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Noller K, Cahan P. Cell cycle expression heterogeneity predicts degree of differentiation. Brief Bioinform 2024; 25:bbae536. [PMID: 39446193 PMCID: PMC11500603 DOI: 10.1093/bib/bbae536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 09/23/2024] [Accepted: 10/08/2024] [Indexed: 10/25/2024] Open
Abstract
Methods that predict fate potential or degree of differentiation from transcriptomic data have identified rare progenitor populations and uncovered developmental regulatory mechanisms. However, some state-of-the-art methods are too computationally burdensome for emerging large-scale data and all methods make inaccurate predictions in certain biological systems. We developed a method in R (stemFinder) that predicts single cell differentiation time based on heterogeneity in cell cycle gene expression. Our method is computationally tractable and is as good as or superior to competitors. As part of our benchmarking, we implemented four different performance metrics to assist potential users in selecting the tool that is most apt for their application. Finally, we explore the relationship between differentiation time and cell fate potential by analyzing a lineage tracing dataset with clonally labelled hematopoietic cells, revealing that metrics of differentiation time are correlated with the number of downstream lineages.
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Affiliation(s)
- Kathleen Noller
- Institute for Cell Engineering, Johns Hopkins University, 733 N. Broadway, Baltimore MD, 21205, United States
- Department of Biomedical Engineering, Johns Hopkins University, 733 N. Broadway, Baltimore MD, 21205, United States
| | - Patrick Cahan
- Institute for Cell Engineering, Johns Hopkins University, 733 N. Broadway, Baltimore MD, 21205, United States
- Department of Biomedical Engineering, Johns Hopkins University, 733 N. Broadway, Baltimore MD, 21205, United States
- Department of Molecular Biology and Genetics, Johns Hopkins University, 733 N. Broadway, Baltimore MD, 21205, United States
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Noller K, Cahan P. Cell cycle expression heterogeneity predicts degree of differentiation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.19.604184. [PMID: 39091773 PMCID: PMC11291076 DOI: 10.1101/2024.07.19.604184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
Methods that predict fate potential or degree of differentiation from transcriptomic data have identified rare progenitor populations and uncovered developmental regulatory mechanisms. However, some state-of-the-art methods are too computationally burdensome for emerging large-scale data and all methods make inaccurate predictions in certain biological systems. We developed a method in R (stemFinder) that predicts single cell differentiation time based on heterogeneity in cell cycle gene expression. Our method is computationally tractable and is as good as or superior to competitors. As part of our benchmarking, we implemented four different performance metrics to assist potential users in selecting the tool that is most apt for their application. Finally, we explore the relationship between differentiation time and cell fate potential by analyzing a lineage tracing dataset with clonally labelled hematopoietic cells, revealing that metrics of differentiation time are correlated with the number of downstream lineages.
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Affiliation(s)
- Kathleen Noller
- Institute for Cell Engineering, Johns Hopkins University, Baltimore MD USA
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore MD USA
| | - Patrick Cahan
- Institute for Cell Engineering, Johns Hopkins University, Baltimore MD USA
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore MD USA
- Department of Molecular Biology and Genetics, Johns Hopkins University, Baltimore MD USA
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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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Wang J, Li Q, Li W, Méndez-Sánchez N, Liu X, Qi X. Stem Cell Therapy for Liver Diseases: Current Perspectives. FRONT BIOSCI-LANDMRK 2023; 28:359. [PMID: 38179765 DOI: 10.31083/j.fbl2812359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 10/03/2023] [Accepted: 10/17/2023] [Indexed: 01/06/2024]
Abstract
Stem cell therapy offers a promising avenue for advanced liver disease cases as an alternative to liver transplantation. Clinical studies are underway to explore the potential of stem cells from various sources in treating different liver diseases. However, due to the variability among current studies, further validation is needed to ensure the safety and effectiveness of stem cell therapy. To establish a strong foundation for optimal stem cell therapy applications, selection of suitable stem cell sources, standardization of transplantation protocols, and patient criteria are vital. This review comprehensively examines existing literature on stem cell sources, transplantation methods, and patient selection. Additionally, we discuss novel strategies, including stem cell preconditioning, cell-free therapy, genetic modification of stem cells, and the use of liver organoids, addressing the limitations of current stem cell therapies. Nevertheless, these innovative approaches require further validation.
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Affiliation(s)
- Jing Wang
- Department of Gastroenterology, The 960th Hospital of the PLA, 250000 Jinan, Shandong, China
| | - Qun Li
- Department of Gastroenterology, The 960th Hospital of the PLA, 250000 Jinan, Shandong, China
| | - Wenbo Li
- Department of Gastroenterology, The 960th Hospital of the PLA, 250000 Jinan, Shandong, China
| | - Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic & Foundation and Faculty of Medicine, National Autonomous University of Mexico, 14050 Mexico City, Mexico
| | - Xiaofeng Liu
- Department of Gastroenterology, The 960th Hospital of the PLA, 250000 Jinan, Shandong, China
| | - Xingshun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), 110840 Shenyang, Liaoning, China
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Mitaka T, Ichinohe N, Tanimizu N. "Small Hepatocytes" in the Liver. Cells 2023; 12:2718. [PMID: 38067145 PMCID: PMC10705974 DOI: 10.3390/cells12232718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 11/17/2023] [Accepted: 11/21/2023] [Indexed: 12/18/2023] Open
Abstract
Mature hepatocytes (MHs) in an adult rodent liver are categorized into the following three subpopulations based on their proliferative capability: type I cells (MH-I), which are committed progenitor cells that possess a high growth capability and basal hepatocytic functions; type II cells (MH-II), which possess a limited proliferative capability; and type III cells (MH-III), which lose the ability to divide (replicative senescence) and reach the final differentiated state. These subpopulations may explain the liver's development and growth after birth. Generally, small-sized hepatocytes emerge in mammal livers. The cells are characterized by being morphologically identical to hepatocytes except for their size, which is substantially smaller than that of ordinary MHs. We initially discovered small hepatocytes (SHs) in the primary culture of rat hepatocytes. We believe that SHs are derived from MH-I and play a role as hepatocytic progenitors to supply MHs. The population of MH-I (SHs) is distributed in the whole lobules, a part of which possesses a self-renewal capability, and decreases with age. Conversely, injured livers of experimental models and clinical cases showed the emergence of SHs. Studies demonstrate the involvement of SHs in liver regeneration. SHs that appeared in the injured livers are not a pure population but a mixture of two distinct origins, MH-derived and hepatic-stem-cell-derived cells. The predominant cell-derived SHs depend on the proliferative capability of the remaining MHs after the injury. This review will focus on the SHs that appeared in the liver and discuss the significance of SHs in liver regeneration.
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Affiliation(s)
- Toshihiro Mitaka
- Department of Tissue Development and Regeneration, Institute of Regenerative Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (N.I.); (N.T.)
| | - Norihisa Ichinohe
- Department of Tissue Development and Regeneration, Institute of Regenerative Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (N.I.); (N.T.)
| | - Naoki Tanimizu
- Department of Tissue Development and Regeneration, Institute of Regenerative Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (N.I.); (N.T.)
