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Ooka A, Yamaguchi M, Suzuki K, Saito SY, Kaneko YK, Kimura T, Ishikawa T. Differentiation-inducing factor-1 ameliorates liver fibrosis through the reversion of activated hepatic stellate cells. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167802. [PMID: 40101372 DOI: 10.1016/j.bbadis.2025.167802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 02/25/2025] [Accepted: 03/14/2025] [Indexed: 03/20/2025]
Affiliation(s)
- Akira Ooka
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka City, Shizuoka 422-8526, Japan
| | - Momoka Yamaguchi
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka City, Shizuoka 422-8526, Japan.
| | - Kensuke Suzuki
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka City, Shizuoka 422-8526, Japan
| | - Shin-Ya Saito
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka City, Shizuoka 422-8526, Japan; Faculty of Veterinary Medicine, Okayama University of Science, 1-3 Ikoinooka, Imabari City, Ehime 794-8555, Japan
| | - Yukiko K Kaneko
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka City, Shizuoka 422-8526, Japan
| | - Toshihide Kimura
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka City, Shizuoka 422-8526, Japan
| | - Tomohisa Ishikawa
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka City, Shizuoka 422-8526, Japan
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2
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Zhang Y, Jin D, Zhu H, Lin M, Peng X. Hepatocytes and Hepatic Stellate Cells Carry Different Levels of DNA Damage due to Their Sensitivity to Oxidative Stress in Chronic Hepatitis B. J Viral Hepat 2025; 32:e70017. [PMID: 39991880 DOI: 10.1111/jvh.70017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 02/14/2025] [Indexed: 02/25/2025]
Abstract
Hepatocellular carcinoma (HCC) and liver cirrhosis (LC) occur in spite of current antiviral therapies in patients with chronic hepatitis (CHB). It is not yet known why HCC and LC are related to hepatocytes and hepatic stellate cells (HSCs), respectively, in the same inflammation circumstances. The expression of the phosphorylated form of histone H2AX (γ-H2AX), a biomarker of DNA damage, was detected in hepatocytes and interstitial cells within the liver tissues of 69 patients with CHB using immunohistochemical assay and immunofluorescence colocalisation technique. Hydrogen peroxide (H2O2) was applied to establish an oxidative DNA damage model. Hepatocytes in CHB patients carried much higher levels of DNA damage than interstitial cells. The DNA damage-carried interstitial cells were confirmed to be HSCs. They lost the damaged DNA during differentiation into myofibroblasts near the foci of inflammatory necrosis. Hepatocyte was much more sensitive to oxidative stress and DNA damage than HSCs, but both MIHA and LX-2 repaired DNA damage efficiently in vitro. Hepatocytes carried much higher levels of DNA damage than HSCs due to their remarkable difference in sensitivity to inflammation-induced oxidative DNA damage. The different sensitivity may render hepatocytes and HSCs to be respectively involved in HCC and LC in the same inflammation circumstances.
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Affiliation(s)
- Yansong Zhang
- Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, China
| | - Danjing Jin
- Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, China
| | - Hongqiong Zhu
- Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, China
| | - Minyi Lin
- Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, China
| | - Xiaomou Peng
- Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, China
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3
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Haaker MW, Goossens V, Hoogland NAN, van Doorne H, Wang Z, Jansen JWA, Kaloyanova DV, van de Lest CHA, Houweling M, Vaandrager AB, Helms JB. Early activation of hepatic stellate cells induces rapid initiation of retinyl ester breakdown while maintaining lecithin:retinol acyltransferase (LRAT) activity. Biochim Biophys Acta Mol Cell Biol Lipids 2024; 1869:159540. [PMID: 39068984 DOI: 10.1016/j.bbalip.2024.159540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 06/30/2024] [Accepted: 07/25/2024] [Indexed: 07/30/2024]
Abstract
Lecithin:retinol acyltransferase (LRAT) is the main enzyme producing retinyl esters (REs) in quiescent hepatic stellate cells (HSCs). When cultured on stiff plastic culture plates, quiescent HSCs activate and lose their RE stores in a process similar to that in the liver following tissue damage, leading to fibrosis. Here we validated HSC cultures in soft gels to study RE metabolism in stable quiescent HSCs and investigated RE synthesis and breakdown in activating HSCs. HSCs cultured in a soft gel maintained characteristics of quiescent HSCs, including the size, amount and composition of their characteristic large lipid droplets. Quiescent gel-cultured HSCs maintained high expression levels of Lrat and a RE storing phenotype with low levels of RE breakdown. Newly formed REs are highly enriched in retinyl palmitate (RP), similar to freshly isolated quiescent HSCs, which is associated with high LRAT activity. Comparison of these quiescent gel-cultured HSCs with activated plastic-cultured HSCs showed that although during early activation the total RE levels and RP-enrichment are reduced, levels of RE formation are maintained and mediated by LRAT. Loss of REs was caused by enhanced RE breakdown in activating HSCs. Upon prolonged culturing, activated HSCs have lost their LRAT activity and produce small amounts of REs by DGAT1. This study reveals unexpected dynamics in RE metabolism during early HSC activation, which might be important in liver disease as early stages are reversible. Soft gel cultures provide a promising model to study RE metabolism in quiescent HSCs, allowing detailed molecular investigations on the mechanisms for storage and release.
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Affiliation(s)
- Maya W Haaker
- Department of Biomolecular Health Sciences, Division of Cell Biology, Metabolism & Cancer, Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, the Netherlands
| | - Vera Goossens
- Department of Biomolecular Health Sciences, Division of Cell Biology, Metabolism & Cancer, Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, the Netherlands
| | - Nina A N Hoogland
- Department of Biomolecular Health Sciences, Division of Cell Biology, Metabolism & Cancer, Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, the Netherlands
| | - Hidde van Doorne
- Department of Biomolecular Health Sciences, Division of Cell Biology, Metabolism & Cancer, Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, the Netherlands
| | - Ziqiong Wang
- Department of Biomolecular Health Sciences, Division of Cell Biology, Metabolism & Cancer, Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, the Netherlands
| | - Jeroen W A Jansen
- Department of Biomolecular Health Sciences, Division of Cell Biology, Metabolism & Cancer, Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, the Netherlands
| | - Dora V Kaloyanova
- Department of Biomolecular Health Sciences, Division of Cell Biology, Metabolism & Cancer, Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, the Netherlands
| | - Chris H A van de Lest
- Department of Biomolecular Health Sciences, Division of Cell Biology, Metabolism & Cancer, Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, the Netherlands
| | - Martin Houweling
- Department of Biomolecular Health Sciences, Division of Cell Biology, Metabolism & Cancer, Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, the Netherlands
| | - A Bas Vaandrager
- Department of Biomolecular Health Sciences, Division of Cell Biology, Metabolism & Cancer, Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, the Netherlands
| | - J Bernd Helms
- Department of Biomolecular Health Sciences, Division of Cell Biology, Metabolism & Cancer, Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, the Netherlands.
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4
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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5
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Hereditary Tyrosinemia Type 1 Mice under Continuous Nitisinone Treatment Display Remnants of an Uncorrected Liver Disease Phenotype. Genes (Basel) 2023; 14:genes14030693. [PMID: 36980965 PMCID: PMC10047938 DOI: 10.3390/genes14030693] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/02/2023] [Accepted: 03/08/2023] [Indexed: 03/18/2023] Open
Abstract
Hereditary tyrosinemia type 1 (HT1) is a genetic disorder of the tyrosine degradation pathway (TIMD) with unmet therapeutic needs. HT1 patients are unable to fully break down the amino acid tyrosine due to a deficient fumarylacetoacetate hydrolase (FAH) enzyme and, therefore, accumulate toxic tyrosine intermediates. If left untreated, they experience hepatic failure with comorbidities involving the renal and neurological system and the development of hepatocellular carcinoma (HCC). Nitisinone (NTBC), a potent inhibitor of the 4-hydroxyphenylpyruvate dioxygenase (HPD) enzyme, rescues HT1 patients from severe illness and death. However, despite its demonstrated benefits, HT1 patients under continuous NTBC therapy are at risk to develop HCC and adverse reactions in the eye, blood and lymphatic system, the mechanism of which is poorly understood. Moreover, NTBC does not restore the enzymatic defects inflicted by the disease nor does it cure HT1. Here, the changes in molecular pathways associated to the development and progression of HT1-driven liver disease that remains uncorrected under NTBC therapy were investigated using whole transcriptome analyses on the livers of Fah- and Hgd-deficient mice under continuous NTBC therapy and after seven days of NTBC therapy discontinuation. Alkaptonuria (AKU) was used as a tyrosine-inherited metabolic disorder reference disease with non-hepatic manifestations. The differentially expressed genes were enriched in toxicological gene classes related to liver disease, liver damage, liver regeneration and liver cancer, in particular HCC. Most importantly, a set of 25 genes related to liver disease and HCC development was identified that was differentially regulated in HT1 vs. AKU mouse livers under NTBC therapy. Some of those were further modulated upon NTBC therapy discontinuation in HT1 but not in AKU livers. Altogether, our data indicate that NTBC therapy does not completely resolves HT1-driven liver disease and supports the sustained risk to develop HCC over time as different HCC markers, including Moxd1, Saa, Mt, Dbp and Cxcl1, were significantly increased under NTBC.
