Publications by authors named "Tania Roskams"

260 Publications

A fully defined matrix to support a pluripotent stem cell derived multi-cell-liver steatohepatitis and fibrosis model.

Biomaterials 2021 09 9;276:121006. Epub 2021 Jul 9.

Stem Cell Institute, Department of Stem Cell and Developmental Biology, KU Leuven, Leuven, Belgium. Electronic address:

Chronic liver injury, as observed in non-alcoholic steatohepatitis (NASH), progressive fibrosis, and cirrhosis, remains poorly treatable. Steatohepatitis causes hepatocyte loss in part by a direct lipotoxic insult, which is amplified by derangements in the non-parenchymal cellular (NPC) interactive network wherein hepatocytes reside, including, hepatic stellate cells, liver sinusoidal endothelial cells and liver macrophages. To create an in vitro culture model encompassing all these cells, that allows studying liver steatosis, inflammation and fibrosis caused by NASH, we here developed a fully defined hydrogel microenvironment, termed hepatocyte maturation (HepMat) gel, that supports maturation and maintenance of pluripotent stem cell (PSC) derived hepatocyte- and NPC-like cells for at least one month. The HepMat-based co-culture system modeled key molecular and functional features of TGFβ-induced liver fibrosis and fatty-acid induced inflammation and fibrosis better than monocultures of its constituent cell populations. The novel co-culture system should open new avenues for studying mechanisms underlying liver steatosis, inflammation and fibrosis as well as for assessing drugs counteracting these effects.
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http://dx.doi.org/10.1016/j.biomaterials.2021.121006DOI Listing
September 2021

Regeneration Defects in Yap and Taz Mutant Mouse Livers Are Caused by Bile Duct Disruption and Cholestasis.

Gastroenterology 2021 02 28;160(3):847-862. Epub 2020 Oct 28.

Vlaams Instituut voor Biotechnologie-Katholieke Universiteit Leuven, Center for Cancer Biology, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium. Electronic address:

Background And Aims: The Hippo pathway and its downstream effectors YAP and TAZ (YAP/TAZ) are heralded as important regulators of organ growth and regeneration. However, different studies provided contradictory conclusions about their role during regeneration of different organs, ranging from promoting proliferation to inhibiting it. Here we resolve the function of YAP/TAZ during regeneration of the liver, where Hippo's role in growth control has been studied most intensely.

Methods: We evaluated liver regeneration after carbon tetrachloride toxic liver injury in mice with conditional deletion of Yap/Taz in hepatocytes and/or biliary epithelial cells, and measured the behavior of different cell types during regeneration by histology, RNA sequencing, and flow cytometry.

Results: We found that YAP/TAZ were activated in hepatocytes in response to carbon tetrachloride toxic injury. However, their targeted deletion in adult hepatocytes did not noticeably impair liver regeneration. In contrast, Yap/Taz deletion in adult bile ducts caused severe defects and delay in liver regeneration. Mechanistically, we showed that Yap/Taz mutant bile ducts degenerated, causing cholestasis, which stalled the recruitment of phagocytic macrophages and the removal of cellular corpses from injury sites. Elevated bile acids activated pregnane X receptor, which was sufficient to recapitulate the phenotype observed in mutant mice.

Conclusions: Our data show that YAP/TAZ are practically dispensable in hepatocytes for liver development and regeneration. Rather, YAP/TAZ play an indirect role in liver regeneration by preserving bile duct integrity and securing immune cell recruitment and function.
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http://dx.doi.org/10.1053/j.gastro.2020.10.035DOI Listing
February 2021

Donor Hepatectomy and Implantation Time Are Associated With Early Complications After Liver Transplantation: A Single-center Retrospective Study.

Transplantation 2021 05;105(5):1030-1038

Lab of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.

Background: Donor hepatectomy and liver implantation time reduce long-term graft and patient survival after liver transplantation. It is not known whether these surgical times influence early outcomes after liver transplantation.

Methods: This single-center study evaluated the effect of donor hepatectomy and implantation time on the risk of nonanastomotic biliary strictures (NAS) occurring within 1 year and of early allograft dysfunction (EAD) after deceased-donor solitary liver transplantation, adjusting for other donors, recipient, and surgical factors.

Results: Of 917 transplants performed between January 2000 and December 2016, 106 (11.56%) developed NAS and 247 (27%) developed EAD. Donor hepatectomy time (median 35 min, IQR: 26-46) was an independent risk factor of NAS [adjusted hazard ratio, 1.19; 95% CI, 1.04-1.35; P = 0.01]. Implantation time (median 80 min, IQR: 69-95) was independently associated with EAD [adjusted odds ratio (OR), 1.15; 95% CI,1.07-1.23; P < 0.0001). The risk of EAD was increased by anastomosis time of both portal vein (adjusted OR, 1.26; 95% CI, 1.12-14.42; P = 0.0001) and hepatic artery (adjusted OR, 1.13; 95% CI, 1.04-1.22; P = 0.005). The magnitude of these effects was similar in donation after circulatory death liver grafts.

Conclusions: Donor hepatectomy and implantation time negatively affect short-term outcomes.
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http://dx.doi.org/10.1097/TP.0000000000003335DOI Listing
May 2021

Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers.

Gastroenterology 2020 08 4;159(2):534-548.e11. Epub 2020 May 4.

Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zürich, Switzerland.

Background & Aims: Homozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease.

Methods: We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi∗MZ genotype, 309 adults with the Pi∗ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi∗Z variant. Levels of serum transaminases were retrieved from 444,642 participants, available in the United Kingdom biobank.

