Cylindrospermopsin (CYN) has been recognized as a potent waterborne hepatotoxin with an increasing environmental occurrence. However, CYN effects on the specific populations of hepatic cells involved in liver tissue development, renewal, and regeneration, have not been characterized yet. We used human embryonic stem cells to analyze the hepatic differentiation stage-specific effect of CYN. Our results strongly suggest that CYN might contribute to the development of chronic adverse outcomes by disrupting liver tissue homeostasis in terms of (1) cellular stress and damage induced in the mature differentiated hepatocytes, which was associated with a necrotic cell death and thus possibly also inflammatory responses; (2) selective elimination of HNF4α+ cells from populations of progenitor cells and immature hepatocytes during hepatic differentiation, which could possibly lead to an impaired liver renewal and regeneration; (3) impaired hepatic functions of immature hepatocytes, such as decreased albumin secretion or increased lipid accumulation, which could contribute to the development of liver steatosis; and (4) survival of the immature and AFP-expressing cells with the limited ability to further differentiate, which could represent a tumor-promoting condition.

• Klíčová slova
• cyanotoxin, cylindrospermopsin, hepatic differentiation, human embryonic stem cells, liver,
• MeSH
• albuminy metabolismus   MeSH
• alkaloidy MeSH
• apoptóza MeSH
• bakteriální toxiny toxicita   MeSH
• buněčná diferenciace účinky léků   MeSH
• hepatocytární jaderný faktor 4 metabolismus   MeSH
• hepatocyty účinky léků   MeSH
• játra účinky léků   MeSH
• kmenové buňky MeSH
• lidé MeSH
• lidské embryonální kmenové buňky MeSH
• metabolismus lipidů MeSH
• nekróza MeSH
• oxidační stres účinky léků   MeSH
• sinice MeSH
• sladká voda MeSH
• toxiny kmene Cyanobacteria MeSH
• uracil analogy a deriváty   toxicita   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• albuminy MeSH
• alkaloidy MeSH
• bakteriální toxiny MeSH
• cylindrospermopsin MeSH Prohlížeč
• hepatocytární jaderný faktor 4 MeSH
• HNF4A protein, human MeSH Prohlížeč
• toxiny kmene Cyanobacteria MeSH
• uracil MeSH

Myofibroblast expansion is a critical event in the pathogenesis of liver fibrosis. The activation of hepatic stellate cells (HSC) to myofibroblast (MFB) results in the enhanced production of extracellular matrix (ECM). In this study, we explored the effect of acidic fibroblast growth factor (FGF-1) treatment on a transforming growth factor (TGF-β1) induced MFB conversion. We used HSC-T6 cell line, which represents well-established model of activated HSC. These cells strongly expressed α-smooth muscle actin (α-SMA) and fibronectin (FN-EDA) after stimulation with TGF-β1, which is a stimulus for MFB differentiation and ECM production. FGF-1 reduced proteins expression to levels comparable with untreated cells. Mild repression of secreted gelatinases was seen in culture media after FGF-1 treatment. The exposure of cells to collagen gel leads to changes in cell morphology and in expression of MFB markers. Lack of α-SMA in cells embedded to collagen gel was detected. When stimulated with TGF-β1, the cells increased expression of FN-EDA, but not α-SMA. Although the cells on plastic and in collagen gel show different properties, FGF-1 reduced expression of FN-EDA in both conditions. Disrupting TGF-β1 signalling pathway represents a potential strategy for the treatment of fibrosis. We showed that FGF-1 could antagonize signals initiated by TGF-β1.

• Klíčová slova
• Collagen type I, FGF-1, Hepatic stellate cells, Myofibroblast, TGF-β1, α -SMA,
• MeSH
• aktiny genetika   metabolismus   MeSH
• buněčná diferenciace účinky léků   MeSH
• buněčné linie MeSH
• exprese genu účinky léků   MeSH
• fibroblastový růstový faktor 1 farmakologie   MeSH
• fibronektiny genetika   metabolismus   MeSH
• jaterní hvězdicovité buňky fyziologie   MeSH
• kolagen farmakologie   MeSH
• krysa rodu Rattus MeSH
• messenger RNA analýza   MeSH
• myofibroblasty MeSH
• transformující růstový faktor beta genetika   metabolismus   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aktiny MeSH
• fibroblastový růstový faktor 1 MeSH
• fibronektiny MeSH
• kolagen MeSH
• messenger RNA MeSH
• smooth muscle actin, rat MeSH Prohlížeč
• transformující růstový faktor beta MeSH