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Liu Y, Jian J, Zhang Y, Wang L, Liu X, Chen Z. Construction of cancer- associated fibroblasts related risk signature based on single-cell RNA-seq and bulk RNA-seq data in bladder urothelial carcinoma. Front Oncol 2023; 13:1170893. [PMID: 37124542 PMCID: PMC10140328 DOI: 10.3389/fonc.2023.1170893] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 03/27/2023] [Indexed: 05/02/2023] Open
Abstract
Background The ability of cancer-associated fibroblasts (CAFs) to encourage angiogenesis, tumor cell spread, and increase treatment resistance makes them pro-tumorigenic. We aimed to investigate the CAF signature in Bladder urothelial carcinoma (BLCA) and, for clinical application, to build a CAF-based risk signature to decipher the immune landscape and screen for suitable treatment BLCA samples. Methods CAF-related genes were discovered by superimposing CAF marker genes discovered from single-cell RNA-seq (scRNA-seq) data taken from the GEO database with CAF module genes discovered by weighted gene co-expression network analysis (WGCNA) using bulk RNA-seq data from TCGA. After identifying prognostic genes related with CAF using univariate Cox regression, Lasso regression was used to build a risk signature. With microarray data from the GEO database, prognostic characteristics were externally verified. For high and low CAF-risk categories, immune cells and immunotherapy responses were analyzed. Finally, a nomogram model based on the risk signature and prospective chemotherapeutic drugs were examined. Results Combining scRNA-seq and bulk-seq data analysis yielded a total of 124 CAF-related genes. LRP1, ANXA5, SERPINE2, ECM1, RBP1, GJA1, and FKBP10 were the seven BLCA prognostic genes that remained after univariate Cox regression and LASSO regression analyses. Then, based on these genes, prognostic characteristics were created and validated to predict survival in BLCA patients. Additionally, risk signature had a strong correlation with known CAF scores, stromal scores, and certain immune cells. The CAF-risk signature was identified as an independent prognostic factor for BLCA using multifactorial analysis, and its usefulness in predicting immunotherapy response was confirmed. Based on risk classification, we projected six highly sensitive anticancer medicines for the high-risk group. Conclusion The prognosis of BLCA may be accurately predicted using CAF-based risk signature. With a thorough understanding of the BLCA CAF-signature, it might be able to explain the BLCA patients' response to immunotherapy and identify a potential target for BLCA treatment.
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Affiliation(s)
- Yunxun Liu
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, China
- Institute of Urologic Disease, Renmin Hospital, Wuhan University, Wuhan, China
| | - Jun Jian
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, China
- Institute of Urologic Disease, Renmin Hospital, Wuhan University, Wuhan, China
| | - Ye Zhang
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, China
- Institute of Urologic Disease, Renmin Hospital, Wuhan University, Wuhan, China
| | - Lei Wang
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, China
- Institute of Urologic Disease, Renmin Hospital, Wuhan University, Wuhan, China
| | - Xiuheng Liu
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, China
- Institute of Urologic Disease, Renmin Hospital, Wuhan University, Wuhan, China
- *Correspondence: Xiuheng Liu, ; Zhiyuan Chen,
| | - Zhiyuan Chen
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, China
- Institute of Urologic Disease, Renmin Hospital, Wuhan University, Wuhan, China
- *Correspondence: Xiuheng Liu, ; Zhiyuan Chen,
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Cha JJ, Mandal C, Ghee JY, Yoo JA, Lee MJ, Kang YS, Hyun YY, Lee JE, Kim HW, Han SY, Han JY, Chung AY, Yoon DW, Rhyu IJ, Oh J, Cha DR. Inhibition of Renal Stellate Cell Activation Reduces Renal Fibrosis. Biomedicines 2020; 8:biomedicines8100431. [PMID: 33086608 PMCID: PMC7603238 DOI: 10.3390/biomedicines8100431] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/16/2020] [Accepted: 10/16/2020] [Indexed: 02/06/2023] Open
Abstract
Interstitial fibrosis is a common feature of chronic kidney disease, and platelet-derived growth factor receptor-β (PDGFR-β)-positive mesenchymal cells are reportedly the major source of scar-producing myofibroblasts. We had previously demonstrated that albumin and its derivative R-III (a retinol-binding protein-albumin domain III fusion protein) inhibited the transdifferentiation/activation of hepatic stellate cells (HSCs) to myofibroblasts and that R-III administration reduced liver fibrosis. In this study, we isolated cells (referred to as renal stellate cells, RSCs) from rat kidney tissues using the HSC isolation protocol and compared their morphological and biochemical characteristics with those of HSCs. RSCs shared many characteristics with HSCs, such as storage of vitamin A-containing lipid droplets and expression of HSC markers as well as pericyte markers. RSCs underwent spontaneous transdifferentiation into myofibroblasts in in vitro culture, which was inhibited by albumin expression or R-III treatment. We also evaluated the therapeutic effects of R-III in unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Injected R-III localized predominantly in cytoglobin/stellate cell activation-associated protein (Cygb/STAP)-positive cells in the kidney and reduced renal fibrosis. These findings suggest that RSCs can be recognized as the renal counterparts of HSCs and that RSCs represent an attractive therapeutic target for anti-fibrotic therapy.
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Affiliation(s)
- Jin Joo Cha
- Department of Nephrology, Korea University Ansan Hospital, Ansan 15355, Korea; (J.J.C.); (J.Y.G.); (J.A.Y.); (M.J.L.); (Y.S.K.)
| | - Chanchal Mandal
- Department of Anatomy, Korea University College of Medicine, Seoul 02841, Korea; (C.M.); (A.Y.C.); (D.W.Y.); (I.J.R.)
| | - Jung Yeon Ghee
- Department of Nephrology, Korea University Ansan Hospital, Ansan 15355, Korea; (J.J.C.); (J.Y.G.); (J.A.Y.); (M.J.L.); (Y.S.K.)
| | - Ji Ae Yoo
- Department of Nephrology, Korea University Ansan Hospital, Ansan 15355, Korea; (J.J.C.); (J.Y.G.); (J.A.Y.); (M.J.L.); (Y.S.K.)
| | - Mi Jin Lee
- Department of Nephrology, Korea University Ansan Hospital, Ansan 15355, Korea; (J.J.C.); (J.Y.G.); (J.A.Y.); (M.J.L.); (Y.S.K.)
| | - Young Sun Kang
- Department of Nephrology, Korea University Ansan Hospital, Ansan 15355, Korea; (J.J.C.); (J.Y.G.); (J.A.Y.); (M.J.L.); (Y.S.K.)
| | - Young Youl Hyun
- Department of Nephrology, Kangbuk Samsung Hospital, Sungkyunkwan University, Seoul 03181, Korea;
| | - Ji Eun Lee
- Department of Nephrology, Wonkwang University Sanbon Hospital, Gunpo 15865, Korea; (J.E.L.); (H.W.K.)
| | - Hyun Wook Kim
- Department of Nephrology, Wonkwang University Sanbon Hospital, Gunpo 15865, Korea; (J.E.L.); (H.W.K.)
| | - Sang Youb Han
- Department of Nephrology, Inje University Ilsan Paik Hospital, Ilsan 10380, Korea;
| | - Jee Young Han
- Department of Pathology, Inha University Hospital, Incheon 22332, Korea;
| | - Ah Young Chung
- Department of Anatomy, Korea University College of Medicine, Seoul 02841, Korea; (C.M.); (A.Y.C.); (D.W.Y.); (I.J.R.)
| | - Dae Wui Yoon
- Department of Anatomy, Korea University College of Medicine, Seoul 02841, Korea; (C.M.); (A.Y.C.); (D.W.Y.); (I.J.R.)
| | - Im Joo Rhyu
- Department of Anatomy, Korea University College of Medicine, Seoul 02841, Korea; (C.M.); (A.Y.C.); (D.W.Y.); (I.J.R.)
| | - Junseo Oh
- Department of Anatomy, Korea University College of Medicine, Seoul 02841, Korea; (C.M.); (A.Y.C.); (D.W.Y.); (I.J.R.)
- Correspondence: (J.O.); (D.R.C.); Tel.: +82-2-2286-1389 (J.O.); +82-31-412-5572 (D.R.C.)
| | - Dae Ryong Cha
- Department of Nephrology, Korea University Ansan Hospital, Ansan 15355, Korea; (J.J.C.); (J.Y.G.); (J.A.Y.); (M.J.L.); (Y.S.K.)
- Correspondence: (J.O.); (D.R.C.); Tel.: +82-2-2286-1389 (J.O.); +82-31-412-5572 (D.R.C.)
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Zanchi A, Reidy J, Feldman HJ, Qualter J, Gouw AS, Osbeck J, Kofman A, Balabaud C, Bioulac-Sage P, Tiniakos DG, Theise ND. Innervation of the proximal human biliary tree. Virchows Arch 2020; 477:385-392. [DOI: 10.1007/s00428-020-02761-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 01/06/2020] [Accepted: 01/21/2020] [Indexed: 01/03/2023]
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Yokoyama H, Masaki T, Inoue I, Nakamura M, Mezaki Y, Saeki C, Oikawa T, Saruta M, Takahashi H, Ikegami M, Hano H, Ikejima K, Kojima S, Matsuura T. Histological and biochemical evaluation of transforming growth factor-β activation and its clinical significance in patients with chronic liver disease. Heliyon 2019; 5:e01231. [PMID: 30815603 PMCID: PMC6378908 DOI: 10.1016/j.heliyon.2019.e01231] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 01/26/2019] [Accepted: 02/11/2019] [Indexed: 12/14/2022] Open
Abstract
Transforming growth factor-β (TGF-β) is a key driver for liver fibrogenesis. TGF-β must be activated in order to function. Plasma kallikrein (PLK) is a TGF-β activator that cleaves the latency-associated protein (LAP) between arginine58 and lysine59 residues and releases active TGF-β from the latent TGF-β-LAP complex. Thus, the generation of two LAP degradation products, ending at arginine58 (R58/LAP-DPs) and beginning from lysine59 (L59/LAP-DPs), reflects PLK-dependent TGF-β activation. However, the significance and details of TGF-β activation in patients with chronic liver disease (CLD) remain uncertain. We herein examined the PLK-dependent TGF-β activation in patients by detecting R58 and L59/LAP-DPs. A total of 234 patients with CLD were included in this study. Liver biopsy specimens were used for immunostaining to detect R58/LAP-DPs, while plasma samples were subjected to an enzyme-linked immunosorbent assay to measure the L59/LAP-DP concentration. R58/LAP-DP was robustly expressed in and around the sinusoidal cells before the development of the fibrous regions. The R58/LAP-DP expression at fibrosis stage 1 was higher than at any other stages, and the relationship between the plasma L59/LAP-DP level and the stage of fibrosis also showed a similar trend. The abundance of plasma L59/LAP-DP showed no correlation with the levels of direct serum biomarkers of liver fibrosis; however, its changes during interferon-based therapy for chronic hepatitis C were significantly associated with virological responses. Our results suggest that PLK-dependent TGF-β activation occurs in the early stages of fibrosis and that its unique surrogate markers, R58 and L59/LAP-DPs, are useful for monitoring the clinical course of CLD.
