• Liver Regeneration/physiology
• Humans
• Animals
• Signal Transduction
• Liver/metabolism
• Liver/physiology
• Hepatectomy

• Biological sciences
• Health sciences

• Adult stem cells
• Hepatology
• Stem cells

An alternative source of mesenchymal stem cells has recently been discovered: dental pulp stem cells (DPSCs), including deciduous teeth, which can thus comprise potential tools for regenerative medicine. DPSCs derive from the neural crest and are normally implicated in dentin homeostasis. The clinical application of mesenchymal stem cells (MSCs) involving DPSCs contains various limitations, such as high cost, low safety, and cell handling issues, as well as invasive sample collection procedures. Although MSCs implantation offers favorable outcomes on specific diseases, implanted MSCs cannot survive for a long period. It is thus considered that their mediated mechanism of action involves paracrine effects. It has been recently reported that secreted molecules in DPSCs-conditioned media (DPSC-CM) contain various trophic factors and cytokines and that DPSC-CM are effective in models of various diseases. In the current study, we focus on the characteristics of DPSC-CM and their therapeutic potential against various disorders.

Liver stem cells and activated macrophages have been implicated as contributors to liver cancer; hence, reducing their abundance is a potential avenue for therapy. In this article, we demonstrate that Maraviroc, a drug approved for human use, reduces the liver stem cell response and macrophage activation in a mouse model of liver cancer. These findings underline the preventive potential of this drug in liver cancer, a deadly disease for which there are few effective treatments.

Maraviroc (MVC), a CCR5 antagonist, reduces liver fibrosis, injury and tumour burden in mice fed a hepatocarcinogenic diet, suggesting it has potential as a cancer therapeutic. We investigated the effect of MVC on liver progenitor cells (LPCs) and macrophages as both have a role in hepatocarcinogenesis. Mice were fed the hepatocarcinogenic choline-deficient, ethionine-supplemented diet (CDE) ± MVC, and immunohistochemistry, RNA and protein expression were used to determine LPC and macrophage abundance, migration and related molecular mechanisms. MVC reduced LPC numbers in CDE mice by 54%, with a smaller reduction seen in macrophages. Transcript and protein abundance of LPC-associated markers correlated with this reduction. The CDE diet activated phosphorylation of AKT and STAT3 and was inhibited by MVC. LPCs did not express Ccr5 in our model; in contrast, macrophages expressed high levels of this receptor, suggesting the effect of MVC is mediated by targeting macrophages. MVC reduced CD45+ cells and macrophage migration in liver and blocked the CDE-induced transition of liver macrophages from an M1- to M2-tumour-associated macrophage (TAM) phenotype. These findings suggest MVC has potential as a re-purposed therapeutic agent for treating chronic liver diseases where M2-TAM and LPC numbers are increased, and the incidence of HCC is enhanced.

• CCL5 chemokine
• Maraviroc
• hepatocellular carcinoma
• liver progenitor cells
• macrophages

• microRNA-454
• migration
• ovarian cancer
• small nucleolar RNA host gene 1
• zinc finger E-box-binding homeobox 1

• Animals
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Carcinoma, Ovarian Epithelial/genetics
• Carcinoma, Ovarian Epithelial/pathology
• Cell Line, Tumor
• Cell Proliferation/genetics
• Disease Progression
• Epithelial-Mesenchymal Transition/genetics
• Female
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs/genetics
• Ovarian Neoplasms/genetics
• Ovarian Neoplasms/pathology
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/physiology
• Zinc Finger E-box-Binding Homeobox 1/genetics

• National Natural Science Foundation of China
• Program for New Century Excellent Talents in University

• HGF
• Long noncoding RNA LINC00619
• PI3K-Akt signalling pathway
• apoptosis
• osteosarcoma
• proliferation

• gut–liver axis
• hepatic portal vein serum
• intestinal flora disorder
• liver regeneration
• proteomics

The purpose of this work was to investigate the bioactive compounds, core genes, and pharmacological mechanisms and to provide a further research orientation of Erzhi pill (EZP) on drug-induced liver injury (DILI).

At first, we collected information of bioactive compounds of EZP from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and previous studies. And then, the targets related to bioactive compounds and DILI were obtained from 4 public databases. At last, Cytoscape was used to establish a visual network. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses and network analysis were performed to investigate potential mechanism of EZP against DILI.

