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Recent Advances in Liver Repair Strategies
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Recent Advances in Liver Repair Strategies

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 92627

Special Issue Editor

Dr. Mustapha Najimi

E-Mail Website
Guest Editor
Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), Université catholique de Louvain, Louvain-la-Neuve, Belgium
Interests: liver cell therapy; mesenchymal stem cells; liver regeneration; hepatogenic differentiation; liver defects; cell therapy; liver cell types
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The liver is a masterful organ that orchestrates the coordination of over 500 functions essential for life. Compared with other organs, the liver displays a high ability to regenerate itself—a well conserved feature from fish to humans—which is crucial to preserve the coordination of those critical functions. Because such a complex and critical organ may experience several problems, keeping the liver healthy is a necessity in order to maintain its regeneration potential. Once this ability is altered, significant structural and functional changes occur that could alter other organs.

Liver diseases—either inherited or acquired—are continuously increasing, and represent a significant cause of mortality worldwide. Orthotopic liver transplantation (OLT) remains the gold standard therapeutic option. Unfortunately, it is not widely accessible to all patients for several reasons, among which is the significantly increased donor scarcity. Accordingly, investigations are continuously conducted to develop novel and innovative therapeutic strategies that could support and/or substitute OLT. This could be achieved via the improvement and strengthening of our knowledge on liver diseases, as well as on the underlined cellular and molecular mechanisms hampering the liver regeneration potential.

This Special Issue aims at addressing all aspects related to liver biology, liver diseases, and early proof of concept investigations that are aimed at developing novel clinical solutions. It welcomes high-quality basic and clinical research papers as well as reviews that emphasize these issues.

Dr. Mustapha Najimi
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.

Keywords

  • liver
  • liver diseases
  • signaling pathway
  • cell therapy
  • tissue engineering
  • gene therapy
  • transplantation
  • stem cells
  • tissue regeneration

Published Papers (18 papers)