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Affiliation(s)
- Hiroshi Yokoyama
- Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Takahiro Masaki
- Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Ikuyo Inoue
- Liver Cancer Prevention Research Unit, RIKEN Center for Integrative Medical Sciences, Saitama, Japan
| | - Mariko Nakamura
- Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Yoshihiro Mezaki
- Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Chisato Saeki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Tsunekazu Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Hiroyuki Takahashi
- Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan
| | - Masahiro Ikegami
- Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan
| | - Hiroshi Hano
- Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan
| | - Kenichi Ikejima
- Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Soichi Kojima
- Liver Cancer Prevention Research Unit, RIKEN Center for Integrative Medical Sciences, Saitama, Japan
| | - Tomokazu Matsuura
- Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan
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10
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Melis M, Tang XH, Trasino SE, Patel VM, Stummer DJ, Jessurun J, Gudas LJ. Effects of AM80 compared to AC261066 in a high fat diet mouse model of liver disease. PLoS One 2019; 14:e0211071. [PMID: 30677086 PMCID: PMC6345457 DOI: 10.1371/journal.pone.0211071] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 01/07/2019] [Indexed: 12/13/2022] Open
Abstract
The roles of retinoids in nonalcoholic fatty liver disease (NAFLD) remain unclear and a better understanding may lead to therapies that prevent or limit NAFLD progression. We examined the actions of retinoic acid receptor (RAR) agonists- AM80 for RARα and AC261066 for RARβ2- in a murine model of NAFLD. We fed wild type C57Bl/6 mice a chow or a 45% high fat diet (HFD) for 12 weeks, followed by 4 additional weeks with the HFD+AM80; HFD+AC261066; or HFD. The HFD+AM80 group showed greater hyperglycemia and glucose intolerance compared to other groups. Histopathological evaluation of the livers showed the highest degree of steatosis, triglycerides levels, and inflammation, assessed by F4/80 staining, in the HFD+AM80-treated compared to the HFD, the HFD+AC261066, and chow-fed mice. Liver vitamin A (retinol (ROL)) and retinyl palmitate levels were markedly lower in all HFD groups compared to chow-fed controls. HFD+AC261066-treated mice showed higher levels of a key intracellular ROL transporter, retinol-binding protein-1 (RBP1) compared to the HFD and HFD+AM80 groups. In conclusion, these data demonstrate that the selective RARα agonist AM80 exacerbates HFD-induced NAFLD and hyperglycemia. These findings should inform future studies examining the therapeutic potential of RAR agonists in HFD-related disorders.
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Affiliation(s)
- Marta Melis
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, United States of America
| | - Xiao-Han Tang
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, United States of America
| | - Steven E Trasino
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, United States of America
- School of Urban Public Health, Hunter College, City University of New York, New York, NY, United States of America
| | - Viral M Patel
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, United States of America
| | - Daniel J Stummer
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, United States of America
| | - Jose Jessurun
- Department of Pathology, Weill Cornell Medicine, New York, NY, United States of America
| | - Lorraine J Gudas
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, United States of America
- Weill Cornell Graduate School of Biomedical Sciences, New York, NY, United States of America
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function, and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:1-87. [DOI: 10.1016/b978-0-7020-6697-9.00001-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Nielsen MFB, Mortensen MB, Detlefsen S. Identification of markers for quiescent pancreatic stellate cells in the normal human pancreas. Histochem Cell Biol 2017; 148:359-380. [PMID: 28540429 DOI: 10.1007/s00418-017-1581-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/13/2017] [Indexed: 12/16/2022]
Abstract
Pancreatic stellate cells (PSCs) play a central role as source of fibrogenic cells in pancreatic cancer and chronic pancreatitis. In contrast to quiescent hepatic stellate cells (qHSCs), a specific marker for quiescent PSCs (qPSCs) that can be used in formalin-fixed and paraffin embedded (FFPE) normal human pancreatic tissue has not been identified. The aim of this study was to identify a marker enabling the identification of qPSCs in normal human FFPE pancreatic tissue. Immunohistochemical (IHC), double-IHC, immunofluorescence (IF) and double-IF analyses were carried out using a tissue microarray consisting of cores with normal human pancreatic tissue. Cores with normal human liver served as control. Antibodies directed against adipophilin, α-SMA, CD146, CRBP-1, cytoglobin, desmin, GFAP, nestin, S100A4 and vinculin were examined, with special emphasis on their expression in periacinar cells in the normal human pancreas and perisinusoidal cells in the normal human liver. The immunolabelling capacity was evaluated according to a semiquantitative scoring system. Double-IF of the markers of interest together with markers for other periacinar cells was performed. Moreover, the utility of histochemical stains for the identification of human qPSCs was examined, and their ultrastructure was revisited by electron microscopy. Adipophilin, CRBP-1, cytoglobin and vinculin were expressed in qHSCs in the liver, whereas cytoglobin and adipophilin were expressed in qPSCs in the pancreas. Adipophilin immunohistochemistry was highly dependent on the preanalytical time interval (PATI) from removal of the tissue to formalin fixation. Cytoglobin, S100A4 and vinculin were expressed in periacinar fibroblasts (FBs). The other examined markers were negative in human qPSCs. Our data indicate that cytoglobin and adipophilin are markers of qPSCs in the normal human pancreas. However, the use of adipophilin as a qPSC marker may be limited due to its high dependence on optimal PATI. Cytoglobin, on the other hand, is a sensitive marker for qPSCs but is expressed in FBs as well.
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Affiliation(s)
- Michael Friberg Bruun Nielsen
- Department of Pathology, Odense University Hospital, J.B. Winsløws Vej 15, 5000, Odense C, Denmark.,Department of Clinical Research, University of Southern Denmark, J.B. Winsløws Vej 19, 5000, Odense C, Denmark
| | - Michael Bau Mortensen
- Department of Clinical Research, University of Southern Denmark, J.B. Winsløws Vej 19, 5000, Odense C, Denmark.,Department of Surgery, HPB Section, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark
| | - Sönke Detlefsen
- Department of Pathology, Odense University Hospital, J.B. Winsløws Vej 15, 5000, Odense C, Denmark. .,Department of Clinical Research, University of Southern Denmark, J.B. Winsløws Vej 19, 5000, Odense C, Denmark.
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Carotti S, Perrone G, Amato M, Vespasiani Gentilucci U, Righi D, Francesconi M, Pellegrini C, Zalfa F, Zingariello M, Picardi A, Onetti Muda A, Morini S. Reelin expression in human liver of patients with chronic hepatitis C infection. Eur J Histochem 2017; 61:2745. [PMID: 28348420 PMCID: PMC5365015 DOI: 10.4081/ejh.2017.2745] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 01/31/2017] [Accepted: 02/01/2017] [Indexed: 02/08/2023] Open
Abstract
Reelin is a secreted extracellular glycoprotein that plays a critical role during brain development. Several studies have described Reelin expression in hepatic stellate cells of the human liver. In order to investigate the possible role of Reelin in the process of hepatic fibrogenesis, in this study we investigated Reelin expression in the liver tissue of patients infected with the Hepatitis C Virus (HCV). On this basis, Reelin expression was analysed by immunohistochemistry during liver biopsies of 81 patients with HCV-related chronic hepatitis. A Knodell score was used to stage liver fibrosis. Hepatic stellate cells/myofibroblast immunohistochemical markers (CRBP-1, alpha-SMA) were also evaluated. As further confirmed by co-localization experiments (Reelin +CRBP-1), Reelin protein was expressed by hepatic stellate cells/myofibroblasts, and a significant positive correlation was found between Reelin expression and the stage of liver fibrosis (P=0.002). Moreover, Reelin correlated with CRBP-1 positive cells (P=0.002), but not with alpha-SMA, suggesting that Reelin should not be regarded as a marker of hepatic stellate cells/myofibroblasts differentiation but rather as a functional protein expressed during some phases of liver fibrosis. Furthermore, Disabled-1 (Dab1), a Reelin adaptor protein, was expressed in cells of ductular reaction suggesting a paracrine role for Reelin with regards these elements. In conclusion, Reelin was expressed by human hepatic stellate cells/myofibroblasts and the number of these cells increased significantly in the lobule as the liver fibrosis progressed, suggesting a role for Reelin in the activation of hepatic stellate cells/myofibroblasts during liver injury. Reelin may potentially be incorporated into liver injury evaluations in combination with other histological data.
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Affiliation(s)
- Simone Carotti
- Campus Bio-Medico University, Laboratory of Microscopic and Ultrastructural Anatomy.
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The stellate cell system (vitamin A-storing cell system). Anat Sci Int 2017; 92:387-455. [PMID: 28299597 DOI: 10.1007/s12565-017-0395-9] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 02/15/2017] [Indexed: 01/18/2023]
Abstract
Past, present, and future research into hepatic stellate cells (HSCs, also called vitamin A-storing cells, lipocytes, interstitial cells, fat-storing cells, or Ito cells) are summarized and discussed in this review. Kupffer discovered black-stained cells in the liver using the gold chloride method and named them stellate cells (Sternzellen in German) in 1876. Wake rediscovered the cells in 1971 using the same gold chloride method and various modern histological techniques including electron microscopy. Between their discovery and rediscovery, HSCs disappeared from the research history. Their identification, the establishment of cell isolation and culture methods, and the development of cellular and molecular biological techniques promoted HSC research after their rediscovery. In mammals, HSCs exist in the space between liver parenchymal cells (PCs) or hepatocytes and liver sinusoidal endothelial cells (LSECs) of the hepatic lobule, and store 50-80% of all vitamin A in the body as retinyl ester in lipid droplets in the cytoplasm. SCs also exist in extrahepatic organs such as pancreas, lung, and kidney. Hepatic (HSCs) and extrahepatic stellate cells (EHSCs) form the stellate cell (SC) system or SC family; the main storage site of vitamin A in the body is HSCs in the liver. In pathological conditions such as liver fibrosis, HSCs lose vitamin A, and synthesize a large amount of extracellular matrix (ECM) components including collagen, proteoglycan, glycosaminoglycan, and adhesive glycoproteins. The morphology of these cells also changes from the star-shaped HSCs to that of fibroblasts or myofibroblasts.