Results: In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi∗MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi∗MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi∗ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi∗MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0-11.8). Obesity and diabetes were the most important factors associated with LSMs ≥7.1 kPa in subjects with the Pi∗MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi∗MZ genotype, vs 97% of subjects with the Pi∗ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi∗MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals.

Conclusions: Adults with the Pi∗MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi∗ZZ genotype, but higher than adults without the Pi∗Z variant. These findings should help determine risk of subjects with the Pi∗MZ genotype and aid in counseling.
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http://dx.doi.org/10.1053/j.gastro.2020.04.058DOI Listing
August 2020

DNA methylation-driven EMT is a common mechanism of resistance to various therapeutic agents in cancer.

Clin Epigenetics 2020 02 14;12(1):27. Epub 2020 Feb 14.

Centre for Cancer Biology, VIB, 3000, Leuven, Belgium.

Background: Overcoming therapeutic resistance is one of the major hurdles in cancer care. One mechanism contributing to therapeutic resistance is a process in which epithelial cells switch to a mesenchymal state (epithelial-to-mesenchymal transition or EMT). The precise mechanisms driving EMT-mediated therapeutic resistance have, however, not been elucidated.

Results: Here, we study ten cell line pairs, for which parental cell lines were made resistant to either a targeted or chemotherapy-based treatment. First, we show by miRNA-200 overexpression that treatment resistance is driven by EMT. Next, we demonstrate that DNA methylation changes occur within each cell line pair and show that exposure to 5-azacytidine or knock down of DNA methyltransferases (DNMTs), both of which globally demethylate cells, result in EMT reversal and increased therapeutic sensitivity. This suggests DNA methylation to causally underlie EMT and treatment resistance. We also observe significant overlap in methylation profiles between resistant lines, suggesting a common epigenetic mechanism to cause resistance to therapy. In line with this hypothesis, cross-resistance to other targeted and chemotherapies is observed, while importantly, this is lost upon demethylation of the cells. Finally, we clinically validate that DNA methylation changes drive EMT-mediated resistance to sorafenib in patients with advanced hepatocellular carcinoma (HCC). Specifically, we develop a capture-based protocol to interrogate DNA methylation in low amounts of circulating tumor DNA (ctDNA). By interrogating the methylation status in liquid biopsies, longitudinally collected during sorafenib treatment, we assess whether DNA methylation changes also drive EMT and therapy resistance in a clinical setting. Particularly, by monitoring methylation changes in EMT genes, we are able to predict tumor response and acquired resistance to sorafenib.

Conclusions: We propose methylation changes underlying EMT to constitute a common resistance mechanism to cancer therapies. This process can be reversed pharmacologically and monitored non-invasively in ctDNA to predict resistance to treatment.
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http://dx.doi.org/10.1186/s13148-020-0821-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023776PMC
February 2020

Loss of histone macroH2A1 in hepatocellular carcinoma cells promotes paracrine-mediated chemoresistance and CD4CD25FoxP3 regulatory T cells activation.

Theranostics 2020 1;10(2):910-924. Epub 2020 Jan 1.

International Clinical Research Center, St' Anne's University Hospital, Brno, Czech Republic.

Loss of histone macroH2A1 induces appearance of cancer stem cells (CSCs)-like cells in hepatocellular carcinoma (HCC). How CSCs interact with the tumor microenvironment and the adaptive immune system is unclear. We screened aggressive human HCC for macroH2A1 and CD44 CSC marker expression. We also knocked down (KD) macroH2A1 in HCC cells, and performed integrated transcriptomic and secretomic analyses. Human HCC showed low macroH2A1 and high CD44 expression compared to control tissues. MacroH2A1 KD CSC-like cells transferred paracrinally their chemoresistant properties to parental HCC cells. MacroH2A1 KD conditioned media transcriptionally reprogrammed parental HCC cells activated regulatory CD4/CD25/FoxP3 T cells (Tregs). Loss of macroH2A1 in HCC cells drives cancer stem-cell propagation and evasion from immune surveillance.
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http://dx.doi.org/10.7150/thno.35045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929991PMC
April 2021

Effect of platelet-rich and platelet-poor plasma on peri-implant innervation in dog mandibles.

Int J Implant Dent 2019 Dec 4;5(1):40. Epub 2019 Dec 4.

OMFS IMPATH Research Group, Department of Imaging and Pathology, Faculty of Medicine, KU Leuven and Oral and Maxillofacial Surgery, University Hospitals Leuven, Campus Sint-Rafaël, Kapucijnenvoer 33, BE-3000, Leuven, Belgium.

Background: Autologous plasma fractions, such as platelet-rich plasma (PRP) and platelet-poor plasma (PPP), contain growth factors that can enhance neural cell survival and are therefore likely to have the ability to promote nerve regeneration. The present study compared the effect of PRP and PPP application on myelinated nerve density and diameter in the peri-implant bone region. In addition, the effect of healing time on nerve regeneration was assessed.

Materials And Methods: Nine beagle dogs randomly received 54 dental implants in the bilateral mandible according to a split-mouth design. Each implant was randomly assigned to one of three implant protocols: delayed implant placement with delayed loading (DIP + DL) with local application of PRP, DIP + DL with local application of PPP and DIP + DL without any plasma additive. The animals were euthanized at 1, 3, and 6 months after loading (3 dogs per time point). Block biopsies were prepared for histomorphometry in the peri-implant bone within 500 μm around the implants.