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Research

Jump to: Review

20 pages, 3695 KiB  
Article
Inflammation Differentially Modulates the Biological Features of Adult Derived Human Liver Stem/Progenitor Cells
by Hoda El-Kehdy, Mehdi Najar, Joery De Kock, Douaa Moussa Agha, Vera Rogiers, Makram Merimi, Laurence Lagneaux, Etienne M. Sokal and Mustapha Najimi
Cells 2020, 9(7), 1640; https://doi.org/10.3390/cells9071640 - 08 Jul 2020
Cited by 5 | Viewed by 2388
Abstract
The progression of mesenchymal stem cell-based therapy from concept to cure closely depends on the optimization of conditions that allow a better survival and favor the cells to achieve efficient liver regeneration. We have previously demonstrated that adult-derived human liver stem/progenitor cells (ADHLSC) [...] Read more.
The progression of mesenchymal stem cell-based therapy from concept to cure closely depends on the optimization of conditions that allow a better survival and favor the cells to achieve efficient liver regeneration. We have previously demonstrated that adult-derived human liver stem/progenitor cells (ADHLSC) display significant features that support their clinical development. The current work aims at studying the impact of a sustained pro-inflammatory environment on the principal biological features of ADHLSC in vitro. METHODS: ADHLSC from passages 4–7 were exposed to a cocktail of inflammatory cytokines for 24 h and 9 days and subsequently analyzed for their viability, expression, and secretion profiles by using flow cytometry, RT-qPCR, and antibody array assay. The impact of inflammation on the hepatocytic differentiation potential of ADHLSC was also evaluated. RESULTS: ADHLSC treated with a pro-inflammatory cocktail displayed significant decrease of cell yield at both times of treatment while cell mortality was observed at 9 days post-priming. After 24 h, no significant changes in the immuno-phenotype of ADHLSC expression profile could be noticed while after 9 days, the expression profile of relevant markers has changed both in the basal conditions and after inflammation treatment. Inflammation cocktail enhanced the release of IL-6, IL-8, CCL5, monocyte-chemo-attractant protein-2 and 3, CXCL1/GRO, and CXCL5/ENA78. Furthermore, while IP-10 secretion was increased after 24 h priming, granulocyte macrophage colony-stimulating factor enhanced secretion was noticed after 9 days treatment. Finally, priming of ADHLSC did not affect their potential to differentiate into hepatocyte-like cells. CONCLUSION: These results indicate that ADHLSCs are highly sensitive to inflammation and respond to such signals by adjusting their gene and protein expression. Accordingly, monitoring the inflammatory status of patients at the time of cell transplantation, will certainly help in enhancing ADHLSC safety and efficiency. Full article
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
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16 pages, 5817 KiB  
Article
Long-Term Survival of Transplanted Autologous Canine Liver Organoids in a COMMD1-Deficient Dog Model of Metabolic Liver Disease
by Hedwig S. Kruitwagen, Loes A. Oosterhoff, Monique E. van Wolferen, Chen Chen, Sathidpak Nantasanti Assawarachan, Kerstin Schneeberger, Anne Kummeling, Giora van Straten, Ies C. Akkerdaas, Christel R. Vinke, Frank G. van Steenbeek, Leonie W.L. van Bruggen, Jeannette Wolfswinkel, Guy C.M. Grinwis, Sabine A. Fuchs, Helmuth Gehart, Niels Geijsen, Robert G. Vries, Hans Clevers, Jan Rothuizen, Baukje A. Schotanus, Louis C. Penning and Bart Speeadd Show full author list remove Hide full author list
Cells 2020, 9(2), 410; https://doi.org/10.3390/cells9020410 - 11 Feb 2020
Cited by 34 | Viewed by 5783
Abstract
The shortage of liver organ donors is increasing and the need for viable alternatives is urgent. Liver cell (hepatocyte) transplantation may be a less invasive treatment compared with liver transplantation. Unfortunately, hepatocytes cannot be expanded in vitro, and allogenic cell transplantation requires long-term [...] Read more.
The shortage of liver organ donors is increasing and the need for viable alternatives is urgent. Liver cell (hepatocyte) transplantation may be a less invasive treatment compared with liver transplantation. Unfortunately, hepatocytes cannot be expanded in vitro, and allogenic cell transplantation requires long-term immunosuppression. Organoid-derived adult liver stem cells can be cultured indefinitely to create sufficient cell numbers for transplantation, and they are amenable to gene correction. This study provides preclinical proof of concept of the potential of cell transplantation in a large animal model of inherited copper toxicosis, such as Wilson’s disease, a Mendelian disorder that causes toxic copper accumulation in the liver. Hepatic progenitors from five COMMD1-deficient dogs were isolated and cultured using the 3D organoid culture system. After genetic restoration of COMMD1 expression, the organoid-derived hepatocyte-like cells were safely delivered as repeated autologous transplantations via the portal vein. Although engraftment and repopulation percentages were low, the cells survived in the liver for up to two years post-transplantation. The low engraftment was in line with a lack of functional recovery regarding copper excretion. This preclinical study confirms the survival of genetically corrected autologous organoid-derived hepatocyte-like cells in vivo and warrants further optimization of organoid engraftment and functional recovery in a large animal model of human liver disease. Full article