Over the past decades, the in vitro use of pluripotent cell lines gained a crucial role in toxicology, preclinical drug testing and developmental biology. NTERA2 clone D1 cells were identified as pluripotent cells with high potential for neural differentiation. Although they are commonly used cellular sources in neuropharmacology and neurodevelopmental studies, their endodermal and mesodermal differentiation potential awaits further characterization. Here, we devised improved protocols for hepatogenic and osteogenic differentiation of NTERA2 clone D1 cells. Our in vitro differentiation assays showed significant up-regulation of multiple hepatogenic markers. We also observed robust mineralization and osteogenic marker expression of NTERA2 clone D1 cells upon in vitro osteogenic induction. These results suggest that NTERA2 clone D1 cells may be utilized as an in vitro model system to study various aspects of liver biology and osteogenesis. In addition, tri-lineage differentiation of NTERA2 clone D1 cells may serve as a simple experimental control system when validating pluripotency of other cell types.

• MeSH
• buněčná diferenciace MeSH
• buněčné klony MeSH
• buněčné linie MeSH
• játra * MeSH
• osteogeneze * MeSH
• Publikační typ
• časopisecké články MeSH

Human pluripotent stem cells (hPSCs) have gained a solid foothold in basic research and drug industry as they can be used in vitro to study human development and have potential to offer limitless supply of various somatic cell types needed in drug development. Although the hepatic differentiation of hPSCs has been extensively studied, only a little attention has been paid to the role of the extracellular matrix. In this study we used laminin-511, laminin-521, and fibronectin, found in human liver progenitor cells, as culture matrices for hPSC-derived definitive endoderm cells. We observed that laminin-511 and laminin-521 either alone or in combination support the hepatic specification and that fibronectin is not a vital matrix protein for the hPSC-derived definitive endoderm cells. The expression of the laminin-511/521-specific integrins increased during the definitive endoderm induction and hepatic specification. The hepatic cells differentiated on laminin matrices showed the upregulation of liver-specific markers both at mRNA and protein levels, secreted human albumin, stored glycogen, and exhibited cytochrome P450 enzyme activity and inducibility. Altogether, we found that laminin-511 and laminin-521 can be used as stage-specific matrices to guide the hepatic specification of hPSC-derived definitive endoderm cells.

• Klíčová slova
• Extracellular matrix, Hepatic differentiation, Human embryonic stem cell, Human induced pluripotent stem cell, Laminin-511, Laminin-521,
• MeSH
• biomimetické materiály chemie   MeSH
• buněčná diferenciace fyziologie   MeSH
• buněčné linie MeSH
• extracelulární matrix - proteiny metabolismus   MeSH
• extracelulární matrix metabolismus   MeSH
• hepatocyty cytologie   fyziologie   MeSH
• laminin metabolismus   MeSH
• lidé MeSH
• pluripotentní kmenové buňky cytologie   metabolismus   MeSH
• techniky vsádkové kultivace metody   MeSH
• tkáňové inženýrství metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• extracelulární matrix - proteiny MeSH
• laminin MeSH

BACKGROUND: Differentiated thyroid cancers (DTC) often form metastases in neck lymph nodes, lungs and bones. Other metastases--to the brain, kidneys, skin and liver are rare. Liver metastases of DTC occur in the terminal phase of the disease and predominantly do not accumulate radioiodine. Functional (accumulating radioiodine) metastases are very rare. MATERIAL AND METHODS: In an 85 year old patient with DTC of the follicular type after removal of the thyroid and lymph nodes metastases on the neck and after the elimination of thyroid remnants by radioiodine, a functional metastasis in the liver was detected by combination of whole-body scintigraphy following administration of 131I and liver scintigraphy by using 99mTc-colloid, supplemented by bone scintigraphy after administration of 99mTc-MDP. At first, the high thyroglobulin serum level was falsely negative after repeated radioiodine treatment. The patient was treated for this hepatic accumulating metastasis eight times by 59.2 GBq total dose of radioiodine. Radioiodine treatments were repeated for 7 years, the patient died at the age of 92 years. CONCLUSIONS: It is necessary to distinguish between diffuse and focal radioiodine accumulation in a liver. Only a focal accumulation is characteristic for functional liver metastasis in which thyroxin synthesis is preserved. The correspondence of focal accumulation of radioiodine on whole-body scintigraphy with "cold" area on liver scintigraphy is specific for diagnosis of this metastasis. At the same time, it confirms the fact that radioiodine therapy can be both promising and successful, as we can see in the case of our patient.