A total of 23 bioactive compounds and 89 major proteins of EZP were screened out as potential players against DILI. Association for bioactive compounds, core targets, and related pathways was analyzed, implying that core targets related to these pathways are ALB, AKT1, MAPK1, EGFR, SRC, MAPK8, IGF1, CASP3, HSP90AA1, and MMP9, and potential mechanisms of EZP acting on DILI are closely related to negative regulation of apoptosis process, improvement of lipid metabolism, and positive regulation of liver regeneration process.

This study demonstrated the multicompound, multitarget, and multichannel characteristics of EZP, which provided a novel approach for further research the mechanism of EZP in the treatment of DILI.

• Cell growth
• Cell proliferation
• Fatty liver
• Liver protection
• Liver regeneration
• Programmed cell death

• Animals
• Cell Death
• Cell Proliferation
• Hepatocytes/cytology
• Hepatocytes/metabolism
• Humans
• Liver/cytology
• Liver/physiology
• Liver Regeneration

• FGF
• IGF-1
• NF-kB
• PI3K/AKT
• TGF-β
• VEGF
• hippo/YAP

• Cervical cancer
• FAM83H
• migration
• prognosis
• proliferation

• Cell Movement
• Cell Proliferation
• Cell Survival
• Female
• HeLa Cells
• Humans
• Neoplasm Metastasis
• Prognosis
• Proteins/metabolism
• Uterine Cervical Neoplasms/diagnosis
• Uterine Cervical Neoplasms/metabolism

HGF (hepatocyte growth factor)/HGFR (HGF receptor) signaling pathway is a key pathway in liver protection and regeneration after acute toxic damage. Listeria monocytogenes toxin InlB contains a HGFR-interacting domain and is a functional analog of HGF. The aim of this work was to evaluate the hepatoprotective activity of the InlB HGFR-interacting domain. The recombinant HGFR-interacting domain InlB321/15 was purified from E. coli. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test was used to measure InlB321/15 mitogenic activity in HepG2 cells. Activation of MAPK- and PI3K/Akt-pathways was tracked with fluorescent microscopy, Western blotting, and ELISA. To evaluate hepatoprotective activity, InlB321/15 and recombinant human HGF (rhHGF) were intravenously injected at the same concentration of 2 ng·g⁻¹ to BALB/c mice 2 h before liver injury with CCl₄. InlB321/15 caused dose-dependent activation of MAPK- and PI3K/Akt-pathways and correspondent mitogenic effects. Both InlB321/15 and rhHGF improved macroscopic liver parameters (liver mass was 1.51, 1.27 and 1.15 g for the vehicle, InlB321/15 and rhHGF, respectively, p < 0.05), reduced necrosis (24.0%, 16.18% and 21.66% of the total area for the vehicle, InlB321/15 and rhHGF, respectively, p < 0.05). Obtained data suggest that InlB321/15 is a promising candidate for a tissue repair agent.

• HGF
• HGFR
• acute toxic liver damage
• bacterial protein
• hepatoprotective effect

This present study investigated the impact of the application of stem cells to liver regeneration following the first stage of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). The experiment was conducted on a pig model (n=6, 3 that did not receive application of stem cells, 3 that received application stem cells). Collected samples of liver (day 0 and 9 following surgery) were subjected to complete transcriptome sequencing. In total, 39 differentially expressed genes were found in the group without the application of the stem cells (genes of unwanted processes such as fibrosis and inflammation). In the group that did receive application of stem cells, no significantly differentially expressed genes were found, indicating a properly regenerated liver remnant. The present study therefore demonstrated, to the best of our knowledge for the first time, the positive effect of stem cells application in the liver regeneration process during ALPPS procedure in the pig model.