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
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17 pages, 2658 KiB  
Article
TUG1 Is a Regulator of AFP and Serves as Prognostic Marker in Non-Hepatitis B Non-Hepatitis C Hepatocellular Carcinoma
by Yang-Hsiang Lin, Meng-Han Wu, Ya-Hui Huang, Chau-Ting Yeh and Kwang-Huei Lin
Cells 2020, 9(2), 262; https://doi.org/10.3390/cells9020262 - 21 Jan 2020
Cited by 15 | Viewed by 2786
Abstract
Thyroid hormone (T3) and its receptor (TR) are involved in cell metabolism and cancer progression. Hypothyroidism is associated with significantly elevated risk of hepatocellular carcinoma (HCC). Levels of the glycoprotein alpha-fetoprotein (AFP) are increased in the majority of patients with HCC [...] Read more.
Thyroid hormone (T3) and its receptor (TR) are involved in cell metabolism and cancer progression. Hypothyroidism is associated with significantly elevated risk of hepatocellular carcinoma (HCC). Levels of the glycoprotein alpha-fetoprotein (AFP) are increased in the majority of patients with HCC and may be useful in diagnosis and follow-up. However, the relationship between T3/TR and AFP levels in HCC is currently unclear. The expression profiles of long non-coding RNAs (lncRNAs) were compared in microarrays of HepG2-TRα1 cells treated with/without T3 and HCC specimens. The effects of T3 on taurine upregulated gene 1 (TUG1) and AFP expression were validated using qRT-PCR. A correlation between TUG1 and AFP was confirmed via RNAi and clustered regularly interspaced short palindromic repeats (CRISPR) strategies. Finally, overall and recurrence-free survival rates were analyzed using the Kaplan–Meier method and confirmed in online datasets. T3/TR treatment reduced TUG1 expression in vitro, resulting in the downregulation of AFP mRNA. Knockdown of TUG1 suppressed cell cycle progression and soft agar colony formation and induced cellular senescence. Our data support the involvement of TUG1 in the T3/TR-mediated suppression of cell growth. AFP mRNA levels showed strong positive correlations with TUG1 and unfavorable prognosis in patients with non-hepatitis B/non-hepatitis C HCC (NBNC-HCC). T3/TR, TUG1, and AFP may potentially serve as effective prognostic markers for NBNC-HCC. Full article
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
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16 pages, 2963 KiB  
Article
Cirrhotic Human Liver Extracellular Matrix 3D Scaffolds Promote Smad-Dependent TGF-β1 Epithelial Mesenchymal Transition
by Giuseppe Mazza, Andrea Telese, Walid Al-Akkad, Luca Frenguelli, Ana Levi, Martina Marrali, Lisa Longato, Kessarin Thanapirom, Maria Giovanna Vilia, Benedetta Lombardi, Claire Crowley, Mark Crawford, Morten A. Karsdal, Diana J. Leeming, Giusi Marrone, Katrin Bottcher, Benjamin Robinson, Armando Del Rio Hernandez, Domenico Tamburrino, Gabriele Spoletini, Massimo Malago, Andrew R. Hall, Jasminka Godovac-Zimmermann, Tu Vinh Luong, Paolo De Coppi, Massimo Pinzani and Krista Romboutsadd Show full author list remove Hide full author list
Cells 2020, 9(1), 83; https://doi.org/10.3390/cells9010083 - 28 Dec 2019
Cited by 35 | Viewed by 6417
Abstract
An altered liver microenvironment characterized by a dysregulated extracellular matrix (ECM) supports the development and progression of hepatocellular carcinoma (HCC). The development of experimental platforms able to reproduce these physio-pathological conditions is essential in order to identify and validate new therapeutic targets for [...] Read more.
An altered liver microenvironment characterized by a dysregulated extracellular matrix (ECM) supports the development and progression of hepatocellular carcinoma (HCC). The development of experimental platforms able to reproduce these physio-pathological conditions is essential in order to identify and validate new therapeutic targets for HCC. The aim of this work was to validate a new in vitro model based on engineering three-dimensional (3D) healthy and cirrhotic human liver scaffolds with HCC cells recreating the micro-environmental features favoring HCC. Healthy and cirrhotic human livers ECM scaffolds were developed using a high shear stress oscillation-decellularization procedure. The scaffolds bio-physical/bio-chemical properties were analyzed by qualitative and quantitative approaches. Cirrhotic 3D scaffolds were characterized by biomechanical properties and microarchitecture typical of the native cirrhotic tissue. Proteomic analysis was employed on decellularized 3D scaffolds and showed specific enriched proteins in cirrhotic ECM in comparison to healthy ECM proteins. Cell repopulation of cirrhotic scaffolds highlighted a unique up-regulation in genes related to epithelial to mesenchymal transition (EMT) and TGFβ signaling. This was also supported by the presence and release of higher concentration of endogenous TGFβ1 in cirrhotic scaffolds in comparison to healthy scaffolds. Fibronectin secretion was significantly upregulated in cells grown in cirrhotic scaffolds in comparison to cells engrafted in healthy scaffolds. TGFβ1 induced the phosphorylation of canonical proteins Smad2/3, which was ECM scaffold-dependent. Important, TGFβ1-induced phosphorylation of Smad2/3 was significantly reduced and ECM scaffold-independent when pre/simultaneously treated with the TGFβ-R1 kinase inhibitor Galunisertib. In conclusion, the inherent features of cirrhotic human liver ECM micro-environment were dissected and characterized for the first time as key pro-carcinogenic components in HCC development. Full article
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