• MeSH
• buněčná diferenciace MeSH
• játra diagnostické zobrazování   MeSH
• jednofotonová emisní výpočetní tomografie metody   MeSH
• karcinom patologie   MeSH
• lidé MeSH
• lymfatické metastázy MeSH
• metastázy nádorů MeSH
• nádory jater diagnostické zobrazování   radioterapie   sekundární   MeSH
• nádory štítné žlázy patologie   chirurgie   MeSH
• radioisotopová scintigrafie MeSH
• radioizotopy jodu terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• thyroxin metabolismus   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• radioizotopy jodu MeSH
• thyroxin MeSH

BACKGROUND & AIMS: Growth Differentiation Factor 11 (GDF11) is an anti-aging factor, yet its role in liver diseases is not established. We evaluated the role of GDF11 in healthy conditions and in the transition from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). RESULTS: GDF11 mRNA levels positively correlated with NAFLD activity score and with CPT1, SREBP, PPARγ and Col1A1 mRNA levels, and associated to portal fibrosis, in morbidly obese patients with NAFLD/NASH. GDF11-treated mice showed mildly exacerbated hepatic collagen deposition, accompanied by weight loss and without changes in liver steatosis or inflammation. GDF11 triggered ALK5-dependent SMAD2/3 nuclear translocation and the pro-fibrogenic activation of HSC. CONCLUSIONS: GDF11 supplementation promotes mild liver fibrosis. Even considering its beneficial metabolic effects, caution should be taken when considering therapeutics that regulate GDF11. METHODS: We analyzed liver biopsies from a cohort of 33 morbidly obese adults with NAFLD/NASH. We determined the correlations in mRNA expression levels between GDF11 and genes involved in NAFLD-to-NASH progression and with pathological features. We also exposed wild type or obese mice with NAFLD to recombinant GDF11 by daily intra-peritoneal injection and monitor the hepatic pathological changes. Finally, we analyzed GDF11-activated signaling pathways in hepatic stellate cells (HSC).

• Klíčová slova
• NAFLD, NASH, fibrosis, growth differentiation factor 11, liver,
• MeSH
• buněčné linie MeSH
• dospělí MeSH
• experimentální cirhóza jater chemicky indukované   metabolismus   patologie   MeSH
• jaterní cirhóza diagnóza   etiologie   genetika   metabolismus   MeSH
• jaterní hvězdicovité buňky metabolismus   patologie   MeSH
• játra metabolismus   patologie   MeSH
• kostní morfogenetické proteiny genetika   metabolismus   toxicita   MeSH
• lidé středního věku MeSH
• lidé MeSH
• morbidní obezita komplikace   diagnóza   MeSH
• myši inbrední C57BL MeSH
• nealkoholová steatóza jater diagnóza   etiologie   genetika   metabolismus   MeSH
• progrese nemoci MeSH
• růstové diferenciační faktory genetika   metabolismus   toxicita   MeSH
• signální transdukce MeSH
• studie případů a kontrol MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• GDF11 protein, human MeSH Prohlížeč
• kostní morfogenetické proteiny MeSH
• růstové diferenciační faktory MeSH

