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Cells
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Hepatic Stem Cells in Liver and Biliary Regeneration
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Hepatic Stem Cells in Liver and Biliary Regeneration

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

Deadline for manuscript submissions: closed (1 March 2020) | Viewed by 44637

Special Issue Editor

Prof. Guido Carpino

E-Mail Website
Guest Editor
Università degli Studi di Roma "Foro Italico", Rome, Italy
Interests: stem cells; liver; anatomy; morphology; cholangiocyte; liver diseases; cholangiocarcinoma; histology; biliary tree

Special Issue Information

Dear Colleagues,

The physiological turnover of the liver and the biliary tree is ensured by the proliferation of mature hepatocytes and cholangiocytes. Liver stem cells represent a background compartment activated by a regenerative response after injury. Lineage-tracing models disclosed the contribution of liver stem cells in liver regeneration and further underlined the role of mature parenchymal cell plasticity. In humans, liver stem cells have been indicated as the main drivers of fibrogenesis in chronic liver and biliary diseases, leading to a progression toward cirrhosis. Remarkably, liver stem cells are supposed to be cells of origin in some subtypes of liver cancers. The characterization of the liver stem cell niche and the definition of molecular signaling pathways are crucial to elucidate the pathogenesis of human diseases and to individuate novel therapeutic approaches. Moreover, the development of strategies regarding the application of liver stem cells in clinical programs for end-stage liver disease is a priority.

The aim of this Special Issue is to provide recent advances in the field of liver and biliary regeneration, including the characterization of stem cell niches, the contribution of cellular plasticity, the molecular interactions at the basis of stem cell activation, and their application in regenerative medicine.

Prof. Guido Carpino
Guest Editor

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Keywords

  • liver stem cells
  • liver regeneration
  • plasticity
  • cell therapy
  • liver disease
  • lineage-tracing
  • cirrhosis
  • niche
  • cell morphology
  • liver tumors

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Published Papers (6 papers)

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Research

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19 pages, 9709 KiB  
Article
Large-Scale Profiling of Signaling Pathways Reveals a Distinct Demarcation between Normal and Extended Liver Resection
by Pieter Borger, Anton Buzdin, Maksim Sorokin, Ekaterina Kachaylo, Bostjan Humar, Rolf Graf and Pierre-Alien Clavien
Cells 2020, 9(5), 1149; https://doi.org/10.3390/cells9051149 - 7 May 2020
Cited by 3 | Viewed by 2282
Abstract
Despite numerous studies addressing normal liver regeneration, we still lack comprehensive understanding of the biological processes underlying failed liver regeneration. Therefore, we analyzed the activity of 271 intracellular signaling pathways (ISPs) by genome wide profiling of differentially expressed RNAs in murine liver tissue [...] Read more.
Despite numerous studies addressing normal liver regeneration, we still lack comprehensive understanding of the biological processes underlying failed liver regeneration. Therefore, we analyzed the activity of 271 intracellular signaling pathways (ISPs) by genome wide profiling of differentially expressed RNAs in murine liver tissue biopsies after normal hepatectomy (nHx; 68% of liver removed) and extended hepatectomy (eHx; 86% of liver removed). Comprehensive, genome-wide transcriptome profiling using RNAseq was performed in liver tissue obtained from mice (sham, nHx, and eHx) harvested 1, 8, 16, 32, and 48 h after operation (n = 3 per group) and the OncoFinder toolkit was used for an unsupervised, unbiased identification of intracellular signaling pathways (ISP) activity. We observed that the normal regenerative process requires a transient activation and silencing of approximately two dozen of ISPs. After nHx, the Akt Pathway represented with 13 branches, the Chromatin Pathway and the DDR Pathways dominated. After eHx, the ATM main pathway and two of its branches (Cell Survival; G2_M Checkpoint Arrest) dominated, as well as the Hypoxia Pathways. Further, 14 ISPs demonstrated a strong inverse regulation, with the Hedgehog and the Brca1 Main Pathways as chief activators after nHx, and the ATM Pathway(G2_M Checkpoint Arrest) as the dominating constraining response after eHx. Full article
(This article belongs to the Special Issue Hepatic Stem Cells in Liver and Biliary Regeneration)
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22 pages, 3559 KiB  
Article
Meta-Analysis of Human and Mouse Biliary Epithelial Cell Gene Profiles
by Stefaan Verhulst, Tania Roskams, Pau Sancho-Bru and Leo A. van Grunsven
Cells 2019, 8(10), 1117; https://doi.org/10.3390/cells8101117 - 20 Sep 2019
Cited by 7 | Viewed by 4852
Abstract
Background: Chronic liver diseases are frequently accompanied with activation of biliary epithelial cells (BECs) that can differentiate into hepatocytes and cholangiocytes, providing an endogenous back-up system. Functional studies on BECs often rely on isolations of an BEC cell population from healthy and/or injured [...] Read more.
Background: Chronic liver diseases are frequently accompanied with activation of biliary epithelial cells (BECs) that can differentiate into hepatocytes and cholangiocytes, providing an endogenous back-up system. Functional studies on BECs often rely on isolations of an BEC cell population from healthy and/or injured livers. However, a consensus on the characterization of these cells has not yet been reached. The aim of this study was to compare the publicly available transcriptome profiles of human and mouse BECs and to establish gene signatures that can identify quiescent and activated human and mouse BECs. Methods: We used publicly available transcriptome data sets of human and mouse BECs, compared their profiles and analyzed co-expressed genes and pathways. By merging both human and mouse BEC-enriched genes, we obtained a quiescent and activation gene signature and tested them on BEC-like cells and different liver diseases using gene set enrichment analysis. In addition, we identified several genes from both gene signatures to identify BECs in a scRNA sequencing data set. Results: Comparison of mouse BEC transcriptome data sets showed that the isolation method and array platform strongly influences their general profile, still most populations are highly enriched in most genes currently associated with BECs. Pathway analysis on human and mouse BECs revealed the KRAS signaling as a new potential pathway in BEC activation. We established a quiescent and activated BEC gene signature that can be used to identify BEC-like cells and detect BEC enrichment in alcoholic hepatitis, non-alcoholic steatohepatitis (NASH) and peribiliary sclerotic livers. Finally, we identified a gene set that can distinguish BECs from other liver cells in mouse and human scRNAseq data. Conclusions: Through a meta-analysis of human and mouse BEC gene profiles we identified new potential pathways in BEC activation and created unique gene signatures for quiescent and activated BECs. These signatures and pathways will help in the further characterization of this progenitor cell type in mouse and human liver development and disease. Full article
(This article belongs to the Special Issue Hepatic Stem Cells in Liver and Biliary Regeneration)
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Review