Results: Myelinated nerve fibers were identified in the trabecular bone and in the osteons near the implants surface. The nerve fibers in the PRP group (median ± IQR; 2.88 ± 1.55 μm) had a significantly (p < 0.05) greater diameter compared to the PPP (2.40 ± 0.91 μm) and control (2.11 ± 1.16 μm) group. The nerve diameter after 6 months healing (3.18 ± 1.58 μm) was significantly (p < 0.05) greater compared to 1 (2.08 ± 0.89 μm) and 3 (2.49 ± 1.22 μm) months. No significant difference was found for myelinated nerve density between groups and healing time.

Conclusions: The present study showed that the healing time significantly influenced the diameter of the myelinated nerve fibers in peri-implant bone. PRP exerted a significant effect on the diameter of the myelinated nerve fibers as compared to PPP. Large-scale animal studies and longer follow-up periods are needed to confirm these findings and to verify whether platelet plasma can facilitate nerve regeneration process.
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http://dx.doi.org/10.1186/s40729-019-0193-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890900PMC
December 2019

Granulomatosis with polyangiitis with breast involvement mimicking metastatic cancer: Case report and literature review.

Eur J Rheumatol 2020 01 25;7(1):41-43. Epub 2019 Nov 25.

Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.

Granulomatosis with polyangiitis (GPA) is a systemic inflammatory disease, characterized by the presence of necrotizing vasculitis of small and medium-sized vessels, granulomatous inflammation and anti-neutrophil cytoplasmic antibodies (ANCAs). The diagnosis can be challenging due to the variable clinical presentation and possible involvement of virtually all organ systems. A correct diagnosis is indispensable for a timely start of medical treatment and to avoid unnecessary surgery. Therefore, cooperation with and the input of the pathologist is crucial. We report a case of a woman presenting with suspected metastatic cancer. The diagnosis of GPA was made mainly based on breast biopsy, and the patient was treated accordingly, with full recovery. This report provides a case description and a brief review of the literature.
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http://dx.doi.org/10.5152/eurjrheum.2019.19065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002001PMC
January 2020

Peritumoral activation of the Hippo pathway effectors YAP and TAZ suppresses liver cancer in mice.

Science 2019 11;366(6468):1029-1034

VIB Center for Cancer Biology and KU Leuven Department of Oncology, University of Leuven, Leuven, Belgium.

The Hippo signaling pathway and its two downstream effectors, the YAP and TAZ transcriptional coactivators, are drivers of tumor growth in experimental models. Studying mouse models, we show that YAP and TAZ can also exert a tumor-suppressive function. We found that normal hepatocytes surrounding liver tumors displayed activation of YAP and TAZ and that deletion of and in these peritumoral hepatocytes accelerated tumor growth. Conversely, experimental hyperactivation of YAP in peritumoral hepatocytes triggered regression of primary liver tumors and melanoma-derived liver metastases. Furthermore, whereas tumor cells growing in wild-type livers required YAP and TAZ for their survival, those surrounded by - and -deficient hepatocytes were not dependent on YAP and TAZ. Tumor cell survival thus depends on the relative activity of YAP and TAZ in tumor cells and their surrounding tissue, suggesting that YAP and TAZ act through a mechanism of cell competition to eliminate tumor cells.
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http://dx.doi.org/10.1126/science.aaw9886DOI Listing
November 2019

Meta-Analysis of Human and Mouse Biliary Epithelial Cell Gene Profiles.

Cells 2019 09 20;8(10). Epub 2019 Sep 20.

Liver Cell Biology research group, Department of Basic Biomedical Sciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.

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.
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http://dx.doi.org/10.3390/cells8101117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829476PMC
September 2019

Agreement on endoscopic ultrasonography-guided tissue specimens: Comparing a 20-G fine-needle biopsy to a 25-G fine-needle aspiration needle among academic and non-academic pathologists.

Dig Endosc 2019 Nov 10;31(6):690-697. Epub 2019 Jul 10.

Stony Brook University Hospital, New York, USA.

Background And Aim: A recently carried out randomized controlled trial showed the benefit of a novel 20-G fine-needle biopsy (FNB) over a 25-G fine-needle aspiration (FNA) needle. The current study evaluated the reproducibility of these findings among expert academic and non-academic pathologists.

Methods: This study was a side-study of the ASPRO (ASpiration versus PROcore) study. Five centers retrieved 74 (59%) consecutive FNB and 51 (41%) FNA samples from the ASPRO study according to randomization; 64 (51%) pancreatic and 61 (49%) lymph node specimens. Samples were re-reviewed by five expert academic and five non-academic pathologists and rated in terms of sample quality and diagnosis. Ratings were compared between needles, expert academic and non-academic pathologists, target lesions, and cytology versus histological specimens.

Results: Besides a higher diagnostic accuracy, FNB also provided for a better agreement on diagnosing malignancy (ĸ = 0.59 vs ĸ = 0.76, P < 0.001) and classification according to Bethesda (ĸ = 0.45 vs ĸ = 0.61, P < 0.001). This equally applied for expert academic and non-academic pathologists and for pancreatic and lymph node specimens. Sample quality was also rated higher for FNB, but agreement ranged from poor (ĸ = 0.04) to fair (ĸ = 0.55). Histology provided better agreement than cytology, but only when a core specimen was obtained with FNB (P = 0.004 vs P = 0.432).

Conclusion: This study shows that the 20-G FNB outperforms the 25-G FNA needle in terms of diagnostic agreement, independent of the background and experience of the pathologist. This endorses use of the 20-G FNB needle in both expert and lower volume EUS centers.
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http://dx.doi.org/10.1111/den.13424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900144PMC
November 2019

Human Liver Regeneration: An Etiology Dependent Process.

Int J Mol Sci 2019 May 10;20(9). Epub 2019 May 10.

Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, 3000 Leuven, Belgium.