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15
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Chang ML, Liang KH, Ku CL, Lo CC, Cheng YT, Hsu CM, Yeh CT, Chiu CT. Resistin reinforces interferon λ-3 to eliminate hepatitis C virus with fine-tuning from RETN single-nucleotide polymorphisms. Sci Rep 2016; 6:30799. [PMID: 27477870 PMCID: PMC4967850 DOI: 10.1038/srep30799] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 07/11/2016] [Indexed: 12/16/2022] Open
Abstract
The effect of resistin (RETN) on the response to anti-HCV therapy remains unclear. A prospective cohort study was performed using 655 consecutive HCV patients, of whom 513 had completed a course of interferon-based therapy. Multivariate and GEE analyses revealed four RETN single-nucleotide polymorphisms (SNPs), rs34861192, rs3219175, rs3745367 and rs1423096, to be synergistically associated with resistin levels. After adjusting for co-factors such as interferon λ-3 (IFNL3)-rs12979860, the resistin level and the hyper-resistinemic genotype at the 4 RETN SNPs were positively and negatively associated with a sustained virological response (SVR), respectively. RETN-rs3745367 was in linkage disequilibrium with IFNL3-rs12979860. Compared to non-SVR patients, SVR patients had higher levels of pre-therapy resistin, primarily originating from intrahepatic lymphocytes, stellate cells, Kupffer cells, hepatic progenitor cells and hepatocytes. This difference diminished over the course of therapy, as only SVR patients exhibited a 24-week post-therapy decrease in resistin. Both resistin and IFNL3 mRNAs were upregulated, but only resistin mRNA was upregulated by recombinant resistin in peripheral blood mononuclear cells with and without hyper-resistinemic genotypes of the 4 RETN SNPs, respectively. Fine-tuned by RETN SNPs, intrahepatic, multi-cellular resistin reinforced IFNL3 in eliminating HCV via immunomodulation to counteract pro-inflammation. These results encourage the development of novel resistin-targeted anti-viral agents.
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Affiliation(s)
- Ming-Ling Chang
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Kung-Hao Liang
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Cheng-Lung Ku
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Chia-Chi Lo
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Ya-Ting Cheng
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chen-Ming Hsu
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Cheng-Tang Chiu
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
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Boutin SR, Rogers AB, Shen Z, Fry RC, Love JA, Nambiar PR, Suerbaum S, Fox JG. Hepatic Temporal Gene Expression Profiling in Helicobacter hepaticus-Infected A/JCr Mice. Toxicol Pathol 2016; 32:678-93. [PMID: 15513911 DOI: 10.1080/01926230490524058] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Helicobacter hepaticus infection of A/JCr mice is a model of infectious liver cancer. We monitored hepatic global gene expression profiles in H. hepaticus infected and control male A/JCr mice at 3 months, 6 months, and 1 year of age using an Affymetrix-based oligonucleotide microarray platform on the premise that a specific genetic expression signature at isolated time points would be indicative of disease status. Model based expression index comparisons generated by dChip yielded consistent profiles of differential gene expression for H. hepaticus infected male mice with progressive liver disease versus uninfected control mice within each age group. Linear discriminant analysis and principal component analysis allowed segregation of mice based on combined age and lesion status, or age alone. Up-regulation of putative tumor markers correlated with advancing hepatocellular dysplasia. Transcriptionally down-regulated genes in mice with liver lesions included those related to peroxisome proliferator, fatty acid, and steroid metabolism pathways. In conclusion, transcriptional profiling of hepatic genes documented gene expression signatures in the livers of H. hepaticus infected male A/JCr mice with chronic progressive hepatitis and preneoplastic liver lesions, complemented the histopathological diagnosis, and suggested molecular targets for the monitoring and intervention of disease progression prior to the onset of hepatocellular neoplasia.
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Affiliation(s)
- Samuel R Boutin
- Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
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17
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Loo CKC, Pereira TN, Pozniak KN, Ramsing M, Vogel I, Ramm GA. The development of hepatic stellate cells in normal and abnormal human fetuses - an immunohistochemical study. Physiol Rep 2015; 3:3/8/e12504. [PMID: 26265759 PMCID: PMC4562587 DOI: 10.14814/phy2.12504] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The precise embryological origin and development of hepatic stellate cells is not established. Animal studies and observations on human fetuses suggest that they derive from posterior mesodermal cells that migrate via the septum transversum and developing diaphragm to form submesothelial cells beneath the liver capsule, which give rise to mesenchymal cells including hepatic stellate cells. However, it is unclear if these are similar to hepatic stellate cells in adults or if this is the only source of stellate cells. We have studied hepatic stellate cells by immunohistochemistry, in developing human liver from autopsies of fetuses with and without malformations and growth restriction, using cellular Retinol Binding Protein-1 (cRBP-1), Glial Fibrillary Acidic Protein (GFAP), and α-Smooth Muscle Actin (αSMA) antibodies, to identify factors that influence their development. We found that hepatic stellate cells expressing cRBP-1 are present from the end of the first trimester of gestation and reduce in density throughout gestation. They appear abnormally formed and variably reduced in number in fetuses with abnormal mesothelial Wilms Tumor 1 (WT1) function, diaphragmatic hernia and in ectopic liver nodules without mesothelium. Stellate cells showed similarities to intravascular cells and their presence in a fetus with diaphragm agenesis suggests they may be derived from circulating stem cells. Our observations suggest circulating stem cells as well as mesothelium can give rise to hepatic stellate cells, and that they require normal mesothelial function for their development.
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Affiliation(s)
- Christine K C Loo
- Department of Anatomical Pathology, Prince of Wales Hospital, Randwick Sydney, NSW, Australia Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia Discipline of Pathology, School of Medicine, University of Western Sydney, Sydney, NSW, Australia
| | - Tamara N Pereira
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Katarzyna N Pozniak
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Mette Ramsing
- Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
| | - Ida Vogel
- Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
| | - Grant A Ramm
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
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Lepreux S, Desmoulière A. Human liver myofibroblasts during development and diseases with a focus on portal (myo)fibroblasts. Front Physiol 2015; 6:173. [PMID: 26157391 PMCID: PMC4477071 DOI: 10.3389/fphys.2015.00173] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 05/21/2015] [Indexed: 12/11/2022] Open
Abstract
Myofibroblasts are stromal cells mainly involved in tissue repair. These cells present contractile properties and play a major role in extracellular matrix deposition and remodeling. In liver, myofibroblasts are found in two critical situations. First, during fetal liver development, especially in portal tracts, myofibroblasts surround vessels and bile ducts during their maturation. After complete development of the liver, myofibroblasts disappear and are replaced in portal tracts by portal fibroblasts. Second, during liver injury, myofibroblasts re-appear principally deriving from the activation of local stromal cells such as portal fibroblasts and hepatic stellate cells or can sometimes emerge by an epithelial-mesenchymal transition process. After acute injury, myofibroblasts play also a major role during liver regeneration. While myofibroblastic precursor cells are well known, the spectrum of activation and the fate of myofibroblasts during disease evolution are not fully understood. Some data are in accordance with a possible deactivation, at least partial, or a disappearance by apoptosis. Despite these shadows, liver is definitively a pertinent model showing that myofibroblasts are pivotal cells for extracellular matrix control during morphogenesis, repair and fibrous scarring.
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Affiliation(s)
- Sébastien Lepreux
- Department of Pathology, University Hospital of Bordeaux Bordeaux, France
| | - Alexis Desmoulière
- Department of Physiology, Faculty of Pharmacy, University of Limoges Limoges, France
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Regulator of G-protein signaling-5 is a marker of hepatic stellate cells and expression mediates response to liver injury. PLoS One 2014; 9:e108505. [PMID: 25290689 PMCID: PMC4188519 DOI: 10.1371/journal.pone.0108505] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Accepted: 08/22/2014] [Indexed: 12/11/2022] Open
Abstract
Liver fibrosis is mediated by hepatic stellate cells (HSCs), which respond to a variety of cytokine and growth factors to moderate the response to injury and create extracellular matrix at the site of injury. G-protein coupled receptor (GPCR)-mediated signaling, via endothelin-1 (ET-1) and angiotensin II (AngII), increases HSC contraction, migration and fibrogenesis. Regulator of G-protein signaling-5 (RGS5), an inhibitor of vasoactive GPCR agonists, functions to control GPCR-mediated contraction and hypertrophy in pericytes and smooth muscle cells (SMCs). Therefore we hypothesized that RGS5 controls GPCR signaling in activated HSCs in the context of liver injury. In this study, we localize RGS5 to the HSCs and demonstrate that Rgs5 expression is regulated during carbon tetrachloride (CCl4)-induced acute and chronic liver injury in Rgs5LacZ/LacZ reporter mice. Furthermore, CCl4 treated RGS5-null mice develop increased hepatocyte damage and fibrosis in response to CCl4 and have increased expression of markers of HSC activation. Knockdown of Rgs5 enhances ET-1-mediated signaling in HSCs in vitro. Taken together, we demonstrate that RGS5 is a critical regulator of GPCR signaling in HSCs and regulates HSC activation and fibrogenesis in liver injury.