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
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Martinez Lyons A, Boulter L. NOTCH signalling - a core regulator of bile duct disease? Dis Model Mech 2023; 16:dmm050231. [PMID: 37605966 PMCID: PMC10461466 DOI: 10.1242/dmm.050231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2023] Open
Abstract
The Notch signalling pathway is an evolutionarily conserved mechanism of cell-cell communication that mediates cellular proliferation, fate determination and maintenance of stem/progenitor cell populations across tissues. Although it was originally identified as a critical regulator of embryonic liver development, NOTCH signalling activation has been associated with the pathogenesis of a number of paediatric and adult liver diseases. It remains unclear, however, what role NOTCH actually plays in these pathophysiological processes and whether NOTCH activity represents the reactivation of a conserved developmental programme that is essential for adult tissue repair. In this Review, we explore the concepts that NOTCH signalling reactivation in the biliary epithelium is a reiterative and essential response to bile duct damage and that, in disease contexts in which biliary epithelial cells need to be regenerated, NOTCH signalling supports ductular regrowth. Furthermore, we evaluate the recent literature on NOTCH signalling as a critical factor in progenitor-mediated hepatocyte regeneration, which indicates that the mitogenic role for NOTCH signalling in biliary epithelial cell proliferation has also been co-opted to support other forms of epithelial regeneration in the adult liver.
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Affiliation(s)
| | - Luke Boulter
- MRC Human Genetics Unit, Institute of Genetics and Cancer, Edinburgh EH4 2XU, UK
- CRUK Scottish Centre, Institute of Genetics and Cancer, Edinburgh EH4 2XU, UK
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Chow N, Wong D, Lai CL, Mak LY, Fung J, Ma HT, Lei MW, Seto WK, Yuen MF. Effect of Antiviral Treatment on Hepatitis B Virus Integration and Hepatocyte Clonal Expansion. Clin Infect Dis 2023; 76:e801-e809. [PMID: 35594553 DOI: 10.1093/cid/ciac383] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 04/29/2022] [Accepted: 05/13/2022] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND This study investigated the effect of nucleos(t)ide analogue (NUC) treatment on hepatitis B virus (HBV) DNA integration and hepatocyte clonal expansion, both of which are implicated in hepatocellular carcinoma (HCC) in chronic hepatitis B. METHODS Twenty-eight patients receiving NUCs (11 lamivudine, 7 telbivudine, 10 entecavir) were included. All had liver biopsies at baseline and year 1, and 7 had a third biopsy at year 10. HBV DNA integration and hepatocyte clone size were assessed by inverse polymerase chain reaction. RESULTS All patients had detectable HBV integration at baseline, with a median integration frequency of 1.01 × 109 per liver and hepatocyte clone size of 2.41 × 105. Neither integration frequency nor hepatocyte clone size correlated with age and HBV virologic parameters. After 1 year of treatment, HBV integration was still detectable in all patients, with a median of 5.74 × 108 integration per liver (0.22 log reduction; P = .008) and hepatocyte clone size of 1.22 × 105 (0.40 log reduction; P = .002). HBV integration remained detectable at year 10 of treatment, with a median integration frequency of 4.84 × 107 integration per liver (0.93 log reduction from baseline) and hepatocyte clone size of 2.55 × 104 (1.02 log reduction from baseline). From baseline through year 1 to year 10, there was a decreasing trend in both integration frequency and hepatocyte clone size (P = .066 and.018, respectively). CONCLUSIONS NUCs reduced both HBV DNA integration and hepatocyte clonal expansion, suggesting another alternative pathway besides direct viral suppression to reduce HCC risk. Our findings supported the notion for a long-term NUC treatment to prevent HCC.
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Affiliation(s)
- Ning Chow
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Danny Wong
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Ching-Lung Lai
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Lung-Yi Mak
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - James Fung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Hoi-Tang Ma
- State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.,Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Meng-Wai Lei
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
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Qin L, Liu N, Bao CLM, Yang DZ, Ma GX, Yi WH, Xiao GZ, Cao HL. Mesenchymal stem cells in fibrotic diseases-the two sides of the same coin. Acta Pharmacol Sin 2023; 44:268-287. [PMID: 35896695 PMCID: PMC9326421 DOI: 10.1038/s41401-022-00952-0] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 06/29/2022] [Indexed: 02/06/2023]
Abstract
Fibrosis is caused by extensive deposition of extracellular matrix (ECM) components, which play a crucial role in injury repair. Fibrosis attributes to ~45% of all deaths worldwide. The molecular pathology of different fibrotic diseases varies, and a number of bioactive factors are involved in the pathogenic process. Mesenchymal stem cells (MSCs) are a type of multipotent stem cells that have promising therapeutic effects in the treatment of different diseases. Current updates of fibrotic pathogenesis reveal that residential MSCs may differentiate into myofibroblasts which lead to the fibrosis development. However, preclinical and clinical trials with autologous or allogeneic MSCs infusion demonstrate that MSCs can relieve the fibrotic diseases by modulating inflammation, regenerating damaged tissues, remodeling the ECMs, and modulating the death of stressed cells after implantation. A variety of animal models were developed to study the mechanisms behind different fibrotic tissues and test the preclinical efficacy of MSC therapy in these diseases. Furthermore, MSCs have been used for treating liver cirrhosis and pulmonary fibrosis patients in several clinical trials, leading to satisfactory clinical efficacy without severe adverse events. This review discusses the two opposite roles of residential MSCs and external MSCs in fibrotic diseases, and summarizes the current perspective of therapeutic mechanism of MSCs in fibrosis, through both laboratory study and clinical trials.
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Affiliation(s)
- Lei Qin
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000 China
| | - Nian Liu
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000 China
| | - Chao-le-meng Bao
- CASTD Regengeek (Shenzhen) Medical Technology Co. Ltd, Shenzhen, 518000 China
| | - Da-zhi Yang
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000 China
| | - Gui-xing Ma
- grid.263817.90000 0004 1773 1790Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055 China
| | - Wei-hong Yi
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000 China
| | - Guo-zhi Xiao
- grid.263817.90000 0004 1773 1790Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055 China
| | - Hui-ling Cao
- grid.263817.90000 0004 1773 1790Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055 China
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Pibiri M, Simbula G. Role of the Hippo pathway in liver regeneration and repair: recent advances. Inflamm Regen 2022; 42:59. [PMID: 36471376 PMCID: PMC9720992 DOI: 10.1186/s41232-022-00235-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 11/09/2022] [Indexed: 12/12/2022] Open
Abstract
Although the signaling pathways involved in normal liver regeneration have been well characterized, less has been done for livers affected by chronic tissue damage. These "abnormal livers" have an impaired regenerative response that leads to liver repair and fibrosis. The tumor suppressor Hippo pathway plays a key role in liver regeneration and repair. On this basis, this review discusses recent studies focusing on the involvement of the Hippo signaling pathway during "normal healthy liver regeneration" (i.e., in a normal liver after 2/3 partial hepatectomy) and "abnormal liver regeneration" (i.e., in a liver damaged by chronic disease). This could be an important question to address with respect to new therapies aimed at improving impaired liver regenerative responses. The studies reported here have shown that activation of the Hippo coactivators YAP/TAZ during normal liver regeneration promotes the formation of a new bile duct network through direct BEC proliferation or/and hepatocyte dedifferentiation to HPCs which can trans-differentiate to BECs. Moreover, YAP/TAZ signaling interaction with other signaling pathways mediates the recruitment and activation of Kupffer cells, which release mitogenic cytokines for parenchymal and/or non-parenchymal cells and engage in phagocytosis of cellular debris. In addition, YAP-mediated activation of stellate cells (HSCs) promotes liver regeneration through the synthesis of extracellular matrix. However, in chronically diseased livers, where the predetermined threshold for proper liver regeneration is exceeded, YAP/TAZ activation results in a reparative process characterized by liver fibrosis. In this condition, YAP/TAZ activation in parenchymal and non-parenchymal cells results in (i) differentiation of quiescent HSCs into myofibroblastic HSCs; (ii) recruitment of macrophages releasing inflammatory cytokines; (iii) polarization of macrophages toward the M2 phenotype. Since accumulation of damaged hepatocytes in chronic liver injury represent a significant risk factor for the development of hepatocarcinoma, this review also discussed the involvement of the Hippo pathway in the clearance of damaged cells.