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17 pages, 4542 KiB  
Article
(–)-Catechin-7-O-β-d-Apiofuranoside Inhibits Hepatic Stellate Cell Activation by Suppressing the STAT3 Signaling Pathway
by Yong Joo Park, Dong Min Kim, Mi Ho Jeong, Jae Sik Yu, Hae Min So, In Jae Bang, Ha Ryong Kim, Seung-Hwan Kwon, Ki Hyun Kim and Kyu Hyuck Chung
Cells 2020, 9(1), 30; https://doi.org/10.3390/cells9010030 - 20 Dec 2019
Cited by 20 | Viewed by 4223
Abstract
Hepatic fibrosis is characterized by the abnormal deposition of extracellular matrix (ECM) proteins. During hepatic fibrogenesis, hepatic stellate cell (HSC) activation followed by chronic injuries is considered a key event in fibrogenesis, and activated HSCs are known to comprise approximately 90% of ECM-producing [...] Read more.
Hepatic fibrosis is characterized by the abnormal deposition of extracellular matrix (ECM) proteins. During hepatic fibrogenesis, hepatic stellate cell (HSC) activation followed by chronic injuries is considered a key event in fibrogenesis, and activated HSCs are known to comprise approximately 90% of ECM-producing myofibroblasts. Here, we demonstrated that (–)-catechin-7-O-β-d-apiofuranoside (C7A) significantly inhibited HSC activation via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. This is the first study to show the hepatic protective effects of C7A with possible mechanisms in vitro and in vivo. In our bioactivity screening, we figured out that the EtOH extract of Ulmus davidiana var. japonica root barks, which have been used as a Korean traditional medicine, inhibited collagen synthesis in HSCs. Four catechins isolated from the EtOAc fraction of the EtOH extract were compared with each other in terms of reduction in collagen, which is considered as a marker of hepatic protective effects, and C7A showed the strongest inhibitory effects on HSC activation in protein and qPCR analyses. As a possible mechanism, we investigated the effects of C7A on the STAT3 signaling pathway, which is known to activate HSCs. We found that C7A inhibited phosphorylation of STAT3 and translocation of STAT3 to nucleus. C7A also inhibited expressions of MMP-2 and MMP-9, which are downstream genes of STAT3 signaling. Anti-fibrotic effects of C7A were evaluated in a thioacetamide (TAA)-induced liver fibrosis model, which indicated that C7A significantly inhibited ECM deposition through inhibiting STAT3 signaling. C7A decreased serum levels of aspartate amino transferase and alanine transaminase, which were markedly increased by TAA injection. Moreover, ECM-associated proteins and mRNA expression were strongly suppressed by C7A. Our study provides the experimental evidence that C7A has inhibitory effects on HSC activation after live injury and has preventive and therapeutic potentials for the management of hepatic fibrosis. Full article
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
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15 pages, 5121 KiB  
Article
The Role of GLP1 in Rat Steatotic and Non-Steatotic Liver Transplantation from Cardiocirculatory Death Donors
by Cindy G. Avalos-de León, Mónica B. Jiménez-Castro, María Eugenia Cornide-Petronio, Araní Casillas-Ramírez and Carmen Peralta
Cells 2019, 8(12), 1599; https://doi.org/10.3390/cells8121599 - 09 Dec 2019
Cited by 4 | Viewed by 2312
Abstract
In liver transplantation (LT), organ shortage has led to the use of steatotic and non-steatotic grafts from donors after cardiocirculatory death (DCD). However, these grafts, especially those with steatosis, exhibit poor post-operative outcomes. To address this problem, we investigated the roles of gut-derived [...] Read more.
In liver transplantation (LT), organ shortage has led to the use of steatotic and non-steatotic grafts from donors after cardiocirculatory death (DCD). However, these grafts, especially those with steatosis, exhibit poor post-operative outcomes. To address this problem, we investigated the roles of gut-derived glucagon-like peptide 1 (GLP1) and dipeptidyl peptidase 4 (DPP4), the serine protease that cleaves it, in steatotic and non-steatotic LT from DCDs. Using Zucker rats, liver grafts from DCDs were cold stored and transplanted to recipients. GLP1 was administered to donors. The levels of GLP1 in intestine and of both GLP1 and DDP4 in circulation were unaltered following cardiocirculatory death (CD). In steatotic livers from DCD, increased GLP1 and decreased DPP4 were recorded, and administration of GLP1 caused a rise in hepatic GLP1 and a reduction in DDP4. This protected against inflammation, damage, and proliferation failure. Conversely, low GLP1 and high DDP4 were observed in non-steatotic livers from DCD. The exogenous GLP1 did not modify hepatic DDP4, and the accumulated GLP1 exerted harmful effects, increasing damage, inflammation, and regeneration failure. Herein, we show that there are differences in GLP1/DDP4 regulation depending on the type of liver implanted, suggesting that GLP1 can be used as a novel and effective therapy in steatotic grafts from DCDs but that it is not appropriate for non-steatotic DCDs. Full article
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
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18 pages, 3943 KiB  
Article
A Novel Small Molecule Inhibits Intrahepatocellular Accumulation of Z-Variant Alpha 1-Antitrypsin In Vitro and In Vivo
by Xiaojuan Zhang, Kien Pham, Danmeng Li, Ryan J. Schutte, David Hernandez Gonzalo, Penghui Zhang, Regina Oshins, Weihong Tan, Mark Brantly, Chen Liu and David A. Ostrov
Cells 2019, 8(12), 1586; https://doi.org/10.3390/cells8121586 - 06 Dec 2019
Cited by 10 | Viewed by 3616
Abstract
