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Ratziu V, Rinella M, Beuers U, Loomba R, Anstee QM, Harrison S, Francque S, Sanyal A, Newsome PN, Younossi Z. The times they are a-changin' (for NAFLD as well). J Hepatol 2020; 73:1307-1309. [PMID: 32890593 DOI: 10.1016/j.jhep.2020.08.028] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 08/25/2020] [Indexed: 01/12/2023]
Affiliation(s)
- Vlad Ratziu
- Sorbonne Université, Hôpital Pitié-Salpêtrière, Institute for Cardiometabolism and Nutrition (ICAN) and INSERM UMRS 1138 CRC, Paris, France
| | - Mary Rinella
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Rohit Loomba
- NAFLD Research Center, University of California at San Diego, La Jolla, CA, USA
| | - Quentin M Anstee
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | | | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital and University of Antwerp, Edegem, Belgium
| | - Arun Sanyal
- Division of Gastroenterology, Virginia Commonwealth University, Richmond, VA, USA
| | - Philip N Newsome
- National Institute for Health Research Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, UK.
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Immunoprofiling of Adult-Derived Human Liver Stem/Progenitor Cells: Impact of Hepatogenic Differentiation and Inflammation. Stem Cells Int 2017; 2017:2679518. [PMID: 28491094 PMCID: PMC5405586 DOI: 10.1155/2017/2679518] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 02/15/2017] [Accepted: 03/02/2017] [Indexed: 02/08/2023] Open
Abstract
Adult-derived human liver stem/progenitor cells (ADHLSCs) are, nowadays, developed as therapeutic medicinal product for the treatment of liver defects. In this study, the impact of hepatogenic differentiation and inflammation priming on the ADHLSCs' immune profile was assessed in vitro and compared to that of mature hepatocytes. The constitutive immunological profile of ADHLSCs was greatly different from that of hepatocytes. Differences in the expression of the stromal markers CD90 and CD105, adhesion molecules CD44 and CD49e, immunoregulatory molecules CD73 and HO-1, and NK ligands CD112 and CD155 were noted. While they globally preserved their immunological profile in comparison to undifferentiated counterparts, differentiated ADHLSCs showed a significant downregulation of CD200 expression as in hepatocytes. This was mainly induced by signals issued from EGF and OSM. On the other hand, the impact of inflammation was quite similar for all studied cell populations with an increased expression level of CD54 and CD106 and induction of that of CD40 and CD274. In conclusion, our immune profiling study suggests CD200 as a key factor in regulating the immunobiology of differentiated ADHLSCs. A better understanding of the molecular and physiological events related to such marker could help in designing the optimal conditions for an efficient therapeutic use of ADHLSCs.
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Zhang Y, Zhao X, Chang Y, Zhang Y, Chu X, Zhang X, Liu Z, Guo H, Wang N, Gao Y, Zhang J, Chu L. Calcium channel blockers ameliorate iron overload-associated hepatic fibrosis by altering iron transport and stellate cell apoptosis. Toxicol Appl Pharmacol 2016; 301:50-60. [PMID: 27095094 DOI: 10.1016/j.taap.2016.04.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Revised: 03/24/2016] [Accepted: 04/07/2016] [Indexed: 02/07/2023]
Abstract
Liver fibrosis is the principal cause of morbidity and mortality in patients with iron overload. Calcium channel blockers (CCBs) can antagonize divalent cation entry into renal and myocardial cells and inhibit fibrogenic gene expression. We investigated the potential of CCBs to resolve iron overload-associated hepatic fibrosis. Kunming mice were assigned to nine groups (n=8 per group): control, iron overload, deferoxamine, high and low dose verapamil, high and low dose nimodipine, and high and low dose diltiazem. Iron deposition and hepatic fibrosis were measured in mouse livers. Expression levels of molecules associated with transmembrane iron transport were determined by molecular biology approaches. In vitro HSC-T6 cells were randomized into nine groups (the same groups as the mice). Changes in proliferation, apoptosis, and metalloproteinase expression in cells were detected to assess the anti-fibrotic effects of CCBs during iron overload conditions. We found that CCBs reduced hepatic iron content, intracellular iron deposition, the number of hepatic fibrotic areas, collagen expression levels, and hydroxyproline content. CCBs rescued abnormal expression of α1C protein in L-type voltage-dependent calcium channel (LVDCC) and down-regulated divalent metal transporter-1 (DMT-1) expression in mouse livers. In iron-overloaded HSC-T6 cells, CCBs reduced iron deposition, inhibited proliferation, induced apoptosis, and elevated expression of matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinase-1 (TIMP-1). CCBs are potential therapeutic agents that can be used to address hepatic fibrosis during iron overload. They resolve hepatic fibrosis probably correlated with regulating transmembrane iron transport and inhibiting HSC growth.
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Affiliation(s)
- Ying Zhang
- Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China; Department of Pathology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China; Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Shijiazhuang 050200, Hebei, People's Republic of China
| | - Xin Zhao
- Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei, People's Republic of China
| | - Yanzhong Chang
- Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei, People's Republic of China
| | - Yuanyuan Zhang
- Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China
| | - Xi Chu
- Department of Pharmacy, The Forth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei, People's Republic of China
| | - Xuan Zhang
- Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China
| | - Zhenyi Liu
- Department of Medicinal Chemistry, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China
| | - Hui Guo
- Department of Medicinal Chemistry, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China
| | - Na Wang
- Department of Physiology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China
| | - Yonggang Gao
- Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China
| | - Jianping Zhang
- Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China.
| | - Li Chu
- Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China; Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Shijiazhuang 050200, Hebei, People's Republic of China.