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25 pages, 3762 KiB  
Review
Hepatocyte Injury and Hepatic Stem Cell Niche in the Progression of Non-Alcoholic Steatohepatitis
by Diletta Overi, Guido Carpino, Antonio Franchitto, Paolo Onori and Eugenio Gaudio
Cells 2020, 9(3), 590; https://doi.org/10.3390/cells9030590 - 2 Mar 2020
Cited by 43 | Viewed by 12416
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by lipid accumulation in hepatocytes in the absence of excessive alcohol consumption. The global prevalence of NAFLD is constantly increasing. NAFLD is a disease spectrum comprising distinct stages with different prognoses. Non-alcoholic [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by lipid accumulation in hepatocytes in the absence of excessive alcohol consumption. The global prevalence of NAFLD is constantly increasing. NAFLD is a disease spectrum comprising distinct stages with different prognoses. Non-alcoholic steatohepatitis (NASH) is a progressive condition, characterized by liver inflammation and hepatocyte ballooning, with or without fibrosis. The natural history of NAFLD is negatively influenced by NASH onset and by the progression towards advanced fibrosis. Pathogenetic mechanisms and cellular interactions leading to NASH and fibrosis involve hepatocytes, liver macrophages, myofibroblast cell subpopulations, and the resident progenitor cell niche. These cells are implied in the regenerative trajectories following liver injury, and impairment or perturbation of these mechanisms could lead to NASH and fibrosis. Recent evidence underlines the contribution of extra-hepatic organs/tissues (e.g., gut, adipose tissue) in influencing NASH development by interacting with hepatic cells through various molecular pathways. The present review aims to summarize the role of hepatic parenchymal and non-parenchymal cells, their mutual influence, and the possible interactions with extra-hepatic tissues and organs in the pathogenesis of NAFLD. Full article
(This article belongs to the Special Issue Hepatic Stem Cells in Liver and Biliary Regeneration)
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37 pages, 1808 KiB  
Review
Mesenchymal Stem Cells in the Adult Human Liver: Hype or Hope?
by Irina V. Kholodenko, Leonid K. Kurbatov, Roman V. Kholodenko, Garik V. Manukyan and Konstantin N. Yarygin
Cells 2019, 8(10), 1127; https://doi.org/10.3390/cells8101127 - 22 Sep 2019
Cited by 34 | Viewed by 6224
Abstract
Chronic liver diseases constitute a significant economic, social, and biomedical burden. Among commonly adopted approaches, only organ transplantation can radically help patients with end-stage liver pathologies. Cell therapy with hepatocytes as a treatment for chronic liver disease has demonstrated promising results. However, quality [...] Read more.
Chronic liver diseases constitute a significant economic, social, and biomedical burden. Among commonly adopted approaches, only organ transplantation can radically help patients with end-stage liver pathologies. Cell therapy with hepatocytes as a treatment for chronic liver disease has demonstrated promising results. However, quality human hepatocytes are in short supply. Stem/progenitor cells capable of differentiating into functionally active hepatocytes provide an attractive alternative approach to cell therapy for liver diseases, as well as to liver-tissue engineering, drug screening, and basic research. The application of methods generally used to isolate mesenchymal stem cells (MSCs) and maintain them in culture to human liver tissue provides cells, designated here as liver MSCs. They have much in common with MSCs from other tissues, but differ in two aspects—expression of a range of hepatocyte-specific genes and, possibly, inherent commitment to hepatogenic differentiation. The aim of this review is to analyze data regarding liver MSCs, probably another type of liver stem/progenitor cells different from hepatic stellate cells or so-called hepatic progenitor cells. The review presents an analysis of the phenotypic characteristics of liver MSCs, their differentiation and therapeutic potential, methods for isolating these cells from human liver, and discusses issues of their origin and heterogeneity. Human liver MSCs are a fascinating object of fundamental research with a potential for important practical applications. Full article
(This article belongs to the Special Issue Hepatic Stem Cells in Liver and Biliary Regeneration)
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19 pages, 1523 KiB  
Review
Functions and the Emerging Role of the Foetal Liver into Regenerative Medicine
by Antonella Giancotti, Marco Monti, Lorenzo Nevi, Samira Safarikia, Valentina D’Ambrosio, Roberto Brunelli, Cristina Pajno, Sara Corno, Violante Di Donato, Angela Musella, Michele Francesco Chiappetta, Daniela Bosco, Pierluigi Benedetti Panici, Domenico Alvaro and Vincenzo Cardinale
Cells 2019, 8(8), 914; https://doi.org/10.3390/cells8080914 - 16 Aug 2019
Cited by 27 | Viewed by 11148
Abstract
During foetal life, the liver plays the important roles of connection and transient hematopoietic function. Foetal liver cells develop in an environment called a hematopoietic stem cell niche composed of several cell types, where stem cells can proliferate and give rise to mature [...] Read more.
During foetal life, the liver plays the important roles of connection and transient hematopoietic function. Foetal liver cells develop in an environment called a hematopoietic stem cell niche composed of several cell types, where stem cells can proliferate and give rise to mature blood cells. Embryologically, at about the third week of gestation, the liver appears, and it grows rapidly from the fifth to 10th week under WNT/β-Catenin signaling pathway stimulation, which induces hepatic progenitor cells proliferation and differentiation into hepatocytes. Development of new strategies and identification of new cell sources should represent the main aim in liver regenerative medicine and cell therapy. Cells isolated from organs with endodermal origin, like the liver, bile ducts, and pancreas, could be preferable cell sources. Furthermore, stem cells isolated from these organs could be more susceptible to differentiate into mature liver cells after transplantation with respect to stem cells isolated from organs or tissues with a different embryological origin. The foetal liver possesses unique features given the co-existence of cells having endodermal and mesenchymal origin, and it could be highly available source candidate for regenerative medicine in both the liver and pancreas. Taking into account these advantages, the foetal liver can be the highest potential and available cell source for cell therapy regarding liver diseases and diabetes. Full article
(This article belongs to the Special Issue Hepatic Stem Cells in Liver and Biliary Regeneration)
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Other