Regeneration of the liver has been an interesting and well-investigated topic for many decades. This etiology and time-dependent mechanism has proven to be extremely challenging to investigate, certainly in human diseases. A reason for this challenge is found in the numerous interactions of different cell components, of which some are even only temporarily present (e.g., inflammatory cells). To orchestrate regeneration of the epithelial cells, their interaction with the non-epithelial components is of utmost importance. Hepatocytes, cholangiocytes, liver progenitor cells, and peribiliary glands have proven to be compartments of regeneration. The ductular reaction is a common denominator in virtually all liver diseases; however, it is predominantly found in late-stage hepatic and biliary diseases. Ductular reaction is an intriguing example of interplay between epithelial and non-epithelial cells and encompasses bipotential liver progenitor cells which are able to compensate for the loss of the exhausted hepatocytes and cholangiocytes in biliary and hepatocytic liver diseases. In this manuscript, we focus on the etiology-specific damage that is observed in different human diseases and how the liver regulates the regenerative response in an acute and chronic setting. Furthermore, we describe the importance of morphological keynotes in different etiologies and how spatial information is of relevance for every basic and translational research of liver regeneration.
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http://dx.doi.org/10.3390/ijms20092332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539121PMC
May 2019

Age Matching of Elderly Liver Grafts With Elderly Recipients Does Not Have a Synergistic Effect on Long-term Outcomes When Both Are Carefully Selected.

Transplant Direct 2019 Apr 26;5(4):e342. Epub 2019 Mar 26.

Department of Microbiology and Immunology, Laboratory of Abdominal Transplant Surgery, KU Leuven, Leuven, Belgium.

Background: Older donors and recipients are increasingly considered for liver transplantation. Both donor and recipient age have a negative impact on outcomes. Large registry analyses show that older donors are frequently matched to older recipients. Whether age-related risks accumulate in a synergic negative effect on outcomes because of donor-recipient age matching is poorly understood.

Methods: We investigated the impact of donor-recipient age interaction on patient and death-censored graft survival in multivariate Cox regressions in 849 transplants (January 2000 to December 2015).

Results: Donors 70 years or older did not affect long-term patient or graft survival. Recipient age independently increased the risk of death (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.02-1.05, < 0.0001), but donor-recipient age interaction was noninfluential. The negative impact of recipient age on patient survival was significant as early as 6 months after transplantation (HR, 1.06; 95% CI, 1.03-1.09; = 0.00008). The adjusted risk of death was significant for patients aged 60 to 69 years (HR, 1.995; 95% CI, 1.40-2.85; < 0.0001) and 70 years or older (HR, 2.001; 95% CI, 1.10-2.66; = 0.04). In contrast, the risk of graft loss was not influenced by recipient age (HR, 1.02; 95% CI, 0.996-1.04; = 0.11) or age interaction.

Conclusions: Older livers can be safely used in older recipients without jeopardizing graft and patient survival if other risk factors are minimized.
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http://dx.doi.org/10.1097/TXD.0000000000000883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445659PMC
April 2019

Targeting mTOR and Src restricts hepatocellular carcinoma growth in a novel murine liver cancer model.

PLoS One 2019 22;14(2):e0212860. Epub 2019 Feb 22.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, Australia.

Liver cancer is a poor prognosis cancer with limited treatment options. To develop a new therapeutic approach, we derived HCC cells from a known model of murine hepatocellular carcinoma (HCC). We treated adiponectin (APN) knock-out mice with the carcinogen diethylnitrosamine, and the resulting tumors were 7-fold larger than wild-type controls. Tumors were disassociated from both genotypes and their growth characteristics evaluated. A52 cells from APN KO mice had the most robust growth in vitro and in vivo, and presented with pathology similar to the parental tumor. All primary tumors and cell lines exhibited activity of the mammalian target of Rapamycin (mTOR) and Src pathways. Subsequent combinatorial treatment, with the mTOR inhibitor Rapamycin and the Src inhibitor Dasatinib reduced A52 HCC growth 29-fold in vivo. Through protein and histological analyzes we observed activation of these pathways in human HCC, suggesting that targeting both mTOR and Src may be a novel approach for the treatment of HCC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212860PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386388PMC
November 2019

YAP and TAZ Heterogeneity in Primary Liver Cancer: An Analysis of Its Prognostic and Diagnostic Role.

Int J Mol Sci 2019 Feb 1;20(3). Epub 2019 Feb 1.

Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, 3000 Leuven, Belgium.

Primary liver cancer comprises a diverse group of liver tumors. The heterogeneity of these tumors is seen as one of the obstacles to finding an effective therapy. The Hippo pathway, with its downstream transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), has a decisive role in the carcinogenesis of primary liver cancer. Therefore, we examined the expression pattern of YAP and TAZ in 141 patients with hepatocellular carcinoma keratin 19 positive (HCC K19⁺), hepatocellular carcinoma keratin 19 negative (HCC K19), combined hepatocellular⁻cholangiocarcinoma carcinoma (cHCC-CCA), or cholangiocarcinoma (CCA). All cHCC-CCA and CCA patients showed high expression levels for YAP and TAZ, while only some patients of the HCC group were positive. Notably, we found that a histoscore of both markers is useful in the challenging diagnosis of cHCC-CCA. In addition, positivity for YAP and TAZ was observed in the hepatocellular and cholangiocellular components of cHCC-CCA, which suggests a single cell origin in cHCC-CCA. Within the K19 HCC group, our results demonstrate that the expression of YAP is a statistically significant predictor of poor prognosis when observed in the cytoplasm. Nuclear expression of TAZ is an even more specific and independent predictor of poor disease-free survival and overall survival of K19 HCC patients. Our results thus identify different levels of YAP/TAZ expression in various liver cancers that can be used for diagnostics.
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http://dx.doi.org/10.3390/ijms20030638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386931PMC
February 2019

High-throughput sequencing identifies aetiology-dependent differences in ductular reaction in human chronic liver disease.