• Sus scrofa
• associating liver partition and portal vein ligation for staged hepatectomy
• liver regeneration
• stem cells
• transcriptome sequencing

• AKT
• Hepatocarcinoma
• Metastasis
• MiR-500a
• PTEN

• Adaptor Proteins, Signal Transducing/genetics
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Cell Cycle Proteins
• Cell Line, Tumor
• Cell Movement/genetics
• Cell Proliferation/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• MicroRNAs/genetics
• Neoplasm Invasiveness/genetics
• Neoplasm Invasiveness/pathology
• Neoplasm Metastasis
• PTEN Phosphohydrolase/genetics
• Phosphoproteins/genetics
• Proto-Oncogene Proteins c-akt/genetics
• Ribosomal Protein S6 Kinases, 70-kDa/genetics
• Signal Transduction
• TOR Serine-Threonine Kinases/genetics

• Hepatocellular carcinoma (HCC)
• Metastasis
• MicroRNA-181a
• PTEN
• XIST

• VEGF
• ascites
• cancer biology
• cancer stem cells
• epithelial-mesenchymal transition (EMT)
• malignant pleural effusion
• tumor therapy

The in vivo roles for even the most intensely studied microRNAs remain poorly defined. Here, analysis of mouse models revealed that let-7, a large and ancient microRNA family, performs tumor suppressive roles at the expense of regeneration. Too little or too much let-7 resulted in compromised protection against cancer or tissue damage, respectively. Modest let-7 overexpression abrogated MYC-driven liver cancer by antagonizing multiple let-7 sensitive oncogenes. However, the same level of overexpression blocked liver regeneration, while let-7 deletion enhanced it, demonstrating that distinct let-7 levels can mediate desirable phenotypes. let-7 dependent regeneration phenotypes resulted from influences on the insulin-PI3K-mTOR pathway. We found that chronic high-dose let-7 overexpression caused liver damage and degeneration, paradoxically leading to tumorigenesis. These dose-dependent roles for let-7 in tissue repair and tumorigenesis rationalize the tight regulation of this microRNA in development, and have important implications for let-7 based therapeutics.

DOI:http://dx.doi.org/10.7554/eLife.09431.001

The development of animals is guided by the expression of certain genes at critical moments. Many different mechanisms control development; in one of them, the expression of genes can be decreased by molecules called microRNAs. In particular, the group of microRNAs called let-7 has been intensively studied in roundworms and fruit flies. Although mammals have extremely similar let-7 microRNAs they seem to be more important during adulthood.

Previous studies using cells grown in the laboratory have shown that mammalian let-7 microRNAs decrease cell proliferation and cell growth. Furthermore, in mouse models of various cancers, let-7 microRNAs often reduce tumour growth when they are supplied to adult mice. Therefore, overall the let-7 group has been classified as genes that act to suppress tumors, and thus protect mice (and most likely humans too) from cancers. However, in-depth analysis of let-7 microRNAs was still missing.

Wu and Nguyen et al. have now studied mice with liver cancer using strains where they were able to regulate the levels of let-7. These mice overproduce a strong cancer-inducing gene in the liver; half were used as controls and the other half were further engineered to have moderately elevated levels of let-7 expression. Most of the control mice got large cancerous tumors, but only a few mice in the other group developed cancers and the tumors were smaller. This confirmed that let-7 hinders tumor formation.

Wu and Nguyen et al. also observed that the protected mice were less able to regenerate their liver tissues. Further experiments showed that deleting just two out of ten let-7 microRNAs enhanced the mice’s ability to regenerate liver tissue after injury. These findings indicate that let-7 microRNAs slow down the growth of both cancerous and normal cells. Lastly, when let-7 levels were raised to very high levels for a prolonged amount of time this actually led to liver damage and subsequent tumor formation.

This last observation may have important consequences for possible cancer therapies. Some scientists have shown that providing extra let-7 can slow or even reverse tumour growth, but the findings here clearly point out that too much let-7 could actually worsen the situation. Since the let-7 family comprises a handful of microRNAs in mammals, in the future it will also be important to find out to what extent these molecules play overlapping roles and how much they differ.

DOI:http://dx.doi.org/10.7554/eLife.09431.002

• MYC
• cancer
• cell biology
• developmental biology
• let-7
• liver
• microRNA
• mouse
• regeneration
• stem cells

• Epithelial-mesenchymal transition
• Hepatic progenitor cell
• Hepatocarcinogenesis
• Osteopontin