Alpha 1-antitrypsin deficiency (AATD) is the most common genetic cause of liver disease in children and is associated with early-onset chronic liver disease in adults. AATD associated liver injury is caused by hepatotoxic retention of polymerized mutant alpha 1-antitrypsin molecules within the endoplasmic [...] Read more.
Alpha 1-antitrypsin deficiency (AATD) is the most common genetic cause of liver disease in children and is associated with early-onset chronic liver disease in adults. AATD associated liver injury is caused by hepatotoxic retention of polymerized mutant alpha 1-antitrypsin molecules within the endoplasmic reticulum. Currently, there is no curative therapy for AATD. In this study, we selected small molecules with the potential to bind mutant alpha 1-antitrypsin (Z-variant) to inhibit its accumulation in hepatocytes. We used molecular docking to select candidate compounds that were validated in cell and animal models of disease. A crystal structure of polymerized alpha 1-antitrypsin molecule was used as the basis for docking 139,735 compounds. Effects of the top scoring compounds were investigated in a cell model that stably expresses Z-variant alpha 1-antitrypsin and in PiZ mice expressing Z-variant human alpha 1-antitrypsin (Z-hAAT), encoded by SERPINA1*E342K. 4′,′5-(Methylenedioxy)-2-nitrocinnamic acid was predicted to bind cleaved alpha 1-antitrypsin at the polymerization interface, and observed to co-localize with Z-hAAT, increase Z-hAAT degradation, inhibit intracellular accumulation of Z-hAAT, and alleviate liver fibrosis. Full article
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
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15 pages, 2763 KiB  
Article
Augmenter of Liver Regeneration Reduces Ischemia Reperfusion Injury by Less Chemokine Expression, Gr-1 Infiltration and Oxidative Stress
by Thomas S. Weiss, Madeleine Lupke, Rania Dayoub, Edward K. Geissler, Hans J. Schlitt, Michael Melter and Elke Eggenhofer
Cells 2019, 8(11), 1421; https://doi.org/10.3390/cells8111421 - 12 Nov 2019
Cited by 10 | Viewed by 3631
Abstract
Hepatic ischemia reperfusion injury (IRI) is a major complication in liver resection and transplantation. Here, we analyzed the impact of recombinant human augmenter of liver regeneration (rALR), an anti-oxidative and anti-apoptotic protein, on the deleterious process induced by ischemia reperfusion (IR). Application of [...] Read more.
Hepatic ischemia reperfusion injury (IRI) is a major complication in liver resection and transplantation. Here, we analyzed the impact of recombinant human augmenter of liver regeneration (rALR), an anti-oxidative and anti-apoptotic protein, on the deleterious process induced by ischemia reperfusion (IR). Application of rALR reduced tissue damage (necrosis), levels of lipid peroxidation (oxidative stress) and expression of anti-oxidative genes in a mouse IRI model. Damage associated molecule pattern (DAMP) and inflammatory cytokines such as HMGB1 and TNFα, were not affected by rALR. Furthermore, we evaluated infiltration of inflammatory cells into liver tissue after IRI and found no change in CD3 or γδTCR positive cells, or expression of IL17/IFNγ by γδTCR cells. The quantity of Gr-1 positive cells (neutrophils), and therefore, myeloperoxidase activity, was lower in rALR-treated mice. Moreover, we found under hypoxic conditions attenuated ROS levels after ALR treatment in RAW264.7 cells and in primary mouse hepatocytes. Application of rALR also led to reduced expression of chemo-attractants like CXCL1, CXCL2 and CCl2 in hepatocytes. In addition, ALR expression was increased in IR mouse livers after 3 h and in biopsies from human liver transplants with minimal signs of tissue damage. Therefore, ALR attenuates IRI through reduced neutrophil tissue infiltration mediated by lower expression of key hepatic chemokines and reduction of ROS generation. Full article
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
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15 pages, 3748 KiB  
Article
CX3CR1 Mediates the Development of Monocyte-Derived Dendritic Cells during Hepatic Inflammation
by Salvatore Sutti, Stefania Bruzzì, Felix Heymann, Anke Liepelt, Oliver Krenkel, Alberto Toscani, Naresh Naik Ramavath, Diego Cotella, Emanuele Albano and Frank Tacke
Cells 2019, 8(9), 1099; https://doi.org/10.3390/cells8091099 - 18 Sep 2019
Cited by 24 | Viewed by 5096
Abstract
Recent evidence suggests that hepatic dendritic cells (HDCs) contribute to the evolution of chronic liver diseases. However, the HDC subsets involved and the mechanisms driving these responses are still poorly understood. In this study, we have investigated the role of the fractalkine receptor [...] Read more.
Recent evidence suggests that hepatic dendritic cells (HDCs) contribute to the evolution of chronic liver diseases. However, the HDC subsets involved and the mechanisms driving these responses are still poorly understood. In this study, we have investigated the role of the fractalkine receptor CX3CR1 in modulating monocyte-derived dendritic cell (moDC) differentiation during liver inflammation. The phenotype of HDC and functional relevance of CX3CR1 was assessed in mice following necro-inflammatory liver injury induced by the hepatotoxic agent carbon tetrachloride (CCl4) and in steatohepatitis caused by a methionine/choline-deficient (MCD) diet. In both the experimental models, hepatic inflammation was associated with a massive expansion of CD11c+/MHCIIhigh/CD11b+ myeloid HDCs. These cells also expressed the monocyte markers Ly6C, chemokine (C-C Motif) receptor 2 (CCR2), F4/80 and CD88, along with CX3CR1, allowing their tentative identification as moDCs. Mice defective in CX3CR1 showed a reduction in liver-moDC recruitment following CCl4 poisoning in parallel with a defective maturation of monocytes into moDCs. The lack of CX3CR1 also affected moDC differentiation from bone marrow myeloid cells induced by granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) in vitro. In wild-type mice, treatment with the CX3CR1 antagonist CX3-AT (150 µg, i.p.) 24 h after CCl4 administration reduced liver moDCS and significantly ameliorated hepatic injury and inflammation. Altogether, these results highlight the possible involvement of moDCs in promoting hepatic inflammation following liver injury and indicated a novel role of CX3CL1/CX3CR1 dyad in driving the differentiation of hepatic moDCs. Full article