J Pathol 2019 05 30;248(1):66-76. Epub 2019 Jan 30.

Department of Imaging and Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium.

Ductular reaction (DR) represents the activation of hepatic progenitor cells (HPCs) and has been associated with features of advanced chronic liver disease; yet it is not clear whether these cells contribute to disease progression and how the composition of their micro-environment differs depending on the aetiology. This study aimed to identify HPC-associated signalling pathways relevant in different chronic liver diseases using a high-throughput sequencing approach. DR/HPCs were isolated using laser microdissection from patient samples diagnosed with HCV or primary sclerosing cholangitis (PSC), as models for hepatocellular or biliary regeneration. Key signals were validated at the protein level for a cohort of 56 patients (20 early and 36 advanced stage). In total, 330 genes were significantly differentially expressed between the HPCs in HCV and PSC. Recruitment and homing of inflammatory cells were distinctly different depending on the aetiology. HPCs in PSC were characterised by a response to oxidative stress (e.g. JUN, VNN1) and neutrophil-attractant chemokines (CXCL5, CXCL6, IL-8), whereas HPCs in HCV were identified by T- and B-lymphocyte infiltration. Moreover, we found that communication between HPCs and macrophages was aetiology driven. In PSC, a high frequency of CCL28-positive macrophages was observed in the portal infiltrate, already in early disease in the absence of advanced fibrosis, while in HCV, HPCs showed a strong expression of the macrophage scavenger receptor MARCO. Interestingly, DR/HPCs in PSC showed more deposition of ECM (e.g. FN1, LAMC2, collagens) compared to HCV, where an increase of pro-invasive genes (e.g. PDGFRA, IGF2) was observed. Additionally, endothelial cells in the vicinity of DR/HPCs showed differential immunopositivity (e.g. IGF2 and INHBA expression). In conclusion, our data shine light on the role of DR/HPCs in immune signalling, fibrogenesis and angiogenesis in chronic liver disease. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5228DOI Listing
May 2019

Inhibition of glutamine synthetase in monocytes from patients with acute-on-chronic liver failure resuscitates their antibacterial and inflammatory capacity.

Gut 2019 10 22;68(10):1872-1883. Epub 2018 Dec 22.

Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium.

Objective: Acute-on-chronic liver failure (ACLF) is associated with dysfunctional circulating monocytes whereby patients become highly susceptible to bacterial infections. Here, we identify the pathways underlying monocyte dysfunction in ACLF and we investigate whether metabolic rewiring reinstates their phagocytic and inflammatory capacity.

Design: Following phenotypic characterisation, we performed RNA sequencing on CD14CD16 monocytes from patients with ACLF and decompensated alcoholic cirrhosis. Additionally, an model mimicking ACLF patient-derived features was implemented to investigate the efficacy of metabolic regulators on monocyte function.

Results: Monocytes from patients with ACLF featured elevated frequencies of interleukin (IL)-10-producing cells, reduced human leucocyte antigen DR isotype (HLA-DR) expression and impaired phagocytic and oxidative burst capacity. Transcriptional profiling of isolated CD14CD16 monocytes in ACLF revealed upregulation of an array of immunosuppressive parameters and compromised antibacterial and antigen presentation machinery. In contrast, monocytes in decompensated cirrhosis showed intact capacity to respond to inflammatory triggers. Culturing healthy monocytes in ACLF plasma mimicked the immunosuppressive characteristics observed in patients, inducing a blunted phagocytic response and metabolic program associated with a tolerant state. Metabolic rewiring of the cells using a pharmacological inhibitor of glutamine synthetase, partially restored the phagocytic and inflammatory capacity of generated- as well as ACLF patient-derived monocytes. Highlighting its biological relevance, the glutamine synthetase/glutaminase ratio of ACLF patient-derived monocytes positively correlated with disease severity scores.

Conclusion: In ACLF, monocytes feature a distinct transcriptional profile, polarised towards an immunotolerant state and altered metabolism. We demonstrated that metabolic rewiring of ACLF monocytes partially revives their function, opening up new options for therapeutic targeting in these patients.
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http://dx.doi.org/10.1136/gutjnl-2018-316888DOI Listing
October 2019

A multicenter randomized trial comparing a 25-gauge EUS fine-needle aspiration device with a 20-gauge EUS fine-needle biopsy device.

Gastrointest Endosc 2019 02 24;89(2):329-339. Epub 2018 Oct 24.

Department of Endoscopy, Stony Brook University Hospital, Stony Brook, New York, USA.

Background And Aims: Several studies have compared EUS-guided FNA with fine-needle biopsy (FNB), but none have proven superiority. We performed a multicenter randomized controlled trial to compare the performance of a commonly used 25-gauge FNA needle with a newly designed 20-gauge FNB needle.

Methods: Consecutive patients with a solid lesion were randomized in this international multicenter study between a 25-gauge FNA (EchoTip Ultra) or a 20-gauge FNB needle (ProCore). The primary endpoint was diagnostic accuracy for malignancy and the Bethesda classification (non-diagnostic, benign, atypical, malignant). Technical success, safety, and sample quality were also assessed. Multivariable and supplementary analyses were performed to adjust for confounders.