Various liver diseases result in terminal hepatic failure, and liver transplantation, cell transplantation and artificial liver support systems are emerging as effective therapies for severe hepatic disease. However, all of these treatments are limited by organ or cell resources, so developing a sufficient number of functional hepatocytes for liver regeneration is a priority. Liver regeneration is a complex process regulated by growth factors (GFs), cytokines, transcription factors (TFs), hormones, oxidative stress products, metabolic networks, and microRNA. It is well-known that the function of isolated primary hepatocytes is hard to maintain; when cultured in vitro, these cells readily undergo dedifferentiation, causing them to lose hepatocyte function. For this reason, most studies focus on inducing stem cells, such as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), hepatic progenitor cells (HPCs), and mesenchymal stem cells (MSCs), to differentiate into hepatocyte-like cells (HLCs) in vitro. In this review, we mainly focus on the nature of the liver regeneration process and discuss how to maintain and enhance in vitro hepatic function of isolated primary hepatocytes or stem cell-derived HLCs for liver regeneration. In this way, hepatocytes or HLCs may be applied for clinical use for the treatment of terminal liver diseases and may prolong the survival time of patients in the near future.

The effective treatment for cerebral ischemia has not yet been established. Hepatocyte growth factor (HGF) is a potent pleiotropic cytokine that is involved in cell and tissue regeneration, including in the central nervous system. Studies have demonstrated that an exogenous administration of HGF protects brain tissue from ischemic damage. In response to binding to the receptor c-Met, HGF activates the downstream signaling pathways (including the phosphatidylinositol 3-kinase/Akt, Ras/MAPK and signal transducer and activator of transcription pathways) which leads to various cellular responses involved in angiogenesis, glial scar formation, anti-apoptosis and neurogenesis. The purpose of this review is to summarize the present understanding of the therapeutic potential of HGF in cerebral ischemia.

• angiogenesis
• antifibrosis
• c-Met
• cerebral ischemia
• hepatocyte growth factor
• neurogenesis

• rat liver regeneration
• signal transduction
• hepatocyte g0/g1 transition
• hgf
• il-10
• il-6
• jak/stat
• p38mapk
• ras/erk
• stat3
• ingenuity pathway analysis 9.0 (ipa)

• Animals
• Cells, Cultured
• G1 Phase
• Gene Expression Regulation
• Genome
• Hepatocyte Growth Factor/metabolism
• Hepatocytes/cytology
• Hepatocytes/metabolism
• Interleukin-10/metabolism
• Interleukin-6/metabolism
• Janus Kinases/metabolism
• Liver Regeneration/genetics
• Male
• Oligonucleotide Array Sequence Analysis
• Rats
• Rats, Sprague-Dawley
• Resting Phase, Cell Cycle
• STAT Transcription Factors/metabolism
• Signal Transduction

• Animals
• Blood Platelets/chemistry
• Blood Platelets/metabolism
• Blood Platelets/physiology
• Endothelial Cells/metabolism
• Hepatectomy
• Hepatocytes
• Humans
• Intercellular Signaling Peptides and Proteins/metabolism
• Intercellular Signaling Peptides and Proteins/physiology
• Interleukin-6/metabolism
• Interleukin-6/physiology
• Kupffer Cells/physiology
• Liver/cytology
• Liver Diseases/physiopathology
• Liver Diseases/therapy
• Liver Regeneration/drug effects
• Lysophospholipids/physiology
• Platelet Count
• Platelet Transfusion
• Sphingosine/analogs & derivatives
• Sphingosine/physiology
• Thrombopoietin/administration & dosage
• Thrombopoietin/pharmacology

AIM: To investigate the effects of mammalian target of rapamycin (mTOR) inhibition on liver regeneration and autophagy in a surgical resection model.

METHODS: C57BL/6 mice were subjected to a 70% partial hepatectomy (PH) and treated intraperitoneally every 24 h with a combination of the mTOR inhibitor rapamycin (2.5 mg/kg per day) and the steroid dexamethasone (2.0 mg/kg per day) in phosphate buffered saline (PBS) or with PBS alone as vehicle control. In the immunosuppressant group, part of the group was treated subcutaneously 4 h prior to and 24 h after PH with a combination of human recombinant interleukin 6 (IL-6; 500 μg/kg per day) and hepatocyte growth factor (HGF; 100 μg/kg per day) in PBS. Animals were sacrificed 2, 3 or 5 d after PH and liver tissue and blood were collected for further analysis. Immunohistochemical staining for 5-Bromo-2’-deoxyuridine (BrdU) was used to quantify hepatocyte proliferation. Western blotting was used to detect hepatic microtubule-associated protein 1 light chain 3 (LC3)-II protein expression as a marker for autophagy. Hepatic gene expression levels of proliferation-, inflammation- and angiogenesis-related genes were examined by real-time reverse transcription-polymerase chain reaction and serum bilirubin and transaminase levels were analyzed at the clinical chemical core facility of the Erasmus MC-University Medical Center.