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
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16 pages, 3143 KiB  
Article
Clinical Protocol to Prevent Thrombogenic Effect of Liver-Derived Mesenchymal Cells for Cell-Based Therapies
by Louise Coppin, Mustapha Najimi, Julie Bodart, Marie-Sophie Rouchon, Patrick van der Smissen, Stéphane Eeckhoudt, Géraldine Dahlqvist, Diego Castanares-Zapatero, Mina Komuta, Sanne L. Brouns, Constance C. Baaten, Johan W. M. Heemskerk, Sandrine Horman, Nathalie Belmonte, Etienne Sokal and Xavier Stéphenne
Cells 2019, 8(8), 846; https://doi.org/10.3390/cells8080846 - 07 Aug 2019
Cited by 16 | Viewed by 3408
Abstract
The efficacy of mesenchymal stem cell infusion is currently tested in numerous clinical trials. However, therapy-induced thrombotic consequences have been reported in several patients. The aim of this study was to optimize protocols for heterologous human adult liver-derived progenitor cell (HHALPC) infusion, in [...] Read more.
The efficacy of mesenchymal stem cell infusion is currently tested in numerous clinical trials. However, therapy-induced thrombotic consequences have been reported in several patients. The aim of this study was to optimize protocols for heterologous human adult liver-derived progenitor cell (HHALPC) infusion, in order to eliminate acute thrombogenesis in liver-based metabolic or acute decompensated cirrhotic (ADC) patients. In rats, thrombotic effects were absent when HHALPCs were infused at low cell dose (5 × 106 cells/kg), or at high cell dose (5 × 107 cells/kg) when combined with anticoagulants. When HHALPCs were exposed to human blood in a whole blood perfusion assay, blocking of the tissue factor (TF) coagulation pathway suppressed fibrin generation and platelet activation. In a Chandler tubing loop model, HHALPCs induced less explosive activation of coagulation with blood from ADC patients, when compared to blood from healthy controls, without alterations in coagulation factor levels other than fibrinogen. These studies confirm a link between TF and thrombogenesis, when TF-expressing cells are exposed to human blood. This phenomenon however, could be controlled using either a low, or a high cell dose combined with anticoagulants. In clinical practice, this points to the suitability of a low HHALPC dose infusion to cirrhotic patients, provided that platelet and fibrinogen levels are monitored. Full article
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
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26 pages, 6170 KiB  
Article
Emerging Role of l-Dopa Decarboxylase in Flaviviridae Virus Infections
by Efseveia Frakolaki, Katerina I. Kalliampakou, Panagiota Kaimou, Maria Moraiti, Nikolaos Kolaitis, Haralabia Boleti, John Koskinas, Dido Vassilacopoulou and Niki Vassilaki
Cells 2019, 8(8), 837; https://doi.org/10.3390/cells8080837 - 05 Aug 2019
Cited by 19 | Viewed by 5557
Abstract
l-dopa decarboxylase (DDC) that catalyzes the biosynthesis of bioactive amines, such as dopamine and serotonin, is expressed in the nervous system and peripheral tissues, including the liver, where its physiological role remains unknown. Recently, we reported a physical and functional interaction of [...] Read more.
l-dopa decarboxylase (DDC) that catalyzes the biosynthesis of bioactive amines, such as dopamine and serotonin, is expressed in the nervous system and peripheral tissues, including the liver, where its physiological role remains unknown. Recently, we reported a physical and functional interaction of DDC with the major signaling regulator phosphoinosite-3-kinase (PI3K). Here, we provide compelling evidence for the involvement of DDC in viral infections. Studying dengue (DENV) and hepatitis C (HCV) virus infection in hepatocytes and HCV replication in liver samples of infected patients, we observed a negative association between DDC and viral replication. Specifically, replication of both viruses reduced the levels of DDC mRNA and the ~120 kDa SDS-resistant DDC immunoreactive functional complex, concomitant with a PI3K-dependent accumulation of the ~50 kDa DDC monomer. Moreover, viral infection inhibited PI3K-DDC association, while DDC did not colocalize with viral replication sites. DDC overexpression suppressed DENV and HCV RNA replication, while DDC enzymatic inhibition enhanced viral replication and infectivity and affected DENV-induced cell death. Consistently, we observed an inverse correlation between DDC mRNA and HCV RNA levels in liver biopsies from chronically infected patients. These data reveal a novel relationship between DDC and Flaviviridae replication cycle and the role of PI3K in this process. Full article
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
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Review