Results: A total of 608 patients were allocated to FNA (n = 306) or FNB (n = 302); 312 pancreatic lesions (51%), 147 lymph nodes (24%), and 149 other lesions (25%). Technical success rate was 100% for the 25-gauge FNA and 99% for the 20-gauge FNB needle (P = .043), with no differences in adverse events. The 20-gauge FNB needle outperformed 25-gauge FNA in terms of histologic yield (77% vs 44%, P < .001), accuracy for malignancy (87% vs 78%, P = .002) and Bethesda classification (82% vs 72%, P = .002). This was robust when corrected for indication, lesion size, number of passes, and presence of an on-site pathologist (odds ratio, 3.53; 95% confidence interval, 1.55-8.56; P = .004), and did not differ among centers (P = .836).

Conclusion: The 20-gauge FNB needle outperformed the 25-gauge FNA needle in terms of histologic yield and diagnostic accuracy. This benefit was irrespective of the indication and was consistent among participating centers, supporting the general applicability of our findings. (Clinical trial registration number: NCT02167074.).
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http://dx.doi.org/10.1016/j.gie.2018.10.026DOI Listing
February 2019

CCL20, a direct-acting pro-angiogenic chemokine induced by hepatitis C virus (HCV): Potential role in HCV-related liver cancer.

Exp Cell Res 2018 11 2;372(2):168-177. Epub 2018 Oct 2.

Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, University of Leuven (KU Leuven), Belgium.

The CCL20/CCR6 chemokine/receptor axis has previously been shown to contribute to the initiation and progression of hepatocellular carcinoma (HCC) through the recruitment of CCR6-positive leukocytes to the tumor microenvironment. In particular, high serum levels of CCL20 are reported in patients with HCC induced by the hepatitis C virus (HCV). A potential non-immune role for the CCL20/CCR6 axis in HCC development has not yet been investigated. Microarray analysis (Benkheil et al., paper submitted for publication), revealed that CCL20 is highly upregulated in hepatoma cells infected with HCV compared with non-infected hepatoma cells. To determine the role of the CCL20/CCR6 axis in HCV-related HCC, we first explored which cell populations express CCR6 in human liver tissue with chronic disease or HCC. Immunohistochemical (IHC) analysis revealed that CCR6 is present on endothelial cells (ECs) of portal blood vessels in livers with chronic HCV infection and in HCV- and alcoholic-HCC tissue. In addition, we found CCR6 to be expressed on primary macrovascular (HUVECs) and microvascular ECs (HMVEC-ds) where it co-expressed with the endothelial marker CD31. In vitro angiogenesis experiments revealed that CCL20 is a direct pro-angiogenic molecule that induces EC invasion, sprouting and migration through CCR6. Moreover, using the angiogenesis matrigel plug assay in immunodeficient NMRI-nu mice, we clearly showed that CCL20 induces blood vessel formation, by attracting CCR6-positive ECs. Finally, we demonstrated that HCV-induced CCL20 protein expression and secretion in hepatoma cells could be abolished by antiviral treatment, indicating that CCL20 expression is dependent on HCV replication. In contrast to HCV, HBV-infection resulted in a decreased expression of CCL20, implying a virus-specific effect. Taken together, we identified HCV-induced CCL20 as a direct pro-angiogenic factor that acts on endothelial CCR6. These results suggest that the CCL20/CCR6 axis contributes to hepatic angiogenesis, promoting the hypervascular state of HCV-HCC.
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http://dx.doi.org/10.1016/j.yexcr.2018.09.023DOI Listing
November 2018

TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence.

Sci Transl Med 2018 08;10(454)

School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.

Liver injury results in rapid regeneration through hepatocyte proliferation and hypertrophy. However, after acute severe injury, such as acetaminophen poisoning, effective regeneration may fail. We investigated how senescence may underlie this regenerative failure. In human acute liver disease, and murine models, p21-dependent hepatocellular senescence was proportionate to disease severity and was associated with impaired regeneration. In an acetaminophen injury mouse model, a transcriptional signature associated with the induction of paracrine senescence was observed within 24 hours and was followed by one of impaired proliferation. In mouse genetic models of hepatocyte injury and senescence, we observed transmission of senescence to local uninjured hepatocytes. Spread of senescence depended on macrophage-derived transforming growth factor-β1 (TGFβ1) ligand. In acetaminophen poisoning, inhibition of TGFβ receptor 1 (TGFβR1) improved mouse survival. TGFβR1 inhibition reduced senescence and enhanced liver regeneration even when delivered beyond the therapeutic window for treating acetaminophen poisoning. This mechanism, in which injury-induced senescence impairs liver regeneration, is an attractive therapeutic target for developing treatments for acute liver failure.
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http://dx.doi.org/10.1126/scitranslmed.aan1230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420144PMC
August 2018

HCV-induced EGFR-ERK signaling promotes a pro-inflammatory and pro-angiogenic signature contributing to liver cancer pathogenesis.

Biochem Pharmacol 2018 09 21;155:305-315. Epub 2018 Jul 21.

Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medical Research, University of Leuven (KU Leuven), Belgium.