RESULTS: mTOR inhibition significantly suppressed regeneration, shown by decreased hepatocyte proliferation (2% vs 12% BrdU positive hepatocyte nuclei at day 2, P < 0.01; 0.8% vs 1.4% at day 5, P = 0.02) and liver weight reconstitution (63% vs 76% of initial total liver weight at day 3, P = 0.04), and furthermore increased serum transaminase levels (aspartate aminotransferase 641 U/L vs 185 U/L at day 2, P = 0.02). Expression of the autophagy marker LC3-II, which was reduced during normal liver regeneration, increased after mTOR inhibition (46% increase at day 2, P = 0.04). Hepatic gene expression showed an increased inflammation-related response [tumor necrosis factor (TNF)-α 3.2-fold upregulation at day 2, P = 0.03; IL-1Ra 6.0-fold upregulation at day 2 and 42.3-fold upregulation at day 5, P < 0.01] and a reduced expression of cell cycle progression and angiogenesis-related factors (HGF 40% reduction at day 2; vascular endothelial growth factor receptor 2 50% reduction at days 2 and 5; angiopoietin 1 60% reduction at day 2, all P≤ 0.01). Treatment with the regeneration stimulating cytokine IL-6 and growth factor HGF could overcome the inhibitory effect on liver weight (75% of initial total liver weight at day 3, P = 0.02 vs immunosuppression alone and P = 0.90 vs controls) and partially reversed gene expression changes caused by rapamycin (TNF-α and IL-1Ra levels at day 2 were restored to control levels). However, no significant changes in hepatocyte proliferation, serum injury markers or autophagy were found.

CONCLUSION: mTOR inhibition severely impairs liver regeneration and increases autophagy after PH. These effects are partly reversed by stimulation of the IL-6 and HGF pathways.

• Hepatocyte proliferation
• Autophagy
• Microtubule-associated protein 1 light chain 3
• Partial hepatectomy
• Rapamycin

• Aged
• Esophageal Neoplasms/metabolism
• Esophageal Neoplasms/pathology
• Female
• Humans
• Immunohistochemistry
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Neoplasm Metastasis
• Prognosis
• Regression Analysis
• Trans-Activators
• Transcription Factors/biosynthesis
• Transcription Factors/metabolism

We have previously shown that oval cells harboring a genetically inactivated Met tyrosine kinase (Met^−/− oval cells) are more sensitive to TGF-β-induced apoptosis than cells expressing a functional Met (Met^flx/flx), demonstrating that the HGF/Met axis plays a pivotal role in oval cell survival. Here, we have examined the mechanism behind this effect and have found that TGF-β induced a mitochondria-dependent apoptotic cell death in Met^flx/flx and Met^−/− oval cells, associated with a marked increase in levels of the BH3-only proteins Bim and Bmf. Bmf plays a key role during TGF-β-mediated apoptosis since knocking down of BMF significantly diminished the apoptotic response in Met^−/− oval cells. TGF-β also induced oxidative stress accompanied by NADPH oxidase 4 (Nox4) mRNA up-regulation and decreased protein levels of antioxidant enzymes. Antioxidants inhibit both TGF-β-induced caspase 3 activity and Bmf up-regulation, revealing an oxidative stress-dependent Bmf regulation by TGF-β. Notably, oxidative stress-related events were strongly amplified in Met^−/− oval cells, emphasizing the critical role of Met in promoting survival. Pharmacological inhibition of PI3K did impair HGF-driven protection from TGF-β-induced apoptosis and increased sensitivity of Met^flx/flx oval cells to TGF-ß by enhancing oxidative stress, reaching apoptotic indices similar to those obtained in Met^−/− oval cells. Interestingly, both PI3K inhibition and/or knockdown itself resulted in caspase-3 activation and loss of viability in Met^flx/flx oval cells, whereas no effect was observed in Met^−/− oval cells. Altogether, results presented here provide solid evidences that both paracrine and autocrine HGF/Met signaling requires PI3K to promote mouse hepatic oval cell survival against TGF-β-induced oxidative stress and apoptosis.