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Affiliation(s)
- Monica Pibiri
- grid.7763.50000 0004 1755 3242Department of Biomedical Sciences, Oncology and Molecular Pathology Unit, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. Monserrato-Sestu km 0.700, Blocco A. 09042 Monserrato, Cagliari, Italy
| | - Gabriella Simbula
- grid.7763.50000 0004 1755 3242Department of Biomedical Sciences, Oncology and Molecular Pathology Unit, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. Monserrato-Sestu km 0.700, Blocco A. 09042 Monserrato, Cagliari, Italy
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Park JW, Kim JH, Kim SE, Jung JH, Jang MK, Park SH, Lee MS, Kim HS, Suk KT, Kim DJ. Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: Current Knowledge of Pathogenesis and Therapeutics. Biomedicines 2022; 10:1288. [PMID: 35740310 PMCID: PMC9220082 DOI: 10.3390/biomedicines10061288] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/24/2022] [Accepted: 05/28/2022] [Indexed: 02/07/2023] Open
Abstract
Cholangiopathies encompass various biliary diseases affecting the biliary epithelium, resulting in cholestasis, inflammation, fibrosis, and ultimately liver cirrhosis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most important progressive cholangiopathies in adults. Much research has broadened the scope of disease biology to genetic risk, epigenetic changes, dysregulated mucosal immunity, altered biliary epithelial cell function, and dysbiosis, all of which interact and arise in the context of ill-defined environmental triggers. An in-depth understanding of the molecular pathogenesis of these cholestatic diseases will help clinicians better prevent and treat diseases. In this review, we focus on the main underlying mechanisms of disease initiation and progression, and novel targeted therapeutics beyond currently approved treatments.
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Affiliation(s)
- Ji-Won Park
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Jung-Hee Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Sung-Eun Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Jang Han Jung
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Myoung-Kuk Jang
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Sang-Hoon Park
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
| | - Myung-Seok Lee
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
| | - Hyoung-Su Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Ki Tae Suk
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
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11
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Mak KM, Kee D, Cheng CP. A review of hepatic fibrosis-associated histopathology in aged cadavers. Anat Rec (Hoboken) 2022; 306:1031-1053. [PMID: 35446463 DOI: 10.1002/ar.24931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/09/2022] [Accepted: 03/10/2022] [Indexed: 11/08/2022]
Abstract
This article reviews hepatic fibrosis-associated histopathology of aged cadavers (mean age 82 years). A study of 68 livers identified steatosis in 35.5%, central vein fibrosis in 49.2%, perisinusoidal fibrosis in 63.2%, portal tract fibrosis in 47.7%, septa formation in 44.1%, bridging fibrosis in 30.8%, and cirrhosis in 4.4% of the samples as well as one hepatocellular carcinoma and six metastatic tumors. Other studies have revealed that collagens I, III, IV, V, and VI and fibronectin constitute the matrices of fibrous central veins, perisinusoidal space, portal tracts, and septa. Elastin is rich in portal tracts and fibrous septa but absent from the perisinusoidal space. Hepatic stellate cells are ubiquitous in the liver parenchyma while myofibroblasts localize in fibrotic foci. Factor VIII-related antigen expression signals sinusoidal to systemic vascular endothelium transformation while collagen IV and laminin codistribution indicates formation of perisinusoidal membranes. Their coincidence reflects focalized capillarization of sinusoids in the aged liver. In response to fibrogenesis, hepatic progenitor cells residing in the canal of Hering in the periportal parenchyma undergo expansion and migration deep into the lobule. Concomitantly, intermediate hepatocyte-like cells increase in advanced fibrosis stages, which is possibly related to hepatic regeneration. Metabolic zonation of glutamine synthetase expands from the perivenous to non-perivenous parenchyma in fibrosis progression but its expression is lost in cirrhosis, while cytochrome P-4502E1 expression is maintained in centrilobular and midlobular zones in fibrosis progression and expressed in cirrhosis. Hence, cadaveric livers provide a platform for further investigation of hepatic histopathologies associated with the aging liver.
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Affiliation(s)
- Ki M Mak
- Department of Medical Education, Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Dustin Kee
- Department of Medical Education, Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Christopher P Cheng
- Department of Medical Education, Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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12
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Abstract
Interleukin 17A (IL-17A)-producing T helper 17 (Th17) cells were identified as a subset of T helper cells that play a critical role in host defense against bacterial and fungal pathogens. Th17 cells differentiate from Th0 naïve T-cells in response to transforming growth factor β1 (TGF-β1) and IL-6, the cytokines which also drive development of liver fibrosis, require activation of transcription factor retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt). IL-17A signals through the ubiquitously expressed receptor IL-17RA. Expression of IL-17RA is upregulated in patients with hepatitis B virus/hepatitis C virus (HBV/HCV) infections, nonalcoholic steatohepatitis (NASH), alcohol-associated liver disease (AALD), hepatocellular carcinoma (HCC), and experimental models of chronic toxic liver injury. The role of IL-17 signaling in the pathogenesis of NASH- and AALD-induced metabolic liver injury and HCC will be the focus of this review. The role of IL-17A-IL-17RA axis in mediation of the cross-talk between metabolically injured hepatic macrophages, hepatocytes, and fibrogenic myofibroblasts will be discussed.
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Affiliation(s)
- Na Li
- Shanghai University of Medicine & Health Sciences, Shanghai, P.R. China.,Department of Medicine, University of California, San Diego, La Jolla, CA.,Department of Surgery, University of California, San Diego, La Jolla, CA
| | - Gen Yamamoto
- Department of Medicine, University of California, San Diego, La Jolla, CA.,Department of Surgery, University of California, San Diego, La Jolla, CA
| | - Hiroaki Fuji
- Department of Medicine, University of California, San Diego, La Jolla, CA.,Department of Surgery, University of California, San Diego, La Jolla, CA
| | - Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla, CA
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13
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Crosas-Molist E, Samain R, Kohlhammer L, Orgaz J, George S, Maiques O, Barcelo J, Sanz-Moreno V. RhoGTPase Signalling in Cancer Progression and Dissemination. Physiol Rev 2021; 102:455-510. [PMID: 34541899 DOI: 10.1152/physrev.00045.2020] [Citation(s) in RCA: 134] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Rho GTPases are a family of small G proteins that regulate a wide array of cellular processes related to their key roles controlling the cytoskeleton. On the other hand, cancer is a multi-step disease caused by the accumulation of genetic mutations and epigenetic alterations, from the initial stages of cancer development when cells in normal tissues undergo transformation, to the acquisition of invasive and metastatic traits, responsible for a large number of cancer related deaths. In this review, we discuss the role of Rho GTPase signalling in cancer in every step of disease progression. Rho GTPases contribute to tumour initiation and progression, by regulating proliferation and apoptosis, but also metabolism, senescence and cell stemness. Rho GTPases play a major role in cell migration, and in the metastatic process. They are also involved in interactions with the tumour microenvironment and regulate inflammation, contributing to cancer progression. After years of intensive research, we highlight the importance of relevant models in the Rho GTPase field, and we reflect on the therapeutic opportunities arising for cancer patients.