• MeSH
• angiografie MeSH
• arteria coeliaca diagnostické zobrazování   MeSH
• arteria hepatica diagnostické zobrazování   MeSH
• diferenciální diagnóza MeSH
• hemangiom diagnostické zobrazování   MeSH
• jaterní oběh MeSH
• lidé MeSH
• metody MeSH
• nádory jater diagnostické zobrazování   MeSH
• nemoci jater diagnostické zobrazování   MeSH
• portografie * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Fibrosis contributes to tissue repair, but excessive fibrosis disrupts organ function. Alagille syndrome (ALGS, caused by mutations in JAGGED1) results in liver disease and characteristic fibrosis. Here, we show that Jag1Ndr/Ndr mice, a model for ALGS, recapitulate ALGS-like fibrosis. Single-cell RNA-seq and multi-color flow cytometry of the liver revealed immature hepatocytes and paradoxically low intrahepatic T cell infiltration despite cholestasis in Jag1Ndr/Ndr mice. Thymic and splenic regulatory T cells (Tregs) were enriched and Jag1Ndr/Ndr lymphocyte immune and fibrotic capacity was tested with adoptive transfer into Rag1-/- mice, challenged with dextran sulfate sodium (DSS) or bile duct ligation (BDL). Transplanted Jag1Ndr/Ndr lymphocytes were less inflammatory with fewer activated T cells than Jag1+/+ lymphocytes in response to DSS. Cholestasis induced by BDL in Rag1-/- mice with Jag1Ndr/Ndr lymphocytes resulted in periportal Treg accumulation and three-fold less periportal fibrosis than in Rag1-/- mice with Jag1+/+ lymphocytes. Finally, the Jag1Ndr/Ndr hepatocyte expression profile and Treg overrepresentation were corroborated in patients' liver samples. Jag1-dependent hepatic and immune defects thus interact to determine the fibrotic process in ALGS.

• Klíčová slova
• Alagille syndrome, Fibrosis, Jagged1, Notch, Treg,
• MeSH
• Alagillův syndrom patologie   genetika   MeSH
• buněčná diferenciace * MeSH
• hepatocyty * metabolismus   patologie   MeSH
• jaterní cirhóza * patologie   genetika   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• protein jagged-1 * metabolismus   genetika   MeSH
• regulační T-lymfocyty imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• JAG1 protein, human MeSH Prohlížeč
• Jag1 protein, mouse MeSH Prohlížeč
• protein jagged-1 * MeSH

Activated hepatic stellate cells (HSC) are a major source offibrous proteins in cirrhotic liver. Inducing or accelerating their apoptosis is a potential way of liver fibrosis treatment. Extracellular matrix (ECM) surrounding cells in tissue affects their differentiation, migration, proliferation and function. Type I collagen is the main ECM component in fibrotic liver. We have examined how this protein modifies apoptosis of normal rat HSC induced by gliotoxin, cycloheximide and cytochalasin D in vitro and spontaneous apoptosis of HSC isolated from CCl4-damaged liver. We have found that type I collagen gel enhances HSC apoptosis regardless of the agent triggering this process.

• MeSH
• apoptóza účinky léků   MeSH
• buněčné kultury MeSH
• chlorid uhličitý MeSH
• cykloheximid MeSH
• cytochalasin D MeSH
• gliotoxin MeSH
• jaterní cirhóza patologie   MeSH
• jaterní hvězdicovité buňky účinky léků   patologie   MeSH
• kolagen typu I farmakologie   MeSH
• krysa rodu Rattus MeSH
• modely nemocí na zvířatech MeSH
• potkani Sprague-Dawley MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chlorid uhličitý MeSH
• cykloheximid MeSH
• cytochalasin D MeSH
• gliotoxin MeSH
• kolagen typu I MeSH

The liver has a unique vascular supply, and triple-phase contrast-enhanced computed tomography examinations are being performed in order to characterize liver lesions. This study aimed to look for any associations between the attenuation values of liver lesions and their histological classification. The inclusion criteria for this retrospective study were focal or multifocal liver lesions and histological diagnosis. All of the dogs underwent pre-contrast and triple-phase postcontrast computed tomography (CT) examinations with identical timings of the postcontrast series. Thirty-one dogs were included in the study, and various benign and malignant pathologies were identified. The results did not identify any significant differences between the benign and malignant liver lesions, nor between the individual histological diagnoses. Inflammatory lesions were significantly different compared to the normal liver parenchyma, and significant hypoattenuation was found in the portal and delayed venous phases. Hemangiosarcomas were significantly hypoattenuating to the normal liver parenchyma in the pre-contrast and arterial phases, and also to all of the benign lesions in the arterial phase. The other pathologies showed variable attenuation patterns in the different postcontrast phases, and differentiation was not possible. On the basis of this study, triple-phase contrast-enhanced computed tomography cannot differentiate between benign and malignant liver lesions, and biopsy and further histological analysis are necessary.

• Klíčová slova
• attenuation value, hemangiosarcoma, hepatic inflammation, hepatopathy, liver neoplasia,
• Publikační typ
• časopisecké články MeSH