HCV is a major risk factor for hepatocellular carcinoma (HCC). HCC development in chronically infected HCV patients has until now been attributed to persistent inflammation and interference of viral proteins with host cell signaling. Since activation of the epidermal growth factor receptor (EGFR) presents a crucial step in HCV entry, we aimed at investigating whether EGFR signaling may contribute to the pathogenesis of HCV-related HCC. By applying microarray analysis, we generated a gene expression signature for secreted proteins in HCV-infected hepatoma cells. This gene signature was enriched for inflammatory and angiogenic processes; both crucially involved in HCC development. RT-qPCR analysis, conducted on the entire list of upregulated genes, confirmed induction of 11 genes (AREG, IL8, CCL20, CSF1, GDF15, IGFBP1, VNN3, THBS1 and PAI-1) in a virus titer- and replication-dependent manner. EGFR activation in hepatoma cells largely mimicked the gene signature seen in the infectious HCV model. Further, the EGFR-ERK pathway, but not Akt signaling, was responsible for this gene expression profile. Finally, microarray analysis conducted on clinical data from the GEO database, revealed that our validated gene expression profile is significantly represented in livers of patients with HCV-related liver pathogenesis (cirrhosis and HCC) compared to healthy livers. Taken together, our data indicate that persistent activation of EGFR-ERK signaling in chronically infected HCV patients may induce a specific pro-inflammatory and pro-angiogenic signature that presents a new mechanism by which HCV can promote liver cancer pathogenesis. A better understanding of the key factors in HCV-related oncogenesis, may efficiently direct HCC drug development.
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http://dx.doi.org/10.1016/j.bcp.2018.07.011DOI Listing
September 2018

Liver transplantation for very severe hepatopulmonary syndrome due to vitamin A-induced chronic liver disease in a patient with Shwachman-Diamond syndrome.

Orphanet J Rare Dis 2018 05 2;13(1):69. Epub 2018 May 2.

Laboratory of Inborn Errors of Immunity, Department of Microbiology and Immunology, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.

Vitamin A intoxication is a rare cause of liver disease, but the risk increases in patients with underlying liver dysfunction. We present a patient with Shwachman-Diamond Syndrome who developed liver fibrosis, portal hypertension and very severe hepatopulmonary syndrome as a consequence of chronic vitamin A intoxication. She underwent successful liver transplantation with complete resolution of the pulmonary shunting.
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http://dx.doi.org/10.1186/s13023-018-0818-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930429PMC
May 2018

Multiple Solid Organ Transplantation in Telomeropathy: Case Series and Literature Review.

Transplantation 2018 10;102(10):1747-1755

Department of Respiratory Diseases, University Hospitals Leuven.

Background: Solid organ transplantation is a valid treatment option for selected patients with organ failure due to an underlying telomeropathy; however, the feasibility of multiple-organ transplantation if several organs are compromised is unclear.

Methods: We describe 2 patients with telomeropathy due to heterozygous telomerase RNA component or telomerase reverse transcriptase mutation, who successfully underwent serial or combined liver and lung transplantation for concurrent liver fibrosis/cirrhosis and pulmonary fibrosis.

Results: Despite a challenging posttransplant course, long-term outcomes were favorable, with both patients doing fine now, respectively, 12/20 and 24 months after multiple-organ transplantation.

Conclusions: To our knowledge, this is the first report of multiple solid organ transplantation in documented telomeropathy. These cases highlight current difficulties of timely diagnosis, therapeutic approach, and postoperative complications in telomeropathy patients in whom several organs are affected.
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http://dx.doi.org/10.1097/TP.0000000000002198DOI Listing
October 2018

cHCC-CCA: Consensus terminology for primary liver carcinomas with both hepatocytic and cholangiocytic differentation.

Hepatology 2018 07 9;68(1):113-126. Epub 2018 May 9.

Kurume University School of Medicine, Pathology, Japan.

Primary liver carcinomas with both hepatocytic and cholangiocytic differentiation have been referred to as "combined (or mixed) hepatocellular-cholangiocarcinoma." These tumors, although described over 100 years ago, have attracted greater attention recently because of interest in possible stem cell origin and perhaps because of greater frequency and clinical recognition. Currently, because of a lack of common terminology in the literature, effective treatment and predictable outcome data have been challenging to accrue. This article represents a consensus document from an international community of pathologists, radiologists, and clinicians who have studied and reported on these tumors and recommends a working terminology for diagnostic and research approaches for further study and evaluation.

Conclusion: It is recommended that diagnosis is based on routine histopathology with hematoxylin and eosin (H&E); immunostains are supportive, but not essential for diagnosis. (Hepatology 2018;68:113-126).
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http://dx.doi.org/10.1002/hep.29789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340292PMC
July 2018

RNA-sequencing-based comparative analysis of human hepatic progenitor cells and their niche from alcoholic steatohepatitis livers.

Cell Death Dis 2017 11 2;8(11):e3164. Epub 2017 Nov 2.

Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals, Leuven, Belgium.

Hepatic progenitor cells (HPCs) are small cells with a relative large oval nucleus and a scanty cytoplasm situated in the canals of Hering that express markers of (immature) hepatocytes and cholangiocytes. HPCs are present in large numbers in alcoholic steatohepatitis (ASH), one of the leading causes of chronic liver disease. To date, the mechanisms responsible for proliferation and differentiation of human HPCs are still poorly understood and the role of HPCs in ASH development is unknown. In this study, we aimed to characterise human HPCs and their interactions with other cells through comparison, on both protein and RNA level, of HPC-enriched cell populations from adult human liver tissue using different isolation methods. Fresh human liver tissue was collected from ASH explant livers and HPC-enriched cell populations were obtained via four different isolation methods: side population (SP), epithelial cell adhesion molecule (EpCAM) and trophoblast antigen 2 (TROP-2) membrane marker isolation and laser capture microdissection. Gene expression profiles of fluorescent-activated cell-sorted HPCs, whole liver extracts and laser microdissected HPC niches were determined by RNA-sequencing. Immunohistochemical evaluation of the isolated populations indicated the enrichment of HPCs in the SP, EpCAM and TROP-2 cell populations. Pathway analysis of the transcription profiles of human HPCs showed an enrichment and activation of known HPC pathways like Wnt/β-catenin, TWEAK and HGF. Integration of the HPC niche profile suggests autocrine signalling by HPCs (TNFα, PDGFB and VEGFA) as well as paracrine signalling from the surrounding niche cells including MIF and IGF-1. In addition, we identified IL-17 A signalling as a potentially novel pathway in HPC biology. In conclusion, we provide the first RNA-seq-based, comparative transcriptome analysis of isolated human HPCs from ASH patients and revealed active signalling between HPCs and their surrounding niche cells in ASH livers and suggest that HPCs can actively contribute to liver inflammation.
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http://dx.doi.org/10.1038/cddis.2017.543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775409PMC
November 2017

Comparative study of the organisation and phenotypes of bladder interstitial cells in human, mouse and rat.