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Affiliation(s)
- Eva Crosas-Molist
- Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Remi Samain
- Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Leonie Kohlhammer
- Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Jose Orgaz
- Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.,Instituto de Investigaciones Biomédicas 'Alberto Sols', CSIC-UAM, 28029, Madrid, Spain
| | - Samantha George
- Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Oscar Maiques
- Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Jaume Barcelo
- Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
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14
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Baglieri J, Zhang C, Liang S, Liu X, Nishio T, Rosenthal SB, Dhar D, Su H, Cong M, Jia J, Hosseini M, Karin M, Kisseleva T, Brenner DA. Nondegradable Collagen Increases Liver Fibrosis but Not Hepatocellular Carcinoma in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:1564-1579. [PMID: 34119473 PMCID: PMC8406794 DOI: 10.1016/j.ajpath.2021.05.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/20/2021] [Accepted: 05/25/2021] [Indexed: 12/13/2022]
Abstract
Although hepatocellular cancer (HCC) usually occurs in the setting of liver fibrosis, the causal relationship between liver fibrosis and HCC is unclear. in vivo and in vitro models of HCC involving Colr/r mice (that produce a collagenase-resistant type I collagen) or wild-type (WT) mice were used to assess the relationship between type I collagen, liver fibrosis, and experimental HCC. HCC was either chemically induced in WT and Colr/r mice or Hepa 1-6 cells were engrafted into WT and Colr/r livers. The effect of hepatic stellate cells (HSCs) from WT and Colr/r mice on the growth of Hepa 1-6 cells was studied by using multicellular tumor spheroids and xenografts. Collagen type I deposition and fibrosis were increased in Colr/r mice, but they developed fewer and smaller tumors. Hepa 1-6 cells had reduced tumor growth in the livers of Colr/r mice. Although Colr/r HSCs exhibited a more activated phenotype, Hepa 1-6 growth and malignancy were suppressed in multicellular tumor spheroids and in xenografts containing Colr/r HSCs. Treatment with vitronectin, which mimics the presence of degraded collagen fragments, converted the Colr/r phenotype into a WT phenotype. Although Colr/r mice have increased liver fibrosis, they exhibited decreased HCC in several models. Thus, increased liver type I collagen does not produce increased experimental HCC.
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Affiliation(s)
- Jacopo Baglieri
- Department of Medicine, University of California San Diego, San Diego, California; Department of Surgery, University of California San Diego, San Diego, California
| | - Cuili Zhang
- Department of Medicine, University of California San Diego, San Diego, California
| | - Shuang Liang
- Department of Medicine, University of California San Diego, San Diego, California
| | - Xiao Liu
- Department of Medicine, University of California San Diego, San Diego, California
| | - Takahiro Nishio
- Department of Medicine, University of California San Diego, San Diego, California
| | - Sara B Rosenthal
- Center for Computational Biology and Bioinformatics, University of California San Diego, San Diego, California
| | - Debanjan Dhar
- Department of Medicine, University of California San Diego, San Diego, California
| | - Hua Su
- Department of Pharmacology, University of California San Diego, San Diego, California
| | - Min Cong
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China
| | - Mojgan Hosseini
- Department of Pathology, University of California San Diego, San Diego, California
| | - Michael Karin
- Department of Pharmacology, University of California San Diego, San Diego, California
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, San Diego, California
| | - David A Brenner
- Department of Medicine, University of California San Diego, San Diego, California.
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15
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Benign Bile Duct Strictures. Indian J Surg 2021. [DOI: 10.1007/s12262-019-02060-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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16
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Macrophages and Stem Cells-Two to Tango for Tissue Repair? Biomolecules 2021; 11:biom11050697. [PMID: 34066618 PMCID: PMC8148606 DOI: 10.3390/biom11050697] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 04/26/2021] [Accepted: 05/04/2021] [Indexed: 12/25/2022] Open
Abstract
Macrophages (MCs) are present in all tissues, not only supporting homeostasis, but also playing an important role in organogenesis, post-injury regeneration, and diseases. They are a heterogeneous cell population due to their origin, tissue specificity, and polarization in response to aggression factors, depending on environmental cues. Thus, as pro-inflammatory M1 phagocytic MCs, they contribute to tissue damage and even fibrosis, but the anti-inflammatory M2 phenotype participates in repairing processes and wound healing through a molecular interplay with most cells in adult stem cell niches. In this review, we emphasize MC phenotypic heterogeneity in health and disease, highlighting their systemic and systematic contribution to tissue homeostasis and repair. Unraveling the intervention of both resident and migrated MCs on the behavior of stem cells and the regulation of the stem cell niche is crucial for opening new perspectives for novel therapeutic strategies in different diseases.
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17
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Hassan HM, Isovic M, Underhill MT, Torchia J. TDG is a novel tumor suppressor of liver malignancies. Mol Cell Oncol 2020; 7:1768819. [PMID: 32944627 PMCID: PMC7469547 DOI: 10.1080/23723556.2020.1768819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
In a recent publication, we demonstrated that conditional deletion of the gene encoding thymine DNA glycosylase (TDG) leads to a late onset of hepatocellular carcinoma (HCC). TDG loss causes disruption in active DNA demethylation in the liver and dysregulation of the farnesoid X receptor and small heterodimer partner (FXR-SHP) regulatory cascade. This leads to a loss of bile acid and glucose homeostasis, which predisposes mice to HCC.
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Affiliation(s)
- Haider M Hassan
- Department of Biochemistry, Western University, London, Ontario, Canada.,Department of Oncology, The London Regional Cancer Program and The Lawson Health Research Institute, London, Ontario, Canada
| | - Majdina Isovic
- Department of Biochemistry, Western University, London, Ontario, Canada.,Department of Oncology, The London Regional Cancer Program and The Lawson Health Research Institute, London, Ontario, Canada
| | - Michael Tully Underhill
- Department of Cellular and Physiological Sciences and the Biomedical Research Centre, University of British Columbia, Vancouver, BC, Canada
| | - Joseph Torchia
- Department of Biochemistry, Western University, London, Ontario, Canada.,Department of Oncology, The London Regional Cancer Program and The Lawson Health Research Institute, London, Ontario, Canada
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18
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Pastore N, Huynh T, Herz NJ, Calcagni' A, Klisch TJ, Brunetti L, Kim KH, De Giorgi M, Hurley A, Carissimo A, Mutarelli M, Aleksieva N, D'Orsi L, Lagor WR, Moore DD, Settembre C, Finegold MJ, Forbes SJ, Ballabio A. TFEB regulates murine liver cell fate during development and regeneration. Nat Commun 2020; 11:2461. [PMID: 32424153 PMCID: PMC7235048 DOI: 10.1038/s41467-020-16300-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 04/20/2020] [Indexed: 12/29/2022] Open
Abstract
It is well established that pluripotent stem cells in fetal and postnatal liver (LPCs) can differentiate into both hepatocytes and cholangiocytes. However, the signaling pathways implicated in the differentiation of LPCs are still incompletely understood. Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is known to be involved in osteoblast and myeloid differentiation, but its role in lineage commitment in the liver has not been investigated. Here we show that during development and upon regeneration TFEB drives the differentiation status of murine LPCs into the progenitor/cholangiocyte lineage while inhibiting hepatocyte differentiation. Genetic interaction studies show that Sox9, a marker of precursor and biliary cells, is a direct transcriptional target of TFEB and a primary mediator of its effects on liver cell fate. In summary, our findings identify an unexplored pathway that controls liver cell lineage commitment and whose dysregulation may play a role in biliary cancer.
