but are not limited to, the contribution of the extracellular matrix, cytoskeleton, and cell–cell adhesion molecular mechanisms in the establishment and maintenance of hepatocyte polarity.

Dr. Francisco Lazaro-Dieguez
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • hepatocyte
  • cell polarity
  • cell adhesion
  • extracellular matrix
  • cytoskeleton
  • cell division
  • intracellular protein trafficking

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Published Papers (6 papers)

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Research

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16 pages, 2468 KiB  
Article
Effects of Pro-Inflammatory Cytokines on Hepatic Metabolism in Primary Human Hepatocytes
by Roberto Gramignoli, Aarati R. Ranade, Raman Venkataramanan and Stephen C. Strom
Int. J. Mol. Sci. 2022, 23(23), 14880; https://doi.org/10.3390/ijms232314880 - 28 Nov 2022
Cited by 7 | Viewed by 2210
Abstract
Three decades of hepatocyte transplantation have confirmed such a cell-based approach as an adjunct or alternative treatment to solid organ transplantation. Donor cell survival and engraftment were indirectly measured by hepatospecific secretive or released metabolites, such as ammonia metabolism in urea cycle defects. [...] Read more.
Three decades of hepatocyte transplantation have confirmed such a cell-based approach as an adjunct or alternative treatment to solid organ transplantation. Donor cell survival and engraftment were indirectly measured by hepatospecific secretive or released metabolites, such as ammonia metabolism in urea cycle defects. In cases of sepsis or viral infection, ammonia levels can significantly and abruptly increase in these recipients, erroneously implying rejection. Pro-inflammatory cytokines associated with viral or bacterial infections are known to affect many liver functions, including drug-metabolizing enzymes and hepatic transport activities. We examined the influence of pro-inflammatory cytokines in primary human hepatocytes, isolated from both normal donors or patients with metabolic liver diseases. Different measures of hepatocyte functions, including ammonia metabolism and phase 1–3 metabolism, were performed. All the hepatic functions were profoundly and significantly suppressed after exposure to concentrations of from 0.1 to 10 ng/mL of different inflammatory cytokines, alone and in combination. Our data indicate that, like phase I metabolism, suppression of phase II/III and ammonia metabolism occurs in hepatocytes exposed to pro-inflammatory cytokines in the absence of cell death. Such inflammatory events do not necessarily indicate a rejection response or loss of the cell graft, and these systemic inflammatory signals should be carefully considered when the immunosuppressant regiment is reduced or relieved in a hepatocyte transplantation recipient in response to such alleged rejection. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Hepatocytes)
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16 pages, 4577 KiB  
Article
Expression, Prognostic Value, and Functional Mechanism of Polarity-Related Genes in Hepatocellular Carcinoma
by Dan-Hua Zhu, Yan-Hong Zhang, Xiao-Xi Ou-Yang, Xiao-Hua Meng, Qing-Yi Cao, Xiao-Peng Yu, Juan Lu, Lan-Juan Li and Kun-Kai Su
Int. J. Mol. Sci. 2022, 23(21), 12784; https://doi.org/10.3390/ijms232112784 - 24 Oct 2022
Cited by 1 | Viewed by 1732
Abstract
Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality and poor prognoses around the world. Within-cell polarity is crucial to cell development and function maintenance, and some studies have found that it is closely related to cancer initiation, metastasis, and prognosis. [...] Read more.
Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality and poor prognoses around the world. Within-cell polarity is crucial to cell development and function maintenance, and some studies have found that it is closely related to cancer initiation, metastasis, and prognosis. The aim of our research was to find polarity-related biomarkers which improve the treatment and prognosis of HCC. For the knowledge-driven analysis, 189 polarity-related genes (PRGs) were retrieved and curated manually from the molecular signatures database and reviews. Meanwhile, in the data-driven part, genomic datasets and clinical records of HCC was obtained from the cancer genome atlas database. The potential candidates were considered in the respect to differential expression, mutation rate, and prognostic value. Sixty-one PRGs that passed the knowledge and data-driven screening were applied for function analysis and mechanism deduction. Elastic net model combing least absolute shrinkage and selection operator and ridge regression analysis refined the input into a 12-PRG risk model, and its pharmaceutical potency was evaluated. These findings demonstrated that the integration of multi-omics of PRGs can help us in untangling the liver cancer pathogenesis as well as illustrate the underlying mechanisms and therapeutic targets. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Hepatocytes)
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Review