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Nagatsuma K, Hano H, Murakami K, Shindo D, Matsumoto Y, Mitobe J, Tanaka K, Saito M, Maehashi H, Owada M, Ikegami M, Tsubota A, Ohkusa T, Aizawa Y, Takagi I, Tajiri H, Matsuura T. Hepatic stellate cells that coexpress LRAT and CRBP-1 partially contribute to portal fibrogenesis in patients with human viral hepatitis. Liver Int 2014; 34:243-252. [PMID: 23890161 DOI: 10.1111/liv.12255] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Accepted: 06/12/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Precisely what type of cells mainly contributes to portal fibrosis, especially in chronic viral hepatitis, such as hepatic stellate cells (HSCs) in the parenchyma or myofibroblasts in the portal area, still remains unclear. It is necessary to clarify the characteristics of cells that contribute to portal fibrosis in order to determine the mechanism of portal fibrogenesis and to develop a therapeutic target for portal fibrosis. This study was undertaken to examine whether LRAT+/CRBP-1+ HSCs contribute to portal fibrosis on viral hepatitis. METHODS Antibodies to lecithin:retinol acyltransferase (LRAT), cellular retinol-binding protein-1 (CRBP-1) and widely ascertained antibodies to HSCs (alpha-smooth muscle actin, neurotrophin-3) and endothelial cells (CD31) were used for immunohistochemical studies to assess the distribution of cells that contribute to the development of portal fibrosis with the aid of fluorescence microscopy. A quantitative analysis of LRAT+/CRBP-1+ HSCs was performed. RESULTS The number of LRAT+/CRBP-1+ HSCs was increased in fibrotic liver in comparison with normal liver in the portal area and fibrous septa. The number of double positive cells was less than 20% of all cells/field in maximum. CONCLUSION This study provides evidence that functional HSCs coexpressing both LRAT and CRBP-1 that continue to maintain the ability to store vitamin A contribute in part to the development of portal fibrogenesis in addition to parenchymal fibrogenesis in patients with viral hepatitis.
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Affiliation(s)
- Keisuke Nagatsuma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan; Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan
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Lepreux S, Guyot C, Billet F, Combe C, Balabaud C, Bioulac-Sage P, Desmoulière A. Smoothelin, a new marker to determine the origin of liver fibrogenic cells. World J Gastroenterol 2013; 19:9343-9350. [PMID: 24409061 PMCID: PMC3882407 DOI: 10.3748/wjg.v19.i48.9343] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Revised: 06/18/2013] [Accepted: 07/05/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore this hypothesis that smooth muscle cells may be capable of acquiring a myofibroblastic phenotype, we have studied the expression of smoothelin in fibrotic conditions.
METHODS: Normal liver tissue (n = 3) was obtained from macroscopically normal parts of hepatectomy, taken at a distance from hemangiomas. Pathological specimens included post-burn cutaneous hypertrophic scars (n = 3), fibrotic liver tissue (n = 5), cirrhotic tissue (viral and alcoholic hepatitis) (n = 5), and hepatocellular carcinomas (n = 5). Tissue samples were fixed in 10% formalin and embedded in paraffin for immunohistochemistry or were immediately frozen in liquid nitrogen-cooled isopentane for confocal microscopy analysis. Sections were stained with antibodies against smoothelin, which is expressed exclusively by smooth muscle cells, and α-smooth muscle actin, which is expressed by both smooth muscle cells and myofibroblasts.
RESULTS: In hypertrophic scars, α-smooth muscle actin was detected in vascular smooth muscle cells and in numerous myofibroblasts present in and around nodules, whereas smoothelin was exclusively expressed in vascular smooth muscle cells. In the normal liver, vascular smooth muscle cells were the only cells that express α-smooth muscle actin and smoothelin. In fibrotic areas of the liver, myofibroblasts expressing α-smooth muscle actin were detected. Myofibroblasts co-expressing α-smooth muscle actin and smoothelin were observed, and their number was slightly increased in parallel with the degree of fibrosis (absent in liver with mild or moderate fibrosis; 5% to 10% positive in liver showing severe fibrosis). In cirrhotic septa, numerous myofibroblasts co-expressed α-smooth muscle actin and smoothelin (more than 50%). In hepatocellular carcinomas, the same pattern of expression for α-smooth muscle actin and smoothelin was observed in the stroma reaction surrounding the tumor and around tumoral cell plates. In all pathological liver samples, α-smooth muscle actin and smoothelin were co-expressed in vascular smooth muscle cells.
CONCLUSION: During development of advanced liver fibrosis, a subpopulation of myofibroblasts expressing smoothelin may be derived from vascular smooth muscle cells, illustrating the different cellular origins of myofibroblasts.
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Lemoinne S, Cadoret A, El Mourabit H, Thabut D, Housset C. Origins and functions of liver myofibroblasts. Biochim Biophys Acta Mol Basis Dis 2013; 1832:948-54. [PMID: 23470555 DOI: 10.1016/j.bbadis.2013.02.019] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Revised: 02/22/2013] [Accepted: 02/23/2013] [Indexed: 02/06/2023]
Abstract
Myofibroblasts combine the matrix-producing functions of fibroblasts and the contractile properties of smooth muscle cells. They are the main effectors of fibrosis in all tissues and make a major contribution to other aspects of the wound healing response, including regeneration and angiogenesis. They display the de novo expression of α-smooth muscle actin. Myofibroblasts, which are absent from the normal liver, are derived from two major sources: hepatic stellate cells (HSCs) and portal mesenchymal cells in the injured liver. Reliable markers for distinguishing between the two subpopulations at the myofibroblast stage are currently lacking, but there is evidence to suggest that both myofibroblast cell types, each exposed to a particular microenvironment (e.g. hypoxia for HSC-MFs, ductular reaction for portal mesenchymal cell-derived myofibroblasts (PMFs)), expand and exert specialist functions, in scarring and inflammation for PMFs, and in vasoregulation and hepatocellular healing for HSC-MFs. Angiogenesis is a major mechanism by which myofibroblasts contribute to the progression of fibrosis in liver disease. It has been clearly demonstrated that liver fibrosis can regress, and this process involves a deactivation of myofibroblasts, although probably not to a fully quiescent phenotype. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.
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Affiliation(s)
- Sara Lemoinne
- UPMC Univ Paris 06, UMR_S 938, Paris, France; INSERM, U938, CdR Saint-Antoine, Paris, France
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Penz-Österreicher M, Österreicher CH, Trauner M. Fibrosis in autoimmune and cholestatic liver disease. Best Pract Res Clin Gastroenterol 2011; 25:245-58. [PMID: 21497742 PMCID: PMC3134112 DOI: 10.1016/j.bpg.2011.02.001] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2011] [Accepted: 02/18/2011] [Indexed: 01/31/2023]
Abstract
Autoimmune and cholestatic liver disease account for a significant part of end-stage liver disease and are leading indications for liver transplantation. Especially cholestatic liver diseases (primary biliary cirrhosis and primary sclerosing cholangitis) appear to be different from other chronic liver diseases with regards to pathogenesis. Portal fibroblasts located in the connective tissue surrounding bile ducts appear to be different from hepatic stellate cells with regards to expression of marker proteins and response the profibrogenic and mitogenic stimuli. In addition there is increasing evidence for a cross talk between activated cholangiocytes and portal myofibroblasts. Several animal models have improved our understanding of the mechanisms underlying these chronic liver diseases. In the present review, we discuss the current concepts and ideas with regards to myofibroblastic cell populations, mechanisms of fibrosis, summarize characteristic histological findings and currently employed animal models of autoimmune and cholestatic liver disease.
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Affiliation(s)
- Melitta Penz-Österreicher
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
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Sarrazy V, Desmoulière A. Double immunohistochemistry with horseradish peroxidase and alkaline phosphatase detection systems. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2009; 611:59-71. [PMID: 19960322 DOI: 10.1007/978-1-60327-345-9_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
We describe here a protocol optimized for formalin-fixed paraffin-embedded tissue sections that enables the detection of two antigens. This technique allows immunohistochemistry to be performed with detection systems allowing observation by light microscopy. This chapter discusses the choice of appropriate protocols as well as the choice of visualization systems.In doing so, we provide examples of representative results obtained with this protocol and describe necessary controls; additionally, we discuss common problems associated with this methodology, and detail troubleshooting recommendations. Although this method has been optimized for liver sections, it may be applicable for performing double immunostaining in a variety of tissue samples.
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Affiliation(s)
- Vincent Sarrazy
- Faculté deMédecine et de Pharmacie, EA 3842, Institut Fédératif de Recherche 145, Université de Limoges, Limoges, France
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Morris TJ, Vickers M, Gluckman P, Gilmour S, Affara N. Transcriptional profiling of rats subjected to gestational undernourishment: implications for the developmental variations in metabolic traits. PLoS One 2009; 4:e7271. [PMID: 19787071 PMCID: PMC2749934 DOI: 10.1371/journal.pone.0007271] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2009] [Accepted: 08/05/2009] [Indexed: 12/14/2022] Open
Abstract
A link has been established between prenatal nutrition and the development of metabolic and cardiovascular diseases later in life, a process referred to as developmental programming. It has been suggested that the trajectory of development is shifted by alterations in the maternal nutritional state leading to changes in developmental plasticity, in part underpinned by epigenetic changes in gene regulation. However, to date, only candidate gene approaches have been used to assess expression and molecular changes in the offspring of maternally undernourished animals. Furthermore, most work has focused on animals at an age where the programmed phenotype is already manifest and little is known about changes in gene expression in the offspring prior to development of obesity and related metabolic disorders. Gene expression profiles of liver, retroperitoneal white adipose fat, and biceps femoris skeletal muscle tissue from young adult male rats (55 days old) in which nutritional status had been manipulated in utero by maternal undernutrition (UN) were compared to the profiles of offspring of ad libitum fed mothers serving as the control group (AD) (8 offspring/group). The expression profiles were determined using the Illumina RatRef-12 BeadChip. No significant changes in expression were identified for skeletal muscle or white adipose tissue. However, studies of liver tissue showed 249 differentially expressed genes (143 up regulated, 106 down regulated). Although the animals at day 55 have yet to develop obesity they already show biochemical abnormalities and by day 110 express a phenotype characterized by increased adiposity and altered insulin sensitivity. An analysis of pathways affected suggests that intrauterine programming of UN animals to favor fat as an energy source results in mitochondrial dysfunction which initially affects the postnatal hepatic function and subsequently, via the resultant metabolic changes in other organs leads to the evolution of a phenotype similar to that of the metabolic syndrome.
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Affiliation(s)
- Tiffany J Morris
- Department of Pathology, University of Cambridge, Cambridge, England.