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Affiliation(s)
- Nunzia Pastore
- Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, 77030, USA.
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
| | - Tuong Huynh
- Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Niculin J Herz
- Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Alessia Calcagni'
- Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Tiemo J Klisch
- Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Lorenzo Brunetti
- Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, 77030, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Kangho Ho Kim
- Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Marco De Giorgi
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Ayrea Hurley
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Annamaria Carissimo
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, NA, 80078, Italy
| | | | - Niya Aleksieva
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, EH16 4UU, UK
| | - Luca D'Orsi
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, NA, 80078, Italy
| | - William R Lagor
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - David D Moore
- Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Carmine Settembre
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, NA, 80078, Italy
- Department of Translational Medicine, Medical Genetics, Federico II University, Naples, 80131, Italy
| | - Milton J Finegold
- Department of Pathology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Stuart J Forbes
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, EH16 4UU, UK
| | - Andrea Ballabio
- Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, 77030, USA.
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, NA, 80078, Italy.
- Department of Translational Medicine, Medical Genetics, Federico II University, Naples, 80131, Italy.
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19
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Roehlen N, Crouchet E, Baumert TF. Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives. Cells 2020; 9:cells9040875. [PMID: 32260126 PMCID: PMC7226751 DOI: 10.3390/cells9040875] [Citation(s) in RCA: 700] [Impact Index Per Article: 140.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 03/28/2020] [Accepted: 04/01/2020] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows shared patterns across the main liver disease etiologies. Scientific discoveries within the last decade have transformed the understanding of the mechanisms of liver fibrosis. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications particularly in advanced fibrosis. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and HCC development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, their anti-fibrotic effects in clinical trials have been limited or absent. Thus, no approved therapy exists for liver fibrosis. In this review we summarize cellular drivers and molecular mechanisms of fibrogenesis in chronic liver diseases and discuss their impact for the development of urgently needed anti-fibrotic therapies.
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Affiliation(s)
- Natascha Roehlen
- Université de Strasbourg, 67000 Strasbourg, France; (N.R.); (E.C.)
- Institut de Recherche sur les Maladies Virales et Hépatiques U1110, 67000 Strasbourg, France
| | - Emilie Crouchet
- Université de Strasbourg, 67000 Strasbourg, France; (N.R.); (E.C.)
- Institut de Recherche sur les Maladies Virales et Hépatiques U1110, 67000 Strasbourg, France
| | - Thomas F. Baumert
- Université de Strasbourg, 67000 Strasbourg, France; (N.R.); (E.C.)
- Institut de Recherche sur les Maladies Virales et Hépatiques U1110, 67000 Strasbourg, France
- Pôle Hepato-digestif, Institut Hopitalo-Universitaire, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
- Correspondence: ; Tel.: +33-366853703
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20
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The Cancer Stem Cell in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12030684. [PMID: 32183251 PMCID: PMC7140091 DOI: 10.3390/cancers12030684] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/11/2020] [Accepted: 03/12/2020] [Indexed: 12/11/2022] Open
Abstract
The recognition of intra-tumoral cellular heterogeneity has given way to the concept of the cancer stem cell (CSC). According to this concept, CSCs are able to self-renew and differentiate into all of the cancer cell lineages present within the tumor, placing the CSC at the top of a hierarchical tree. The observation that these cells—in contrast to bulk tumor cells—are able to exclusively initiate new tumors, initiate metastatic spread and resist chemotherapy implies that CSCs are solely responsible for tumor recurrence and should be therapeutically targeted. Toward this end, dissecting and understanding the biology of CSCs should translate into new clinical therapeutic approaches. In this article, we review the CSC concept in cancer, with a special focus on hepatocellular carcinoma.
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21
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Hyslip J, Martins PN. Liver Repair and Regeneration in Transplant: State of the Art. CURRENT TRANSPLANTATION REPORTS 2020. [DOI: 10.1007/s40472-020-00269-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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22
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Pharmacological Benefits and Risk of Using Hormones in Organ Perfusion and Preservation Solutions in the Aspect of Minimizing Hepatic Ischemia-Reperfusion Injury during Storage. BIOMED RESEARCH INTERNATIONAL 2019; 2019:6467134. [PMID: 31828112 PMCID: PMC6881579 DOI: 10.1155/2019/6467134] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 08/31/2019] [Accepted: 10/23/2019] [Indexed: 01/11/2023]
Abstract
For several years, research has been carried out on the effectiveness of solutions for perfusion and preservation of organs, including the liver. There is a search for an optimal pharmacological composition of these solutions, allowing to preserve or improve vital functions of the organ for as long as possible until it is transplanted into a recipient. Hormones due to their properties, often resulting from their pleiotropic effects, may be a valuable component for optimizing the composition of liver perfusion and preservation solutions. The paper presents the current state of knowledge on liver perfusion and preservation solutions modified with hormones. It also shows the characteristics of the hormones evaluated, taking into account their physiological functions in the body.
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23
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Giordano DM, Pinto C, Maroni L, Benedetti A, Marzioni M. Inflammation and the Gut-Liver Axis in the Pathophysiology of Cholangiopathies. Int J Mol Sci 2018; 19:E3003. [PMID: 30275402 PMCID: PMC6213589 DOI: 10.3390/ijms19103003] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 09/26/2018] [Accepted: 09/29/2018] [Indexed: 12/11/2022] Open
Abstract
Cholangiocytes, the epithelial cells lining the bile ducts, represent the unique target of a group of progressive diseases known as cholangiopathies whose pathogenesis remain largely unknown. In normal conditions, cholangiocytes are quiescent and participate to the final bile volume and composition. Following exogenous or endogenous stimuli, cholangiocytes undergo extensive modifications of their phenotype. Reactive cholangiocytes actively proliferate and release a set of proinflammatory molecules, which act in autocrine/paracrine manner mediating the cross-talk with other liver cell types and innate and adaptive immune cells. Cholangiocytes themselves activate innate immune responses against gut-derived microorganisms or bacterial products that reach the liver via enterohepatic circulation. Gut microbiota has been implicated in the development and progression of the two most common cholangiopathies, i.e., primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), which have distinctive microbiota composition compared to healthy individuals. The impairment of intestinal barrier functions or gut dysbiosis expose cholangiocytes to an increasing amount of microorganisms and may exacerbate inflammatory responses thus leading to fibrotic remodeling of the organ. The present review focuses on the complex interactions between the activation of innate immune responses in reactive cholangiocytes, dysbiosis, and gut permeability to bacterial products in the pathogenesis of PSC and PBC.