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20 pages, 1033 KiB  
Review
Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors
by Cheng Ji
Int. J. Mol. Sci. 2023, 24(9), 7938; https://doi.org/10.3390/ijms24097938 - 27 Apr 2023
Cited by 1 | Viewed by 3011
Abstract
Antiviral protease inhibitors are peptidomimetic molecules that block the active catalytic center of viral proteases and, thereby, prevent the cleavage of viral polyprotein precursors into maturation. They continue to be a key class of antiviral drugs that can be used either as boosters [...] Read more.
Antiviral protease inhibitors are peptidomimetic molecules that block the active catalytic center of viral proteases and, thereby, prevent the cleavage of viral polyprotein precursors into maturation. They continue to be a key class of antiviral drugs that can be used either as boosters for other classes of antivirals or as major components of current regimens in therapies for the treatment of infections with human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, sustained/lifelong treatment with the drugs or drugs combined with other substance(s) often leads to severe hepatic side effects such as lipid abnormalities, insulin resistance, and hepatotoxicity. The underlying pathogenic mechanisms are not fully known and are under continuous investigation. This review focuses on the general as well as specific molecular mechanisms of the protease inhibitor-induced hepatotoxicity involving transporter proteins, apolipoprotein B, cytochrome P450 isozymes, insulin-receptor substrate 1, Akt/PKB signaling, lipogenic factors, UDP-glucuronosyltransferase, pregnane X receptor, hepatocyte nuclear factor 4α, reactive oxygen species, inflammatory cytokines, off-target proteases, and small GTPase Rab proteins related to ER-Golgi trafficking, organelle stress, and liver injury. Potential pharmaceutical/therapeutic solutions to antiviral drug-induced hepatic side effects are also discussed. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Hepatocytes)
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14 pages, 1547 KiB  
Review
Implications of Polyploidy and Ploidy Alterations in Hepatocytes in Liver Injuries and Cancers
by Tomonori Matsumoto
Int. J. Mol. Sci. 2022, 23(16), 9409; https://doi.org/10.3390/ijms23169409 - 20 Aug 2022
Cited by 10 | Viewed by 3565
Abstract
Polyploidy, a condition in which more than two sets of chromosomes are present in a cell, is a characteristic feature of hepatocytes. A significant number of hepatocytes physiologically undergo polyploidization at a young age. Polyploidization of hepatocytes is enhanced with age and in [...] Read more.
Polyploidy, a condition in which more than two sets of chromosomes are present in a cell, is a characteristic feature of hepatocytes. A significant number of hepatocytes physiologically undergo polyploidization at a young age. Polyploidization of hepatocytes is enhanced with age and in a diseased liver. It is worth noting that polyploid hepatocytes can proliferate, in marked contrast to other types of polyploid cells, such as megakaryocytes and cardiac myocytes. Polyploid hepatocytes divide to maintain normal liver homeostasis and play a role in the regeneration of the damaged liver. Furthermore, polyploid hepatocytes have been shown to dynamically reduce ploidy during liver regeneration. Although it is still unclear why hepatocytes undergo polyploidization, accumulating evidence has revealed that alterations in the ploidy in hepatocytes are involved in the pathophysiology of liver cirrhosis and carcinogenesis. This review discusses the significance of hepatocyte ploidy in physiological liver function, liver injury, and liver cancer. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Hepatocytes)
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19 pages, 783 KiB  
Review
Three-Dimensional Liver Culture Systems to Maintain Primary Hepatic Properties for Toxicological Analysis In Vitro
by Sarah Kammerer
Int. J. Mol. Sci. 2021, 22(19), 10214; https://doi.org/10.3390/ijms221910214 - 23 Sep 2021
Cited by 27 | Viewed by 4519
Abstract
Drug-induced liver injury (DILI) is the major reason for failures in drug development and withdrawal of approved drugs from the market. Two-dimensional cultures of hepatocytes often fail to reliably predict DILI: hepatoma cell lines such as HepG2 do not reflect important primary-like hepatic [...] Read more.