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12 pages, 2621 KiB  
Technical Note
Comparison of the Opn-CreER and Ck19-CreER Drivers in Bile Ducts of Normal and Injured Mouse Livers
by Bram Lesaffer, Elisabeth Verboven, Leen Van Huffel, Iván M. Moya, Leo A. van Grunsven, Isabelle A. Leclercq, Frédéric P. Lemaigre and Georg Halder
Cells 2019, 8(4), 380; https://doi.org/10.3390/cells8040380 - 25 Apr 2019
Cited by 13 | Viewed by 6670
Abstract
Inducible cyclization recombinase (Cre) transgenic mouse strains are powerful tools for cell lineage tracing and tissue-specific knockout experiments. However, low efficiency or leaky expression can be important pitfalls. Here, we compared the efficiency and specificity of two commonly used cholangiocyte-specific Cre drivers, the [...] Read more.
Inducible cyclization recombinase (Cre) transgenic mouse strains are powerful tools for cell lineage tracing and tissue-specific knockout experiments. However, low efficiency or leaky expression can be important pitfalls. Here, we compared the efficiency and specificity of two commonly used cholangiocyte-specific Cre drivers, the Opn-iCreERT2 and Ck19-CreERT drivers, using a tdTomato reporter strain. We found that Opn-iCreERT2 triggered recombination of the tdTomato reporter in 99.9% of all cholangiocytes while Ck19-CreERT only had 32% recombination efficiency after tamoxifen injection. In the absence of tamoxifen, recombination was also induced in 2% of cholangiocytes for the Opn-iCreERT2 driver and in 13% for the Ck19-CreERT driver. For both drivers, Cre recombination was highly specific for cholangiocytes since recombination was rare in other liver cell types. Toxic liver injury ectopically activated Opn-iCreERT2 but not Ck19-CreERT expression in hepatocytes. However, ectopic recombination in hepatocytes could be avoided by applying a three-day long wash-out period between tamoxifen treatment and toxin injection. Therefore, the Opn-iCreERT2 driver is best suited for the generation of mutant bile ducts, while the Ck19-CreERT driver has near absolute specificity for bile duct cells and is therefore favorable for lineage tracing experiments. Full article
(This article belongs to the Special Issue Hepatic Stem Cells in Liver and Biliary Regeneration)
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