Jump to: Research

26 pages, 1202 KiB  
Review
Alternative Cell Sources for Liver Parenchyma Repopulation: Where Do We Stand?
by Tine Tricot, Jolan De Boeck and Catherine Verfaillie
Cells 2020, 9(3), 566; https://doi.org/10.3390/cells9030566 - 28 Feb 2020
Cited by 13 | Viewed by 3973
Abstract
Acute and chronic liver failure is a highly prevalent medical condition with high morbidity and mortality. Currently, the therapy is orthotopic liver transplantation. However, in some instances, chiefly in the setting of metabolic diseases, transplantation of individual cells, specifically functional hepatocytes, can be [...] Read more.
Acute and chronic liver failure is a highly prevalent medical condition with high morbidity and mortality. Currently, the therapy is orthotopic liver transplantation. However, in some instances, chiefly in the setting of metabolic diseases, transplantation of individual cells, specifically functional hepatocytes, can be an acceptable alternative. The gold standard for this therapy is the use of primary human hepatocytes, isolated from livers that are not suitable for whole organ transplantations. Unfortunately, primary human hepatocytes are scarcely available, which has led to the evaluation of alternative sources of functional hepatocytes. In this review, we will compare the ability of most of these candidate alternative cell sources to engraft and repopulate the liver of preclinical animal models with the repopulation ability found with primary human hepatocytes. We will discuss the current shortcomings of the different cell types, and some of the next steps that we believe need to be taken to create alternative hepatocyte progeny capable of regenerating the failing liver. Full article
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
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21 pages, 309 KiB  
Review
Emerging Noninvasive Biomarkers, and Medical Management Strategies for Alcoholic Hepatitis: Present Understanding and Scope
by Khushboo S. Gala and Vatsalya Vatsalya
Cells 2020, 9(3), 524; https://doi.org/10.3390/cells9030524 - 25 Feb 2020
Cited by 18 | Viewed by 3306
Abstract
Alcohol use disorder is associated with a wide array of hepatic pathologies ranging from steatosis to alcoholic-related cirrhosis (AC), alcoholic hepatitis (AH), or hepatocellular carcinoma (HCC). Biomarkers are categorized into two main categories: biomarkers associated with alcohol consumption and biomarkers of alcoholic liver [...] Read more.
Alcohol use disorder is associated with a wide array of hepatic pathologies ranging from steatosis to alcoholic-related cirrhosis (AC), alcoholic hepatitis (AH), or hepatocellular carcinoma (HCC). Biomarkers are categorized into two main categories: biomarkers associated with alcohol consumption and biomarkers of alcoholic liver disease (ALD). No ideal biomarker has been identified to quantify the degree of hepatocyte death or severity of AH, even though numerous biomarkers have been associated with AH. This review provides information of some of the novel and latest biomarkers that are being investigated and have shown a substantial association with the degree and severity of liver injury and inflammation. Importantly, they can be measured noninvasively. In this manuscript, we consolidate the present understanding and prospects of these biomarkers; and their application in assessing the severity and progression of the alcoholic liver disease (ALD). We also review current and upcoming management options for AH. Full article
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
22 pages, 696 KiB  
Review
Pluripotent-Stem-Cell-Derived Hepatic Cells: Hepatocytes and Organoids for Liver Therapy and Regeneration
by Antonietta Messina, Eléanor Luce, Marwa Hussein and Anne Dubart-Kupperschmitt
Cells 2020, 9(2), 420; https://doi.org/10.3390/cells9020420 - 12 Feb 2020
Cited by 64 | Viewed by 9615
Abstract
The liver is a very complex organ that ensures numerous functions; it is thus susceptible to multiple types of damage and dysfunction. Since 1983, orthotopic liver transplantation (OLT) has been considered the only medical solution available to patients when most of their liver [...] Read more.
The liver is a very complex organ that ensures numerous functions; it is thus susceptible to multiple types of damage and dysfunction. Since 1983, orthotopic liver transplantation (OLT) has been considered the only medical solution available to patients when most of their liver function is lost. Unfortunately, the number of patients waiting for OLT is worryingly increasing, and extracorporeal liver support devices are not yet able to counteract the problem. In this review, the current and expected methodologies in liver regeneration are briefly analyzed. In particular, human pluripotent stem cells (hPSCs) as a source of hepatic cells for liver therapy and regeneration are discussed. Principles of hPSC differentiation into hepatocytes are explored, along with the current limitations that have led to the development of 3D culture systems and organoid production. Expected applications of these organoids are discussed with particular attention paid to bio artificial liver (BAL) devices and liver bio-fabrication. Full article
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
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28 pages, 897 KiB  
Review
Tissue Engineering in Liver Regenerative Medicine: Insights into Novel Translational Technologies
by Zahra Heydari, Mustapha Najimi, Hamed Mirzaei, Anastasia Shpichka, Marc Ruoss, Zahra Farzaneh, Leila Montazeri, Abbas Piryaei, Peter Timashev, Roberto Gramignoli, Andreas Nussler, Hossein Baharvand and Massoud Vosough
Cells 2020, 9(2), 304; https://doi.org/10.3390/cells9020304 - 27 Jan 2020
Cited by 64 | Viewed by 10023
Abstract
Organ and tissue shortage are known as a crucially important public health problem as unfortunately a small percentage of patients receive transplants. In the context of emerging regenerative medicine, researchers are trying to regenerate and replace different organs and tissues such as the [...] Read more.
Organ and tissue shortage are known as a crucially important public health problem as unfortunately a small percentage of patients receive transplants. In the context of emerging regenerative medicine, researchers are trying to regenerate and replace different organs and tissues such as the liver, heart, skin, and kidney. Liver tissue engineering (TE) enables us to reproduce and restore liver functions, fully or partially, which could be used in the treatment of acute or chronic liver disorders and/or generate an appropriate functional organ which can be transplanted or employed as an extracorporeal device. In this regard, a variety of techniques (e.g., fabrication technologies, cell-based technologies, microfluidic systems and, extracorporeal liver devices) could be applied in tissue engineering in liver regenerative medicine. Common TE techniques are based on allocating stem cell-derived hepatocyte-like cells or primary hepatocytes within a three-dimensional structure which leads to the improvement of their survival rate and functional phenotype. Taken together, new findings indicated that developing liver tissue engineering-based techniques could pave the way for better treatment of liver-related disorders. Herein, we summarized novel technologies used in liver regenerative medicine and their future applications in clinical settings. Full article