Drug-induced liver injury (DILI) is the major reason for failures in drug development and withdrawal of approved drugs from the market. Two-dimensional cultures of hepatocytes often fail to reliably predict DILI: hepatoma cell lines such as HepG2 do not reflect important primary-like hepatic properties and primary human hepatocytes (pHHs) dedifferentiate quickly in vitro and are, therefore, not suitable for long-term toxicity studies. More predictive liver in vitro models are urgently required in drug development and compound safety evaluation. This review discusses available human hepatic cell types for in vitro toxicology analysis and their usage in established and emerging three-dimensional (3D) culture systems. Generally, 3D cultures maintain or improve primary hepatic functions (including expression of drug-metabolizing enzymes) of different liver cells for several weeks of culture, thus allowing long-term and repeated-dose toxicity studies. Spheroid cultures of pHHs have been comprehensively tested, but also other cell types such as HepaRG benefit from 3D culture systems. Emerging 3D culture techniques include usage of induced pluripotent stem-cell-derived hepatocytes and primary-like upcyte cells, as well as advanced culture techniques such as microfluidic liver-on-a-chip models. In-depth characterization of existing and emerging 3D hepatocyte technologies is indispensable for successful implementation of such systems in toxicological analysis. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Hepatocytes)
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16 pages, 1707 KiB  
Review
Critical Role of LSEC in Post-Hepatectomy Liver Regeneration and Failure
by Maxime De Rudder, Alexandra Dili, Peter Stärkel and Isabelle A. Leclercq
Int. J. Mol. Sci. 2021, 22(15), 8053; https://doi.org/10.3390/ijms22158053 - 28 Jul 2021
Cited by 28 | Viewed by 4969
Abstract
Liver sinusoids are lined by liver sinusoidal endothelial cells (LSEC), which represent approximately 15 to 20% of the liver cells, but only 3% of the total liver volume. LSEC have unique functions, such as fluid filtration, blood vessel tone modulation, blood clotting, inflammatory [...] Read more.
Liver sinusoids are lined by liver sinusoidal endothelial cells (LSEC), which represent approximately 15 to 20% of the liver cells, but only 3% of the total liver volume. LSEC have unique functions, such as fluid filtration, blood vessel tone modulation, blood clotting, inflammatory cell recruitment, and metabolite and hormone trafficking. Different subtypes of liver endothelial cells are also known to control liver zonation and hepatocyte function. Here, we have reviewed the origin of LSEC, the different subtypes identified in the liver, as well as their renewal during homeostasis. The liver has the exceptional ability to regenerate from small remnants. The past decades have seen increasing awareness in the role of non-parenchymal cells in liver regeneration despite not being the most represented population. While a lot of knowledge has emerged, clarification is needed regarding the role of LSEC in sensing shear stress and on their participation in the inductive phase of regeneration by priming the hepatocytes and delivering mitogenic factors. It is also unclear if bone marrow-derived LSEC participate in the proliferative phase of liver regeneration. Similarly, data are scarce as to LSEC having a role in the termination phase of the regeneration process. Here, we review what is known about the interaction between LSEC and other liver cells during the different phases of liver regeneration. We next explain extended hepatectomy and small liver transplantation, which lead to “small for size syndrome” (SFSS), a lethal liver failure. SFSS is linked to endothelial denudation, necrosis, and lobular disturbance. Using the knowledge learned from partial hepatectomy studies on LSEC, we expose several techniques that are, or could be, used to avoid the “small for size syndrome” after extended hepatectomy or small liver transplantation. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Hepatocytes)
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