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Affiliation(s)
- Debora Maria Giordano
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy.
| | - Claudio Pinto
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy.
| | - Luca Maroni
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy.
| | - Antonio Benedetti
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy.
| | - Marco Marzioni
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy.
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24
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Chen J, Chen CY, Nguyen C, Chen L, Lee K, Stiles BL. Emerging signals regulating liver tumor initiating cells. LIVER RESEARCH 2018. [DOI: 10.1016/j.livres.2018.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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25
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Tsai JM, Weissman IL, Rinkevich Y. Partial Lobular Hepatectomy: A Surgical Model for Morphologic Liver Regeneration. J Vis Exp 2018. [PMID: 29912198 DOI: 10.3791/57302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
Morphological organ regeneration following acute tissue loss is common among lower vertebrates, but is rarely observed in mammalian postnatal life. Adult liver regeneration after 70% partial hepatectomy results in hepatocyte hypertrophy with some replication in remaining lobes with restoration of metabolic activity, but with permanent loss of the injured lobe's morphology and architecture. Here, we detail a new surgical method in the neonate that leaves a physiologic environment conducive to regeneration. This model involves amputation of the left lobe apex and a subsequent conservative management regimen, and lacks the necessity for ligation of major liver vessels or chemical injury, leaving a physiologic environment where regeneration may occur. We extend this protocol to amputations on juvenile (P7-14) mice, during which the injured liver transitions from organ regeneration to compensatory growth by hypertrophy. The presented, brief 30 min protocol provides a framework to study the mechanisms of regeneration, its age-associated decline in mammals, and the characterization of putative hepatic stem or progenitors.
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Affiliation(s)
- Jonathan M Tsai
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine; Department of Developmental Biology, Stanford University School of Medicine
| | - Irving L Weissman
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine; Department of Developmental Biology, Stanford University School of Medicine
| | - Yuval Rinkevich
- Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München; German Center for Lung Research (DZL);
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26
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Immune response involved in liver damage and the activation of hepatic progenitor cells during liver tumorigenesis. Cell Immunol 2018; 326:52-59. [PMID: 28860007 DOI: 10.1016/j.cellimm.2017.08.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 08/02/2017] [Accepted: 08/04/2017] [Indexed: 02/07/2023]
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27
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Abdellatif H. Circulating CD34+ hematopoietic stem/progenitor cells paralleled with level of viremia in patients chronically infected with hepatitis B virus. Regen Med Res 2018; 6:1. [PMID: 29461203 PMCID: PMC5881159 DOI: 10.1051/rmr/170005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 12/25/2017] [Indexed: 12/13/2022] Open
Abstract
Introduction: Liver regeneration is a heterogeneous process involving proliferation of different cell types in response to injury. Bone marrow derived stem cells may be involved in this process, by making contribution to parenchymal restoration and cellular replacement. We aimed to investigate the correlation between level of circulating mobilized CD34+ hematopoietic stem progenitor cells (HSPCs) and viremia level in patients chronically infected with hepatitis B virus (HBV). Methods: Blood samples were prospectively collected for assessing percentage and absolute counts of circulating CD34+ HSPCs and viral load level using flow cytometry and RT-PCR respectively. Patients with chronic hepatitis B (CHB) (n = 30), Entecavir (ETV) treated subjects (n = 30) and 20 age and gender matched healthy controls were enrolled in this study. Results were expressed as mean ± SD. Results and discussion: A significant increase in circulating CD34+ HSPCs level was observed in CHB patients (5 ± 3.1, 324 ± 195 × 103/ml) as compared to ETV treated subjects (0.57 ± 0.27,1022 ± 325) and healthy controls (0.53 ± 0.37, 694 ± 254, P < 0.001) in regards to percentage and absolute counts respectively. Levels of CD34+ HSPCs strongly and positively correlated with HBV DNA viral load levels in CHB patients (r2 = 0.8417, 0.649, P < 0.001).Thus, in chronic liver disorders (CHB), when reduced regenerative capacity of hepatocytes is reached, BMSCs mobilization occurs and their level increases in peripheral blood. The level of circulating CD34+ cells in peripheral blood of CHB patients paralleled with the hepatitis B viral load.
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Affiliation(s)
- Hussein Abdellatif
- Anatomy and Embryology Department, Faculty of Medicine, University of Mansoura, Mansoura, Egypt - Department of Anatomy, College of Medicine, University of Bisha, Bisha, Saudi Arabia
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28
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Qiu L, Li H, Fu S, Chen X, Lu L. Surface markers of liver cancer stem cells and innovative targeted-therapy strategies for HCC. Oncol Lett 2018; 15:2039-2048. [PMID: 29434903 PMCID: PMC5776936 DOI: 10.3892/ol.2017.7568] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 11/02/2017] [Indexed: 12/20/2022] Open
Abstract
Liver cancer stem cells (LCSCs) have important roles in the occurrence, development, recurrence, therapy resistance and metastasis of hepatocellular carcinoma (HCC). Therefore, intensive studies are undergoing to identify the mechanisms by which LCSCs contribute to HCC invasion and metastasis, and to design more efficient treatments for this disease. With continuous efforts in LCSC research over the years, therapies targeting LCSCs are thought to have great potential for the clinical treatment and prognosis of liver cancer. Novel LCSC surface markers are continuously discovered and several have been used in targeted therapies to reduce HCC recurrence, metastasis, and drug resistance following tumor resection. The present review describes the surface markers characterizing LCSCs and the recent progress in therapies targeting these markers, including antibodies and polypeptides.
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Affiliation(s)
- Lige Qiu
- Department of Intervention, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, Guangdong 519000, P.R. China
| | - Hailiang Li
- Department of Intervention, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, Guangdong 519000, P.R. China
- Department of Otolaryngology Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Sirui Fu
- Department of Intervention, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, Guangdong 519000, P.R. China
| | - Xiaofang Chen
- Department of Intervention, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, Guangdong 519000, P.R. China
- Department of Otolaryngology Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
- Stem Cell and Regenerative Medicine Laboratory, Beijing Institute of Transfusion Medicine, Beijing 100850, P.R. China
| | - Ligong Lu
- Department of Intervention, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, Guangdong 519000, P.R. China
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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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Dioxin Receptor Adjusts Liver Regeneration After Acute Toxic Injury and Protects Against Liver Carcinogenesis. Sci Rep 2017; 7:10420. [PMID: 28874739 PMCID: PMC5585208 DOI: 10.1038/s41598-017-10984-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 08/17/2017] [Indexed: 12/15/2022] Open
Abstract
The aryl hydrocarbon receptor (AhR) has roles in cell proliferation, differentiation and organ homeostasis, including the liver. AhR depletion induces undifferentiation and pluripotency in normal and transformed cells. Here, AhR-null mice (AhR-/-) were used to explore whether AhR controls liver regeneration and carcinogenesis by restricting the expansion of stem-like cells and the expression of pluripotency genes. Short-term CCl4 liver damage was earlier and more efficiently repaired in AhR-/- than in AhR+/+ mice. Stem-like CK14 + and TBX3 + and pluripotency-expressing OCT4 + and NANOG + cells expanded sooner in AhR-/- than in AhR+/+ regenerating livers. Stem-like side population cells (SP) isolated from AhR-/- livers had increased β-catenin (β-Cat) signaling with overexpression of Axin2, Dkk1 and Cyclin D1. Interestingly, β-Cat, Axin2 and Dkk1 also increased during regeneration but more notably in AhR-null livers. Liver carcinogenesis induced by diethylnitrosamine (DEN) produced large carcinomas in all AhR-/- mice but mostly premalignant adenomas in less than half of AhR+/+ mice. AhR-null tumoral tissue, but not their surrounding non-tumoral parenchyma, had nuclear β-Cat and Axin2 overexpression. OCT4 and NANOG were nevertheless similarly expressed in AhR+/+ and AhR-/- lesions. We suggest that AhR may serve to adjust liver repair and to block tumorigenesis by modulating stem-like cells and β-Cat signaling.