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Liu K, Guo MG, Lou XL, Li XY, Xu Y, Ji WD, Huang XD, Yang JH, Duan JC. Hepatocyte nuclear factor 4α induces a tendency of differentiation and activation of rat hepatic stellate cells. World J Gastroenterol 2015; 21:5856-5866. [PMID: 26019449 PMCID: PMC4438019 DOI: 10.3748/wjg.v21.i19.5856] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Revised: 01/15/2015] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of hepatocyte nuclear factor 4α (HNF4α) on the differentiation and transformation of hepatic stellate cells (HSCs).
METHODS: By constructing the recombinant adenovirus vector expressing HNF4α and HNF4α shRNA vector, and manipulating HNF4α expression in HSC-T6 cells, we explored the influence of HNF4α and its induction capacity in the differentiation of rat HSCs into hepatocytes.
RESULTS: With increased expression of HNF4α mediated by AdHNF4α, the relative expression of Nanog was downregulated in HSC-T6 cells (98.33 ± 12.33 vs 41.33 ± 5.67, P < 0.001). Consequently, the expression of G-P-6 and PEPCK was upregulated (G-P-6: 14.34 ± 3.33 vs 42.53 ± 5.87, P < 0.01; PEPCK: 10.10 ± 4.67 vs 56.56 ± 5.25, P < 0.001), the expression of AFP and ALB was positive, and the expression of Nanog, Type I collagen, α-SMA, and TIMP-1 was significantly decreased. HNF4α also downregulated vimentin expression and enhanced E-cadherin expression. The ultrastructure of HNF4α-induced cells had more mitochondria and ribosomes compared with the parental cells. After silencing HNF4α expression, EPCK, E-cadherin, AFP, and ALB were downregulated and α-SMA and vimentin were upregulated.
CONCLUSION: HNF4α can induce a tendency of differentiation of HSCs into hepatocyte-like cells. These findings may provide an effective way for the treatment of liver diseases.
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Decker NK, Abdelmoneim SS, Yaqoob U, Hendrickson H, Hormes J, Bentley M, Pitot H, Urrutia R, Gores GJ, Shah VH. Nitric oxide regulates tumor cell cross-talk with stromal cells in the tumor microenvironment of the liver. THE AMERICAN JOURNAL OF PATHOLOGY 2008; 173:1002-12. [PMID: 18755846 PMCID: PMC2543069 DOI: 10.2353/ajpath.2008.080158] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Accepted: 06/20/2008] [Indexed: 12/20/2022]
Abstract
Tumor progression is regulated through paracrine interactions between tumor cells and stromal cells in the microenvironment, including endothelial cells and myofibroblasts. Nitric oxide (NO) is a key molecule in the regulation of tumor-microenvironment interactions, although its precise role is incompletely defined. By using complementary in vitro and in vivo approaches, we studied the effect of endothelial NO synthase (eNOS)-derived NO on liver tumor growth and metastasis in relation to adjacent stromal myofibroblasts and matrix because liver tumors maintain a rich, vascular stromal network enriched with phenotypically heterogeneous myofibroblasts. Mice with an eNOS deficiency developed liver tumors more frequently in response to carcinogens compared with control animals. In a surgical model of pancreatic cancer liver metastasis, eNOS overexpression in the tumor microenvironment attenuated both the number and size of tumor implants. NO promoted anoikis of tumor cells in vitro and limited their invasive capacity. Because tumor cell anoikis and invasion are both regulated by myofibroblast-derived matrix, we explored the effect of NO on tumor cell protease expression. Both microarray and Western blot analysis revealed eNOS-dependent down-regulation of the matrix protease cathepsin B within tumor cells, and silencing of cathepsin B attenuated tumor cell invasive capacity in a similar manner to that observed with eNOS overexpression. Thus, a NO gradient within the tumor microenvironment influences tumor progression through orchestrated molecular interactions between tumor cells and stroma.
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Abstract
Portal hypertension and its complications account for the majority of morbidity and mortality that occurs in patients with cirrhosis. In addition to portal hypertension, a number of other vascular syndromes are also of great importance, especially the ischemia-reperfusion (IR) injury. With the identification of major vascular defects that could account for many of the clinical sequelae of these syndromes, the liver vasculature field has now integrated very closely with the broader vascular biology discipline. In that spirit, the Henry and Lillian Stratton Basic Research Single Topic Conference was held on the topic of Vascular Biology and Pathobiology of the Liver. The course took place approximately 10 years after the first American Association for the Study of Liver Disease (AASLD)-sponsored conference on this topic that occurred in Reston, Virginia. The conference initiated with an introduction to basic vascular cell signaling and then explored vascular biology specifically as it relates to liver cells. Subsequently, specific disease syndromes were discussed in more detail including portal hypertension and IR injury. Finally, clinical and translational sessions focused on emerging therapies and technologies to treat vascular diseases of the liver.
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Affiliation(s)
- Yasuko Iwakiri
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Matthew Grisham
- Department of Molecular & Cellular Physiology, LSU Health Sciences Center, Shreveport, Louisiana 71130, USA
| | - Vijay Shah
- GI Research Unit and Fitterman Center for Digestive Disease, Mayo Clinic, Rochester, Minnesota 55905, USA
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