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Villeneuve J, Pelluard-Nehme F, Combe C, Carles D, Chaponnier C, Ripoche J, Balabaud C, Bioulac-Sage P, Lepreux S. Immunohistochemical study of the phenotypic change of the mesenchymal cells during portal tract maturation in normal and fibrous (ductal plate malformation) fetal liver. COMPARATIVE HEPATOLOGY 2009; 8:5. [PMID: 19602240 PMCID: PMC2721154 DOI: 10.1186/1476-5926-8-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2009] [Accepted: 07/14/2009] [Indexed: 01/03/2023]
Abstract
Background In adult liver, the mesenchymal cells, portal fibroblasts and vascular smooth muscle cells can transdifferentiate into myofibroblasts, and are involved in portal fibrosis. Differential expression of markers, such as alpha-smooth muscle actin (ASMA), h-caldesmon and cellular retinol-binding protein-1 allows their phenotypic discrimination. The aim of our study was to explore the phenotypic evolution of the mesenchymal cells during fetal development in normal liver and in liver with portal fibrosis secondary to ductal plate malformation in a series of Meckel-Gruber syndrome, autosomal recessive polycystic kidney disease and Ivemark's syndrome. Results At the early steps of the portal tract maturation, portal mesenchymal cells expressed only ASMA. During the maturation process, these cells were found condensed around the biliary and vascular structures. At the end of maturation process, only cells around vessels expressed ASMA and cells of the artery tunica media also expressed h-caldesmon. In contrast, ASMA positive cells persisted around the abnormal biliary ducts in fibrous livers. Conclusion As in adult liver, there is a phenotypic heterogeneity of the mesenchymal cells during fetal liver development. During portal tract maturation, myofibroblastic cells disappear in normal development but persist in fibrosis following ductal plate malformation.
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Kohlstedt K, Gershome C, Trouvain C, Hofmann WK, Fichtlscherer S, Fleming I. Angiotensin-converting enzyme (ACE) inhibitors modulate cellular retinol-binding protein 1 and adiponectin expression in adipocytes via the ACE-dependent signaling cascade. Mol Pharmacol 2009; 75:685-92. [PMID: 19114589 DOI: 10.1124/mol.108.051631] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Inhibitors of the angiotensin-converting enzyme (ACE) decrease angiotensin II production and activate an intracellular signaling cascade that affects gene expression in endothelial cells. Because ACE inhibitors have been reported to delay the onset of type 2 diabetes, we determined ACE signaling-modulated gene expression in endothelial cells and adipocytes. Using differential gene expression analysis, several genes were identified that were 3-fold up- or down-regulated by ramiprilat in cells expressing wild-type ACE versus cells expressing a signaling-dead ACE mutant. One up-regulated gene was the cellular retinol-binding protein 1 (CRBP1). In adipocytes, the overexpression of CRBP1 enhanced (4- to 5-fold) the activity of promoters containing response elements for retinol-dependent nuclear receptors [retinoic acid receptor (RAR) and retinoid X receptor (RXR)] or peroxisome proliferator-activated receptors (PPAR). CRBP1 overexpression also enhanced the promoter activity (by 470 +/- 40%) and expression/release of the anti-inflammatory and antiatherogenic adipokine adiponectin (cellular adiponectin by 196 +/- 24%, soluble adiponectin by 228 +/- 74%). Significantly increased adiponectin secretion was also observed after ACE inhibitor treatment of human preadipocytes, an effect prevented by small interfering RNA against CRBP1. Furthermore, in ob/ob mice, ramipril markedly potentiated both the basal (approximately 2-fold) and rosiglitazonestimulated circulating levels of adiponectin. In patients with coronary artery disease or type 2 diabetes, ACE inhibition also significantly increased plasma adiponectin levels (1.6- or 2.1-fold, respectively). In summary, ACE inhibitors affect adipocyte homeostasis via CRBP1 through the activation of RAR/RXR-PPAR signaling and up-regulation of adiponectin. The latter may contribute to the beneficial effects of ACE inhibitors on the development of type 2 diabetes in patients with an activated renin-angiotensin system.
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Affiliation(s)
- Karin Kohlstedt
- Institute for Vascular Signaling, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
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Nagatsuma K, Hayashi Y, Hano H, Sagara H, Murakami K, Saito M, Masaki T, Lu T, Tanaka M, Enzan H, Aizawa Y, Tajiri H, Matsuura T. Lecithin: retinol acyltransferase protein is distributed in both hepatic stellate cells and endothelial cells of normal rodent and human liver. Liver Int 2009; 29:47-54. [PMID: 18544127 DOI: 10.1111/j.1478-3231.2008.01773.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND To determine the extent to which hepatic stellate cell (HSC) activation contributes to liver fibrosis, it was found necessary to develop an alternative structural and functional stellate cell marker for in situ studies. Although several HSC markers have been reported, none of those are associated with particular HSC functions. AIM The present study was undertaken to examine whether lecithin:retinol acyltransferase (LRAT), the physiological retinol esterification enzyme of the liver, is a potential and relevant tissue marker for HSC. METHODS An antibody specific to mouse and human LRAT was prepared based on the amino acid sequences. Antibodies to LRAT were used for immunohistochemical studies to assess the distribution of LRAT-positive cells in the liver with the aid of fluorescence and immunogold electron microscopy. RESULTS LRAT-positive cells were found to be confined in the space of Disse, corresponding with the location of desmin-positive HSC in rodent liver, also in human liver. Interestingly, LRAT-positive staining was also observed along the liver sinusoidal endothelial lining. Furthermore, immune electron microscopic studies revealed that LRAT was mainly distributed in HSC within the rough-endoplasmic reticulum (RER) and multivesicular bodies, whereas LRAT staining within the endothelial cells was largely confined to the perinuclear area and to some extent to the RER. CONCLUSION Evidence has been accumulated that LRAT might serve as an excellent alternative HSC marker for future structural and functional studies. Furthermore, the presence of LRAT in endothelial cells might suggest a currently unknown function of this enzyme in liver endothelial biology.
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Affiliation(s)
- Keisuke Nagatsuma
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine, Tokyo, Japan
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Vinculin and cellular retinol-binding protein-1 are markers for quiescent and activated hepatic stellate cells in formalin-fixed paraffin embedded human liver. Histochem Cell Biol 2008; 131:313-25. [PMID: 19052772 DOI: 10.1007/s00418-008-0544-2] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/13/2008] [Indexed: 12/15/2022]
Abstract
Hepatic stellate cells (HSCs) have important roles in the pathogenesis of liver fibrosis and cirrhosis. As response to chronic injury HSCs are activated and change from quiescent into myofibroblast-like cells. Several HSC-specific markers have been described in rat or mouse models. The aim of our work was to identify the best marker(s) for human HSCs. To this end we used the automated high throughput NexES IHC staining device (Ventana Medical Systems) to incubate sections under standardized conditions. Formalin fixed paraffin embedded (FFPE) normal and diseased human livers were studied. With immunohistochemistry we examined the expression of synemin, desmin, vimentin, vinculin, neurotrophin-3 (NT-3), alpha-smooth muscle actin (alpha-SMA), cellular retinol-binding protein-1 (CRBP-1), glial fibrillary acidic protein (GFAP), cysteine- and glycine-rich protein 2 (CRP2), and cytoglobin/stellate cell activation-associated protein (cygb/STAP). This is the first study in which a series of HSC markers is compared on serial FFPE human tissues. CRBP-1 clearly stains lobular HSCs without reacting with smooth muscle cells (SMCs) and shows variable cholangiocyte positivity. Vinculin has a similar staining pattern as CRBP-1 but additionally stains SMCs, and (myo)fibroblasts. In conclusion, we therefore propose to use CRBP-1 and/or vinculin to stain HSCs in human liver tissues.
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Lepreux S, Doudnikoff E, Aubert I, Bioulac-Sage P, Bloch B, Martin-Negrier ML. Cytoplasmic expression of human telomerase catalytic protein (hTERT) in neutrophils: an immunoelectron microscopy study. Ultrastruct Pathol 2008; 32:178-83. [PMID: 18958789 DOI: 10.1080/01913120802034504] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Human telomerase comprises a catalytic protein subunit (hTERT) and an RNA subunit (hTR). Telomerase extends chromosome ends in compensation for the attrition of the telomeres during replication. In this work, the authors explore the expression of hTERT and hTR in neutrophils, respectively by immunochemistry techniques and in situ hybridization. hTERT was strongly expressed in neutrophils cytoplasm. The ultrastructural study showed that the gold particles were not associated with specific organelles but scattered in the cytosol. hTR was not expressed. hTERT is expressed in the cytoplasm of neutrophils, but its roles-eventually extratelomeric effects-remain to be elucidated.
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Affiliation(s)
- Sebastien Lepreux
- Laboratoire d'Histologie-Embryologie, UFR II, Universite Victor Segalen Bordeaux, France.
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Direct infection and replication of naturally occurring hepatitis C virus genotypes 1, 2, 3 and 4 in normal human hepatocyte cultures. PLoS One 2008; 3:e2660. [PMID: 18628977 PMCID: PMC2442186 DOI: 10.1371/journal.pone.0002660] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2008] [Accepted: 06/12/2008] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) infection afflicts about 170 million individuals worldwide. However, the HCV life cycle is only partially understood because it has not been possible to infect normal human hepatocytes in culture. The current Huh-7 systems use cloned, synthetic HCV RNA expressed in hepatocellular carcinoma cells to produce virions, but these cells cannot be infected with naturally occurring HCV obtained from infected patients. METHODOLOGY/PRINCIPAL FINDINGS Here, we describe a human hepatocyte culture permissible to the direct infection with naturally occurring HCV genotypes 1, 2, 3 and 4 in the blood of HCV-infected patients. The culture system mimics the biology and kinetics of HCV infection in humans, and produces infectious virions that can infect naïve human hepatocytes. CONCLUSIONS/SIGNIFICANCE This culture system should complement the existing systems, and may facilitate the understanding of the HCV life cycle, its effects in the natural host cell, the hepatocyte, as well as the development of novel therapeutics and vaccines.