• Animals
• Antioxidants/metabolism
• Apoptosis
• Caspase 3/metabolism
• Cell Line
• Glutathione/metabolism
• Hepatocyte Growth Factor/metabolism
• Hepatocytes/cytology
• Membrane Potentials
• Mice
• Mitochondria/metabolism
• Oxidative Stress
• Phosphatidylinositol 3-Kinases/metabolism
• Phosphatidylserines/metabolism
• Proto-Oncogene Proteins c-met/metabolism
• RNA, Small Interfering/metabolism
• Reactive Oxygen Species/metabolism
• Signal Transduction
• Transforming Growth Factor beta/pharmacology

• Cyclooxygenase-2
• Hepatic oval cells
• Liver generation

• Animals
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Apoptosis/drug effects
• Apoptosis/physiology
• Carcinoma, Ovarian Epithelial
• Caspases/metabolism
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cisplatin/administration & dosage
• Cisplatin/pharmacology
• Enzyme Activation/drug effects
• Female
• Hepatocyte Growth Factor/metabolism
• Humans
• Immunoblotting
• Immunohistochemistry
• Indoles/administration & dosage
• Indoles/pharmacology
• Mice
• Mice, Nude
• Middle Aged
• Neoplasms, Glandular and Epithelial/drug therapy
• Neoplasms, Glandular and Epithelial/metabolism
• Neoplasms, Glandular and Epithelial/pathology
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/pathology
• Proto-Oncogene Proteins c-akt/metabolism
• Proto-Oncogene Proteins c-met/genetics
• Proto-Oncogene Proteins c-met/metabolism
• RNA Interference
• Signal Transduction/drug effects
• Signal Transduction/physiology
• Sulfones/administration & dosage
• Sulfones/pharmacology
• X-Linked Inhibitor of Apoptosis Protein/metabolism
• Xenograft Model Antitumor Assays
• bcl-X Protein/metabolism

Liver is unique in its capacity to regenerate in response to injury or tissue loss. Hepatocytes and other liver cells are able to proliferate and repopulate the liver. However, when this response is impaired, the contribution of hepatic progenitors becomes very relevant. Here, we present an update of recent studies on growth factors and cytokine-driven intracellular pathways that govern liver stem/progenitor cell expansion and differentiation, and the relevance of these signals in liver development, regeneration and carcinogenesis. Tyrosine kinase receptor signaling, in particular, c-Met, epidermal growth factor receptors or fibroblast growth factor receptors, contribute to proliferation, survival and differentiation of liver stem/progenitor cells. Different evidence suggests a dual role for the transforming growth factor (TGF)-β signaling pathway in liver stemness and differentiation. On the one hand, TGF-β mediates progression of differentiation from a progenitor stage, but on the other hand, it contributes to the expansion of liver stem cells. Hedgehog family ligands are necessary to promote hepatoblast proliferation but need to be shut off to permit subsequent hepatoblast differentiation. In the same line, the Wnt family and β-catenin/T-cell factor pathway is clearly involved in the maintenance of liver stemness phenotype, and its repression is necessary for liver differentiation during development. Collectively, data indicate that liver stem/progenitor cells follow their own rules and regulations. The same signals that are essential for their activation, expansion and differentiation are good candidates to contribute, under adequate conditions, to the paradigm of transformation from a pro-regenerative to a pro-tumorigenic role. From a clinical perspective, this is a fundamental issue for liver stem/progenitor cell-based therapies.

• Hepatocyte growth factor
• Epidermal growth factor
• Fibroblast growth factor
• Transforming growth factor-β
• Hedgehog and β-catenin
• Liver
• Stem cell

• Animals
• Choline Deficiency/metabolism
• DNA Methylation
• DNA, Neoplasm/genetics
• Folic Acid Deficiency/metabolism
• Gene Expression Regulation, Neoplastic/drug effects
• Liver Neoplasms, Experimental/etiology
• Male
• Methionine/deficiency
• Methionine/metabolism
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• MicroRNAs

• R01 ES015241 NIEHS NIH HHS

• hepatocholangiocarcinoma
• oval cell
• liver cancer cell line
• hgf
• g-csf