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
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15 pages, 2668 KiB  
Review
Are Liver Pericytes Just Precursors of Myofibroblasts in Hepatic Diseases? Insights from the Crosstalk between Perivascular and Inflammatory Cells in Liver Injury and Repair
by Lindolfo da Silva Meirelles, Renan Fava Marson, Maria Inês Gonzalez Solari and Nance Beyer Nardi
Cells 2020, 9(1), 188; https://doi.org/10.3390/cells9010188 - 11 Jan 2020
Cited by 15 | Viewed by 3792
Abstract
Cirrhosis, a late form of liver disease, is characterized by extensive scarring due to exacerbated secretion of extracellular matrix proteins by myofibroblasts that develop during this process. These myofibroblasts arise mainly from hepatic stellate cells (HSCs), liver-specific pericytes that become activated at the [...] Read more.
Cirrhosis, a late form of liver disease, is characterized by extensive scarring due to exacerbated secretion of extracellular matrix proteins by myofibroblasts that develop during this process. These myofibroblasts arise mainly from hepatic stellate cells (HSCs), liver-specific pericytes that become activated at the onset of liver injury. Consequently, HSCs tend to be viewed mainly as myofibroblast precursors in a fibrotic process driven by inflammation. Here, the molecular interactions between liver pericytes and inflammatory cells such as macrophages and neutrophils at the first moments after injury and during the healing process are brought into focus. Data on HSCs and pericytes from other tissues indicate that these cells are able to sense pathogen- and damage-associated molecular patterns and have an important proinflammatory role in the initial stages of liver injury. On the other hand, further data suggest that as the healing process evolves, activated HSCs play a role in skewing the initial proinflammatory (M1) macrophage polarization by contributing to the emergence of alternatively activated, pro-regenerative (M2-like) macrophages. Finally, data suggesting that some HSCs activated during liver injury could behave as hepatic progenitor or stem cells will be discussed. Full article
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
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20 pages, 1953 KiB  
Review
Anti-NASH Drug Development Hitches a Lift on PPAR Agonism
by Joost Boeckmans, Alessandra Natale, Matthias Rombaut, Karolien Buyl, Vera Rogiers, Joery De Kock, Tamara Vanhaecke and Robim M. Rodrigues
Cells 2020, 9(1), 37; https://doi.org/10.3390/cells9010037 - 21 Dec 2019
Cited by 89 | Viewed by 9913
Abstract
Non-alcoholic fatty liver disease (NAFLD) affects one-third of the population worldwide, of which a substantial number of patients suffer from non-alcoholic steatohepatitis (NASH). NASH is a severe condition characterized by steatosis and concomitant liver inflammation and fibrosis, for which no drug is yet [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) affects one-third of the population worldwide, of which a substantial number of patients suffer from non-alcoholic steatohepatitis (NASH). NASH is a severe condition characterized by steatosis and concomitant liver inflammation and fibrosis, for which no drug is yet available. NAFLD is also generally conceived as the hepatic manifestation of the metabolic syndrome. Consequently, well-established drugs that are indicated for the treatment of type 2 diabetes and hyperlipidemia are thought to exert effects that alleviate the pathological features of NASH. One class of these drugs targets peroxisome proliferator-activated receptors (PPARs), which are nuclear receptors that play a regulatory role in lipid metabolism and inflammation. Therefore, PPARs are now also being investigated as potential anti-NASH druggable targets. In this paper, we review the mechanisms of action and physiological functions of PPARs and discuss the position of the different PPAR agonists in the therapeutic landscape of NASH. We particularly focus on the PPAR agonists currently under evaluation in clinical phase II and III trials. Preclinical strategies and how refinement and optimization may improve PPAR-targeted anti-NASH drug testing are also discussed. Finally, potential caveats related to PPAR agonism in anti-NASH therapy are stipulated. Full article
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
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22 pages, 969 KiB  
Review
Phenotypical and Functional Polymorphism of Liver Resident Macrophages
by Andrey V. Elchaninov, Timur Kh. Fatkhudinov, Polina A. Vishnyakova, Anastasia V. Lokhonina and Gennady T. Sukhikh
Cells 2019, 8(9), 1032; https://doi.org/10.3390/cells8091032 - 05 Sep 2019
Cited by 51 | Viewed by 5968
Abstract
Liver diseases are one of the main causes of mortality. In this regard, the development of new ways of reparative processes stimulation is relevant. Macrophages play a leading role in the regulation of liver homeostasis in physiological conditions and in pathology. In this [...] Read more.
Liver diseases are one of the main causes of mortality. In this regard, the development of new ways of reparative processes stimulation is relevant. Macrophages play a leading role in the regulation of liver homeostasis in physiological conditions and in pathology. In this regard, the development of new liver treatment methods is impossible without taking into account this cell population. Resident macrophages of the liver, Kupffer cells, represent a unique cell population, first of all, due to their development. Most of the liver macrophages belong to the self-sustaining macrophage cell population, whose origin is not bone marrow. In addition, Kupffer cells are involved in such processes as regulation of hepatocyte proliferation and apoptosis, remodeling of the intercellular matrix, lipid metabolism, protective function, etc. Such a broad spectrum of liver macrophage functions indicates their high functional plasticity. The review summarizes recent data on the development, phenotypic and functional plasticity, and participation in the reparative processes of liver macrophages: resident macrophages (Kupffer cells) and bone marrow-derived macrophages. Full article
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
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