Cell Tissue Res 2017 12 30;370(3):403-416. Epub 2017 Sep 30.

Laboratory for Experimental Urology, Department of Development and Regeneration, Organ Systems, KU Leuven, Leuven, Belgium.

With most research on interstitial cells (IC) in the bladder being conducted on animal models, it remains unclear whether all structural and functional data on IC from animal models can be translated to the human context. This prompted us to compare the structural and immunohistochemical properties of IC in bladders from mouse, rat and human. Tissue samples were obtained from the bladder dome and subsequently processed for immunohistochemistry and electron microscopy. The ultrastructural properties of IC were compared by means of electron microscopy and IC were additionally characterized with single/double immunohistochemistry/immunofluorescence. Our results reveal a similar organization of the IC network in the upper lamina propria (ULP), the deep lamina propria (DLP) and the detrusor muscle in human, rat and mouse bladders. Furthermore, despite several similarities in IC phenotypes, we also found several obvious inter-species differences in IC, especially in the ULP. Most remarkably in this respect, ULP IC in human bladder predominantly displayed a myoid phenotype with abundant presence of contractile micro-filaments, while those in rat and mouse bladders showed a fibroblast phenotype. In conclusion, the organization of ULP IC, DLP IC and detrusor IC is comparable in human, rat and mouse bladders, although several obvious inter-species differences in IC phenotypes were found. The present data show that translating research data on IC in laboratory animals to the human setting should be carried out with caution.
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http://dx.doi.org/10.1007/s00441-017-2694-9DOI Listing
December 2017

Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma.

Hepatology 2018 02 2;67(2):636-650. Epub 2018 Jan 2.

Center for Translational Medicine, International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.

Hepatocellular carcinomas (HCC) contain a subpopulation of cancer stem cells (CSCs), which exhibit stem cell-like features and are responsible for tumor relapse, metastasis, and chemoresistance. The development of effective treatments for HCC will depend on a molecular-level understanding of the specific pathways driving CSC emergence and stemness. MacroH2A1 is a variant of the histone H2A and an epigenetic regulator of stem-cell function, where it promotes differentiation and, conversely, acts as a barrier to somatic-cell reprogramming. Here, we focused on the role played by the histone variant macroH2A1 as a potential epigenetic factor promoting CSC differentiation. In human HCC sections we uncovered a significant correlation between low frequencies of macroH2A1 staining and advanced, aggressive HCC subtypes with poorly differentiated tumor phenotypes. Using HCC cell lines, we found that short hairpin RNA-mediated macroH2A1 knockdown induces acquisition of CSC-like features, including the growth of significantly larger and less differentiated tumors when injected into nude mice. MacroH2A1-depleted HCC cells also exhibited reduced proliferation, resistance to chemotherapeutic agents, and stem-like metabolic changes consistent with enhanced hypoxic responses and increased glycolysis. The loss of macroH2A1 increased expression of a panel of stemness-associated genes and drove hyperactivation of the nuclear factor kappa B p65 pathway. Blocking phosphorylation of nuclear factor kappa B p65 on Ser536 inhibited the emergence of CSC-like features in HCC cells knocked down for macroH2A1. Conclusion: The absence of histone variant macroH2A1 confers a CSC-like phenotype to HCC cells in vitro and in vivo that depends on Ser536 phosphorylation of nuclear factor kappa B p65; this pathway may hold valuable targets for the development of CSC-focused treatments for HCC. (Hepatology 2018;67:636-650).
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http://dx.doi.org/10.1002/hep.29519DOI Listing
February 2018

Hepatic Progenitor Cells: An Update.

Gastroenterol Clin North Am 2017 06;46(2):409-420

Liver Research Unit, Department of Imaging and Pathology, KU Leuven and University Hospitals Leuven, Minderbroederstraat 12, 3000 Leuven, Belgium. Electronic address:

Liver regeneration is a fascinating and complex process with many medical implications. An important component of this regenerative process is the hepatic progenitor cell (HPC). These appealing cells are able to participate in the renewal of hepatocytes and cholangiocytes when the normal homeostatic regeneration is exhausted. Moreover, the HPC niche is of vital importance toward the activation, differentiation, and proliferation of the HPC. This niche provides a rich microenvironment for the regulation of the HPC, thanks to the intercellular secretion of molecules. New findings indicate that the regenerative possibilities in the liver could provide a diverse basis for therapeutic targets.
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http://dx.doi.org/10.1016/j.gtc.2017.01.011DOI Listing
June 2017

Liver disease in cystic fibrosis presents as non-cirrhotic portal hypertension.

J Cyst Fibros 2017 09 25;16(5):e11-e13. Epub 2017 Mar 25.

Liver Research facility, Katholieke universiteit Leuven, Leuven, Belgium; Dept of Gastroenterology-Hepatology, University Hospitals Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1016/j.jcf.2017.03.006DOI Listing
September 2017
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