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Van Beneden K, van Grunsven LA, Geers C, Pauwels M, Desmoulière A, Verbeelen D, Geerts A, Van den Branden C. CRBP-I in the renal tubulointerstitial compartment of healthy rats and rats with renal fibrosis. Nephrol Dial Transplant 2008; 23:3464-71. [PMID: 18503097 DOI: 10.1093/ndt/gfn290] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Cellular retinol-binding protein I (CRBP-I), a member of the intracellular lipid-binding protein (iLBP) superfamily, is a specific marker of quiescent stellate cells in the healthy human liver. In the diseased fibrotic/cirrhotic liver, portal and septal myofibroblasts acquire CRBP-I expression, while activated hepatic stellate cells maintain their CRBP-I expression. Here, we investigate the distribution of CRBP-I in the renal cortex of healthy rats and rats with renal fibrosis. METHODS Kidneys of healthy and adriamycin-treated rats were studied by immunohistochemistry, using antibodies against CRBP-I, desmin, vimentin and alpha-smooth muscle actin (alpha-SMA). Double stainings were done with immunofluorescence. Western blotting was performed to semi-quantify the expression levels of vimentin, desmin, alpha-SMA and CRBP-I. RESULTS In the normal rat kidney, the convoluted proximal tubular epithelial cells express CRBP-I; no expression is found in the interstitium, nor in the glomeruli. In the adriamycin-induced fibrotic rat kidney, CRBP-I expression diminishes in the convoluted proximal tubular epithelial cells, whereas peritubular myofibroblasts in the interstitium acquire CRBP-I expression. CONCLUSIONS In the tubulointerstitial compartment of the adriamycin-induced fibrotic rat kidney, CRBP-I is expressed in a different pattern than in the healthy rat kidney. As the convoluted proximal tubular epithelial cells dedifferentiate during fibrosis, CRBP-I expression decreases. Furthermore, de novo expression of CRBP-I is found in activated myofibroblast-like cells in the interstitium of adriamycin-treated rats. CRBP-I is therefore a useful marker to identify a subpopulation of activated/ myodifferentiated fibroblasts in the rat kidney.
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Affiliation(s)
- Katrien Van Beneden
- Vrije Universiteit Brussel, Menselijke Anatomie, Laarbeeklaan 103, B-1090 Brussels, Belgium.
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Tacke F, Gäbele E, Bataille F, Schwabe RF, Hellerbrand C, Klebl F, Straub RH, Luedde T, Manns MP, Trautwein C, Brenner DA, Schölmerich J, Schnabl B. Bone morphogenetic protein 7 is elevated in patients with chronic liver disease and exerts fibrogenic effects on human hepatic stellate cells. Dig Dis Sci 2007; 52:3404-15. [PMID: 17415633 DOI: 10.1007/s10620-007-9758-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2006] [Accepted: 01/01/2007] [Indexed: 12/09/2022]
Abstract
Hepatic stellate cells (HSCs) are the main extracellular matrix (ECM)-producing cells in liver fibrogenesis. The excessive synthesis of ECM proteins deteriorates hepatic architecture and results in liver fibrosis and cirrhosis. This study investigated the role of bone morphogenetic protein 7 (BMP7) as a member of the transforming growth factor (TGF)-beta superfamily in chronic liver disease. Plasma levels of BMP7 were significantly elevated in patients with chronic liver disease compared with healthy controls. Immunohistochemistry of cirrhotic human liver demonstrated upregulated BMP7 protein expression in hepatocytes as compared with normal human liver. Because gene expression for all putative BMP7 receptors was induced during the culture activation process of primary human HSCs, we studied the effects of BMP7 on hTERT immortalized human HSCs in vitro. BMP7, as expressed and secreted after infection with adenoviruses encoding BMP7 (AdBMP7), increased proliferation of HSCs. The mRNA and protein expression of type I collagen and fibronectin was increased in BMP7-stimulated HSCs. Elevated systemic and hepatic levels of BMP7 in patients with chronic liver disease may contribute to progression of liver fibrogenesis in vivo.
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Affiliation(s)
- Frank Tacke
- Medical Clinic III, University Hospital Aachen, Aachen, Germany
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Li Z, Dranoff JA, Chan EP, Uemura M, Sévigny J, Wells RG. Transforming growth factor-beta and substrate stiffness regulate portal fibroblast activation in culture. Hepatology 2007; 46:1246-56. [PMID: 17625791 DOI: 10.1002/hep.21792] [Citation(s) in RCA: 268] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
UNLABELLED Myofibroblasts derived from portal fibroblasts are important fibrogenic cells in the early stages of biliary fibrosis. In contrast to hepatic stellate cells, portal fibroblasts have not been well studied in vitro, and little is known about their myofibroblastic differentiation. In this article we report the isolation and characterization of rat portal fibroblasts in culture. We demonstrate that primary portal fibroblasts undergo differentiation to alpha-smooth muscle actin-expressing myofibroblasts over 10-14 days. Marker analysis comparing portal fibroblasts to hepatic stellate cells demonstrated that these are distinct populations and that staining with elastin and desmin can differentiate between them. Portal fibroblasts expressed elastin at all stages in culture but never expressed desmin, whereas hepatic stellate cells consistently expressed desmin but never elastin. Immunostaining of rat liver tissue confirmed these results in vivo. Characterization of portal fibroblast differentiation in culture demonstrated that these cells required transforming growth factor-beta (TGF-beta): cells remained quiescent in the presence of a TGF-beta receptor kinase inhibitor, whereas exogenous TGF-beta1 enhanced portal fibroblast alpha-smooth muscle actin expression and stress fiber formation. In contrast, platelet-derived growth factor inhibited myofibroblastic differentiation. Portal fibroblasts were also dependent on mechanical tension for myofibroblastic differentiation, and cells cultured on polyacrylamide supports of variable stiffness demonstrated an increasingly myofibroblastic phenotype as stiffness increased. CONCLUSION Portal fibroblasts are morphologically and functionally distinct from hepatic stellate cells. Portal fibroblast myofibroblastic differentiation can be modeled in culture and requires both TGF-beta and mechanical tension.
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Affiliation(s)
- Zhaodong Li
- Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Schmitt-Graeff A, Koeninger A, Olschewski M, Haxelmans S, Nitschke R, Bochaton-Piallat ML, Lifschitz-Mercer B, Gabbiani G, Langbein L, Czernobilsky B. The Ki67+ proliferation index correlates with increased cellular retinol-binding protein-1 and the coordinated loss of plakophilin-1 and desmoplakin during progression of cervical squamous lesions. Histopathology 2007; 51:87-97. [PMID: 17593084 DOI: 10.1111/j.1365-2559.2007.02724.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
AIMS To investigate the modulation of cellular retinol-binding protein (CRBP)-1 and the desmosomal plaque proteins plakophilin (PKP)-1 and desmoplakin (DP) in correlation with the Ki67+ proliferation index (PI) during the progression of cervical squamous intraepithelial lesions (SIL) to squamous cell carcinoma (SCC). METHODS Using in situ imaging by brightfield and confocal laser scanning microscopy, the expression of CRBP-1 protein and transcripts, PKP-1, DP and the Ki67 PI were analysed in 38 low-grade (L) SIL, 56 high-grade (H) SIL, 49 SCC, 30 control cervices and 10 human papillomavirus-positive condylomatous lesions. RESULTS CRBP-1+ cells increased from 11.4% in the normal cervix to 80.3% in LSILs, 92.3% in HSILs and slightly decreased to 78.3% in invasive SCCs (P = 0.0001) in close association with the Ki67 PI (r =0.41; P < 0.0001). PKP-1+ and DP+ cells were correlated (0.32; P < 0.0001) and decreased from normal (81% versus 92.3%) to LSIL (53.1% versus 85.3%), to HSIL (46.4% versus 67.5%) and SCC (35.1% versus 35.9%). The Ki67+ PI was inversely correlated with DP (-0.20, P = 0.0014) and PKP-1 (-0.19, P = 0.015). Condylomata retained low CRBP-1 and high expression of PKP-1 and DP. CONCLUSIONS The gain of CRBP-1 and the loss of desmosomal proteins occur early in cervical carcinogenesis.
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Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. THE AMERICAN JOURNAL OF PATHOLOGY 2007; 170:1807-16. [PMID: 17525249 PMCID: PMC1899462 DOI: 10.2353/ajpath.2007.070112] [Citation(s) in RCA: 1604] [Impact Index Per Article: 89.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
The crucial role played by the myofibroblast in wound healing and pathological organ remodeling is well established; the general mechanisms of extracellular matrix synthesis and of tension production by this cell have been amply clarified. This review discusses the pattern of myofibroblast accumulation and fibrosis evolution during lung and liver fibrosis as well as during atheromatous plaque formation. Special attention is paid to the specific features characterizing each of these processes, including the spectrum of different myofibroblast precursors and the distinct pathways involved in the formation of differentiated myofibroblasts in each lesion. Thus, whereas in lung fibrosis it seems that most myofibroblasts derive from resident fibroblasts, hepatic stellate cells are the main contributor for liver fibrosis and media smooth muscle cells are the main contributor for the atheromatous plaque. A better knowledge of the molecular mechanisms conducive to the appearance of differentiated myofibroblasts in each pathological situation will be useful for the understanding of fibrosis development in different organs and for the planning of strategies aiming at their prevention and therapy.
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Affiliation(s)
- Boris Hinz
- Laboratory of Cell Biophysics, Ecole Polytechnique Fédérale de Lausanne (EPFL), Bâtiment SG-AA-B143, Station 15, CH-1015 Lausanne, Switzerland.
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Omary MB, Lugea A, Lowe AW, Pandol SJ. The pancreatic stellate cell: a star on the rise in pancreatic diseases. J Clin Invest 2007; 117:50-9. [PMID: 17200706 PMCID: PMC1716214 DOI: 10.1172/jci30082] [Citation(s) in RCA: 547] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pancreatic stellate cells (PaSCs) are myofibroblast-like cells found in the areas of the pancreas that have exocrine function. PaSCs are regulated by autocrine and paracrine stimuli and share many features with their hepatic counterparts, studies of which have helped further our understanding of PaSC biology. Activation of PaSCs induces them to proliferate, to migrate to sites of tissue damage, to contract and possibly phagocytose, and to synthesize ECM components to promote tissue repair. Sustained activation of PaSCs has an increasingly appreciated role in the fibrosis that is associated with chronic pancreatitis and with pancreatic cancer. Therefore, understanding the biology of PaSCs offers potential therapeutic targets for the treatment and prevention of these diseases.