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Rao S, Zaidi S, Banerjee J, Jogunoori W, Sebastian R, Mishra B, Nguyen BN, Wu RC, White J, Deng C, Amdur R, Li S, Mishra L. Transforming growth factor-β in liver cancer stem cells and regeneration. Hepatol Commun 2017; 1:477-493. [PMID: 29404474 PMCID: PMC5678904 DOI: 10.1002/hep4.1062] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 04/27/2017] [Accepted: 06/01/2017] [Indexed: 12/11/2022] Open
Abstract
Cancer stem cells have established mechanisms that contribute to tumor heterogeneity as well as resistance to therapy. Over 40% of hepatocellular carcinomas (HCCs) are considered to be clonal and arise from a stem-like/cancer stem cell. Moreover, HCC is the second leading cause of cancer death worldwide, and an improved understanding of cancer stem cells and targeting these in this cancer are urgently needed. Multiple studies have revealed etiological patterns and multiple genes/pathways signifying initiation and progression of HCC; however, unlike the transforming growth factor β (TGF-β) pathway, loss of p53 and/or activation of β-catenin do not spontaneously drive HCC in animal models. Despite many advances in cancer genetics that include identifying the dominant role of TGF-β signaling in gastrointestinal cancers, we have not reached an integrated view of genetic mutations, copy number changes, driver pathways, and animal models that support effective targeted therapies for these common and lethal cancers. Moreover, pathways involved in stem cell transformation into gastrointestinal cancers remain largely undefined. Identifying the key mechanisms and developing models that reflect the human disease can lead to effective new treatment strategies. In this review, we dissect the evidence obtained from mouse and human liver regeneration, and mouse genetics, to provide insight into the role of TGF-β in regulating the cancer stem cell niche. (Hepatology Communications 2017;1:477-493).
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Affiliation(s)
- Shuyun Rao
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC
| | - Sobia Zaidi
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC
| | - Jaideep Banerjee
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC
| | - Wilma Jogunoori
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC
| | - Raul Sebastian
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC
| | - Bibhuti Mishra
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC.,Institute for Clinical Research, Veterans Affairs Medical Center Washington DC
| | - Bao-Ngoc Nguyen
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC
| | - Ray-Chang Wu
- Department of Biochemistry and Molecular Medicine George Washington University Washington DC
| | - Jon White
- Institute for Clinical Research, Veterans Affairs Medical Center Washington DC
| | - Chuxia Deng
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC.,Health Sciences University of Macau Taipa Macau China
| | - Richard Amdur
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC
| | - Shulin Li
- Department of Pediatrics The University of Texas MD Anderson Cancer Center Houston TX
| | - Lopa Mishra
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC.,Institute for Clinical Research, Veterans Affairs Medical Center Washington DC
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Fn14 hepatic progenitor cells are associated with liver fibrosis in biliary atresia. Pediatr Surg Int 2017; 33:593-599. [PMID: 28180936 DOI: 10.1007/s00383-017-4068-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/18/2017] [Indexed: 12/19/2022]
Abstract
PURPOSE The liver in biliary atresia (BA) is characterized by progressing fibrosis which is promoted by unclear reasons. We aimed to understand the factors influencing liver fibrosis. This study hypothesized that HPCs (hepatic progenitor cells) are activated and associated with liver fibrosis in biliary atresia. METHODS Liver samples from biliary atresia patients are as BA group, and the normal liver derived from hepatoblastoma infants during operation are control group. The extent of fibrosis in liver samples was blindly evaluated by two experienced pathologists depending on Ishak system. The BA liver samples were divided into mild liver fibrosis group (grade I-IV, BAa) and severe liver fibrosis group (grade V-VI, BAb) to detect Fn14 protein expression. RESULTS In mRNA level, Fn14 expression was 21.23 ± 8.3 vs. 1.00 ± 0.17, p = 0.023 < 0.05 and CD133 expression was 6.02 ± 2.16 vs. 1.14 ± 0.75, p = 0.008 < 0.01 between BA group and control group. Fn14 cells co-expressed the progenitor marker CD133 in liver, and activated in BA. Fn14 andα-SMA were co-location in fibrous area in liver. Compared to the control group, Fn14, CD133, and α-SMA protein expression were 2.10 ± 0.53 vs. 0.97 ± 0.2, p = 0.001, 2.23 ± 0.57 vs. 1.00 ± 0.03, p = 0.000, 4.96 ± 2.4 vs. 1.00 ± 0.22, p = 0.001. The Fn14 protein expression was 2.60 ± 0.35 vs. 1.86 ± 0.42, p = 0.012, between BAb and BAa group. CONCLUSION Fn14 cells, which co-express the progenitor marker CD133 in liver, are HPCs and activated in BA. Fn14 + HPCs are associated with liver fibrosis in BA.
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Cazzo E, Pareja JC, Chaim EA. Nonalcoholic fatty liver disease and bariatric surgery: a comprehensive review. SAO PAULO MED J 2017; 135:277-295. [PMID: 28562737 PMCID: PMC10019840 DOI: 10.1590/1516-3180.2016.0306311216] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 12/31/2016] [Indexed: 02/06/2023] Open
Abstract
CONTEXT AND OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) has been increasingly diagnosed worldwide and is now recognized as a source of public health concern. It comprises a wide spectrum of histological features that range from simple steatosis to severe forms of fibrosis, steatohepatitis and even cirrhosis. The impact of bariatric surgery on the course of NAFLD in individuals with obesity has been extensively studied. DESIGN AND SETTING: Narrative review; public university hospital. METHODS: A comprehensive review was conducted based on an online search on the electronic databases MEDLINE and LILACS using the MeSH terms "fatty liver" and "bariatric surgery". RESULTS: The exact mechanisms that lead to improvement in NAFLD following bariatric surgery are not completely understood. Since Roux-en-Y gastric bypass (RYGB) is the bariatric surgical procedure most performed worldwide, it is also the one from which the effects on NAFLD have been most studied, although there is also consistent evidence regarding the effects from gastric banding, sleeve gastrectomy and biliopancreatic diversions. CONCLUSION: According to the currently available evidence, bariatric surgery leads to significant improvement in NAFLD. Further research, especially by means of randomized controlled trials enrolling larger cohorts of individuals, is needed to determine the optimal procedure for this group of subjects.
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Affiliation(s)
- Everton Cazzo
- MD, MSc, PhD. Assistant Professor, Department of Surgery, Universidade Estadual de Campinas (UNICAMP), Campinas (SP), Brazil.
| | - José Carlos Pareja
- MD, PhD. Associate Professor, Department of Surgery, Universidade Estadual de Campinas (UNICAMP), Campinas (SP), Brazil.
| | - Elinton Adami Chaim
- MD, MSc, PhD. Full Professor, Department of Surgery, Universidade Estadual de Campinas (UNICAMP), Campinas, (SP), Brazil.