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Affiliation(s)
- M. Bishr Omary
- Department of Medicine, VA Palo Alto Health Care System, Palo Alto, California, USA.
Stanford University School of Medicine, Stanford, California, USA.
USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases and Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Aurelia Lugea
- Department of Medicine, VA Palo Alto Health Care System, Palo Alto, California, USA.
Stanford University School of Medicine, Stanford, California, USA.
USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases and Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Anson W. Lowe
- Department of Medicine, VA Palo Alto Health Care System, Palo Alto, California, USA.
Stanford University School of Medicine, Stanford, California, USA.
USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases and Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Stephen J. Pandol
- Department of Medicine, VA Palo Alto Health Care System, Palo Alto, California, USA.
Stanford University School of Medicine, Stanford, California, USA.
USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases and Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA
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Schmitt-Graeff A, Jing R, Nitschke R, Desmoulière A, Skalli O. Synemin expression is widespread in liver fibrosis and is induced in proliferating and malignant biliary epithelial cells. Hum Pathol 2006; 37:1200-10. [PMID: 16938526 DOI: 10.1016/j.humpath.2006.04.017] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2006] [Revised: 04/18/2006] [Accepted: 04/20/2006] [Indexed: 01/13/2023]
Abstract
The expression profile of intermediate filament proteins provides valuable information on the differentiation of specific cell populations and their contributions to disease. Synemin is one of the few intermediate filament proteins whose expression pattern during pathological situations is poorly characterized. We conducted a systematic immunohistochemical investigation of synemin expression in human liver diseases. In normal liver and in the early prefibrotic phase of chronic viral hepatitis or steatohepatitis, synemin was localized in hepatic stellate cells (HSCs) and vascular cells. Fibrotic or cirrhotic liver disease promoted intense synemin staining of HSCs in parenchymal and fibrous zones. In portal tract fibroblasts, synemin expression was rare under normal conditions but was widespread in severe inflammatory diseases associated with portal expansion, consistent with the notion that some fibrotic reactions involve HSCs, whereas others involve both HSCs and portal fibroblasts. Most sinusoidal endothelial cells were synemin negative in normal liver but were positive in hepatocellular carcinomas. Synemin was also expressed in the epithelial component of the ductular reaction in various liver diseases and in cholangiocarcinoma cells but not in hepatocellular carcinoma cells. Myofibroblasts in stromal reaction to carcinomas were synemin positive. Thus, synemin helps delineate different types of liver fibrotic reactions and provides a marker for sinusoidal capillarization and for proliferating biliary epithelial and cholangiocarcinoma cells.
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Affiliation(s)
- Annette Schmitt-Graeff
- Department of Pathology, University of Freiburg Medical School, D-79002 Freiburg, Germany
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Garcíade León MDC, Montfort I, Tello Montes E, López Vancell R, Olivos García A, González Canto A, Nequiz-Avendaño M, Pérez-Tamayo R. Hepatocyte production of modulators of extracellular liver matrix in normal and cirrhotic rat liver. Exp Mol Pathol 2005; 80:97-108. [PMID: 16332368 DOI: 10.1016/j.yexmp.2005.03.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2005] [Accepted: 03/28/2005] [Indexed: 01/18/2023]
Abstract
In the present study, we found collagenolytic and gelatinolytic activity in the supernatants of hepatocyte cultures from rats with experimental CCl(4)-induced liver cirrhosis, in levels significantly higher than in comparable supernatants of hepatocyte cultures from normal rats. In addition, we clearly detected the messenger ribonucleic acids (mRNA) of four matrix metalloproteinases (MMP-2, MMP-3, MMP-10, and MMP-13) and of two tissue inhibitors of matrix metalloproteinases (TIMP-1 and TIMP-2) in hepatocytes from both normal and cirrhotic rats by RT-PCR and by in situ hybridization. Finally, we demonstrated MMP-2, MMP-3, and MMP-13 and TIMP-1 and TIMP-2 proteins in the same hepatocyte preparations by immunostaining. We conclude that rat hepatocytes produce the major enzymes and inhibitors involved in liver ECM modulation and therefore suggests that they might participate actively in the pathophysiology of liver cirrhosis in rats.
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Affiliation(s)
- María del Carmen Garcíade León
- Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, y Hospital General, de México, D.F. 06720, México
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Schnabl B, Hu K, Mühlbauer M, Hellerbrand C, Stefanovic B, Brenner DA, Schölmerich J. Zinc finger protein 267 is up-regulated during the activation process of human hepatic stellate cells and functions as a negative transcriptional regulator of MMP-10. Biochem Biophys Res Commun 2005; 335:87-96. [PMID: 16054593 DOI: 10.1016/j.bbrc.2005.07.043] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2005] [Accepted: 07/13/2005] [Indexed: 01/06/2023]
Abstract
Activation of hepatic stellate cells (HSCs) is the central event in the development of liver fibrosis and cirrhosis. The transdifferentiation process of quiescent into activated HSCs requires a complete reprogramming in gene expression, which is governed by modulation of transcriptional activators or repressors. Using microarray analysis to identify genes differentially expressed during the activation process of human HSCs, zinc finger protein 267 (ZNF267) mRNA was up-regulated in activated HSCs and in cirrhotic human liver. ZNF267 belongs to the family of Kruppel-like zinc fingers and contains a conserved KRAB (Kruppel associated box) A and B domain in the N-terminal part outside the C-terminal region of zinc fingers. ZNF267 constructs containing enhanced cyan fluorescence protein were constitutively localized in the nucleus. When fused to GAL4 DNA binding domain, full-length ZNF267 and all constructs encompassing KRAB A domain showed transcriptional repressor activity. Microarray analysis and RNase protection assays showed that ZNF267 represses MMP-10 gene expression, which was confirmed by reporter gene assays. Furthermore, ZNF267 binds to the MMP-10 promoter region as demonstrated by chromatin immunoprecipitation assays. In conclusion, our results suggest that ZNF267 as a negative transcriptional regulator of MMP-10 might promote liver fibrogenesis through alteration of matrix degradation in vivo.
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Affiliation(s)
- Bernd Schnabl
- Department of Internal Medicine I, University of Regensburg, Regensburg, Germany.
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Sá Cunha A, Blanc JF, Trillaud H, De Ledinghen V, Balabaud C, Bioulac-Sage P. Hypervascular nodule in a fibrotic liver overloaded with iron: identification of a premalignant area with preserved liver architecture. COMPARATIVE HEPATOLOGY 2005; 4:5. [PMID: 15871739 PMCID: PMC1112608 DOI: 10.1186/1476-5926-4-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2004] [Accepted: 05/04/2005] [Indexed: 01/13/2023]
Abstract
Background The presence of a hypervascular nodule in a patient with cirrhosis is highly suggestive of a hepatocellular carcinoma. Case presentation A 55 year old man with idiopathic refractory anaemia was addressed for the cure of a recently appeared 3.3 cm hypervascular liver nodule. The nodule was not visible on the resected fresh specimen, but a paler zone was seen after formalin fixation. The surrounding liver was fibrotic (METAVIR score F3) and overloaded with iron. However, the paler zone, thought to be the nodule, had in fact a normal architecture, was less fibrotic, and contained some "portal tract-like structures" (but with arteries only); moreover, this paler area was devoid of iron, contained less glycogen and was characterized by foci of clear hepatocytes. Conclusion In spite of the absence of architectural distortion, and a normal proliferative index, the possibility of premalignancy or malignancy should be considered in this type of hypervascular and hyposiderotic nodule, occurring in the context of an iron overloaded liver.
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Affiliation(s)
- António Sá Cunha
- Fédération d'hépato-gastroentérologie CHU Bordeaux, GREF Inserm E362, Université Bordeaux 2, France
| | - Jean-Frédéric Blanc
- Fédération d'hépato-gastroentérologie CHU Bordeaux, GREF Inserm E362, Université Bordeaux 2, France
| | - Hervé Trillaud
- Fédération d'hépato-gastroentérologie CHU Bordeaux, GREF Inserm E362, Université Bordeaux 2, France
| | - Victor De Ledinghen
- Fédération d'hépato-gastroentérologie CHU Bordeaux, GREF Inserm E362, Université Bordeaux 2, France
| | - Charles Balabaud
- Fédération d'hépato-gastroentérologie CHU Bordeaux, GREF Inserm E362, Université Bordeaux 2, France
| | - Paulette Bioulac-Sage
- Fédération d'hépato-gastroentérologie CHU Bordeaux, GREF Inserm E362, Université Bordeaux 2, France
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N/A. N/A. Shijie Huaren Xiaohua Zazhi 2004; 12:2660-2663. [DOI: 10.11569/wcjd.v12.i11.2660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Abstract
Kidney dysfunction leads to disturbed renal metabolic activities and to impaired glomerular filtration, resulting in the retention of toxic solutes affecting all organs of the body. Cardiovascular disease (CVD) and infections are the main causes for the increased occurrence of morbidity and mortality among patients with chronic kidney disease (CKD). Both complications are directly or indirectly linked to a compromised immune defense. The specific coordinated roles of polymorphonuclear leukocytes (PMNLs), monocytes/macrophages, lymphocytes and antigen-presenting cells (APCs) in maintaining an efficient immune response are affected. Their normal response can be impaired, giving rise to infectious diseases or pre-activated/primed, leading to inflammation and consequently to CVD. Whereas the coordinated removal via apoptosis of activated immune cells is crucial for the resolution of inflammation, inappropriately high apoptotic rates lead to a diminished immune response. In uremia, the balance between pro- and anti-inflammatory and between pro- and anti-apoptotic factors is disturbed. This review summarizes the interrelated parameters interfering with the immune response in uremia, with a special focus on the non-specific immune response and the role of uremic toxins.
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Affiliation(s)
- Gerald Cohen
- Abteilung für Nephrologie und Dialyse, Univ.-Klinik für Innere Medizin III, Währinger Gürtel 18-20, Wien A-1090, Austria.
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