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Localized hepatic lobular regeneration by central-vein-associated lineage-restricted progenitors. Proc Natl Acad Sci U S A 2017; 114:3654-3659. [PMID: 28330992 DOI: 10.1073/pnas.1621361114] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
The regeneration of organ morphology and function following tissue loss is critical to restore normal physiology, yet few cases are documented in mammalian postnatal life. Partial hepatectomy of the adult mammalian liver activates compensatory hepatocyte hypertrophy and cell division across remaining lobes, resulting in restitution of organ mass but with permanent alteration of architecture. Here, we identify a time window in early postnatal life wherein partial amputation culminates in a localized regeneration instead of global hypertrophy and proliferation. Quantifications of liver mass, enzymatic activity, and immunohistochemistry demonstrate that damaged lobes underwent multilineage regeneration, reforming a lobe often indistinguishable from undamaged ones. Clonal analysis during regeneration reveals local clonal expansions of hepatocyte stem/progenitors at injured sites that are lineage but not fate restricted. Tetrachimeric mice show clonal selection occurs during development with further selections following injury. Surviving progenitors associate mainly with central veins, in a pattern of selection different from that of normal development. These results illuminate a previously unknown program of liver regeneration after acute injury and allow for exploration of latent regenerative programs with potential applications to adult liver regeneration.
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Li L, Guo J, Chen Y, Chang C, Xu C. Comprehensive CircRNA expression profile and selection of key CircRNAs during priming phase of rat liver regeneration. BMC Genomics 2017; 18:80. [PMID: 28086788 PMCID: PMC5237265 DOI: 10.1186/s12864-016-3476-6] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Accepted: 12/26/2016] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Rat liver regeneration (LR) proceeds along a process of highly organized and ordered tissue growth in response to the loss or injury of liver tissue, during which many physiological processes may play important roles. The molecular mechanism of hepatocyte proliferation, energy metabolism and substance metabolism during rat LR had been elucidated. Further, the correlation of circular RNA (circRNA) abundance with proliferation has recently been clarified. However, the regulatory capacity of circRNA in rat LR remains a fascinating topic. RESULTS To investigate the regulatory mechanism of circRNA during priming phase of rat LR, high-throughput RNA sequencing technology was performed to unbiasedly profile the expression of circRNA during priming phase of rat LR. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway analysis was conducted to predict the functions of differentially expressed circRNAs and their host linear transcripts. Co-expression networks of circRNA-miRNA were constructed based on the correlation analysis between the differentially expressed LR-related circRNAs and the condition of their miRNA binding sites. To excavate the key circRNAs in the early phase of rat LR, we comprehensively evaluated and integrated the relationship of expression level between the circRNAs and the linear transcripts as well as the distribution of miRNA binding sites in circRNA sequences. CONCLUSIONS This paper is the first to employ the comprehensive circRNA expression profile and to investigate circRNA-miRNA interactions during priming phase of rat LR. Two thousand four hundred twelve circRNAs were detected, and 159 circRNAs deriving from 116 host linear transcripts differentially expressed (p < 0.05). Six significantly changed circRNAs during priming phase of rat LR were screened as key circle molecules, and then were validated by qRT-PCR. This study will lay the foundation for revealing the functional roles of circRNAs during rat LR and help solve the remaining clinical problems.
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Affiliation(s)
- Lifei Li
- College of Life Science, Henan Normal University, Xinxiang, 453007, Henan Province, China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation and Henan Engineering Laboratory for Bioengineering and Drug Development, Xinxiang, 453007, Henan Province, China
| | - Jianlin Guo
- College of Life Science, Henan Normal University, Xinxiang, 453007, Henan Province, China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation and Henan Engineering Laboratory for Bioengineering and Drug Development, Xinxiang, 453007, Henan Province, China
| | - Yanhui Chen
- College of Life Science, Henan Normal University, Xinxiang, 453007, Henan Province, China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation and Henan Engineering Laboratory for Bioengineering and Drug Development, Xinxiang, 453007, Henan Province, China
| | - Cuifang Chang
- College of Life Science, Henan Normal University, Xinxiang, 453007, Henan Province, China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation and Henan Engineering Laboratory for Bioengineering and Drug Development, Xinxiang, 453007, Henan Province, China
| | - Cunshuan Xu
- College of Life Science, Henan Normal University, Xinxiang, 453007, Henan Province, China. .,State Key Laboratory Cultivation Base for Cell Differentiation Regulation and Henan Engineering Laboratory for Bioengineering and Drug Development, Xinxiang, 453007, Henan Province, China.
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Mfsd2a+ hepatocytes repopulate the liver during injury and regeneration. Nat Commun 2016; 7:13369. [PMID: 27857132 PMCID: PMC5120209 DOI: 10.1038/ncomms13369] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Accepted: 09/26/2016] [Indexed: 02/07/2023] Open
Abstract
Hepatocytes are functionally heterogeneous and are divided into two distinct populations based on their metabolic zonation: the periportal and pericentral hepatocytes. During liver injury and regeneration, the cellular dynamics of these two distinct populations remain largely elusive. Here we show that major facilitator super family domain containing 2a (Mfsd2a), previously known to maintain blood–brain barrier function, is a periportal zonation marker. By genetic lineage tracing of Mfsd2a+ periportal hepatocytes, we show that Mfsd2a+ population decreases during liver homeostasis. Nevertheless, liver regeneration induced by partial hepatectomy significantly stimulates expansion of the Mfsd2a+ periportal hepatocytes. Similarly, during chronic liver injury, the Mfsd2a+ hepatocyte population expands and completely replaces the pericentral hepatocyte population throughout the whole liver. After injury recovery, the adult liver re-establishes the metabolic zonation by reprogramming the Mfsd2a+-derived hepatocytes into pericentral hepatocytes. The evidence of entire zonation replacement during injury increases our understanding of liver biology and disease. Hepatocytes are highly specialized cells and their fate is determined by their position in the liver as either periportal or perivenous hepatocytes. Here, Pu et al. show through genetic lineage tracing for Mfsd2 that periportal hepatocytes proliferate and reprogram into pericentral hepatocytes during liver regeneration and injury.
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Kopp JL, Grompe M, Sander M. Stem cells versus plasticity in liver and pancreas regeneration. Nat Cell Biol 2016; 18:238-45. [PMID: 26911907 DOI: 10.1038/ncb3309] [Citation(s) in RCA: 181] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cell replacement in adult organs can be achieved through stem cell differentiation or the replication or transdifferentiation of existing cells. In the adult liver and pancreas, stem cells have been proposed to replace tissue cells, particularly following injury. Here we review how specialized cell types are produced in the adult liver and pancreas. Based on current evidence, we propose that the plasticity of differentiated cells, rather than stem cells, accounts for tissue repair in both organs.
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Affiliation(s)
- Janel L Kopp
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
| | - Markus Grompe
- Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Oregon Health and Science University, Portland, Oregon 97239, USA
| | - Maike Sander
- Department of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, California 92093-0695, USA
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Huch M, Dollé L. The plastic cellular states of liver cells: Are EpCAM and Lgr5 fit for purpose? Hepatology 2016; 64:652-62. [PMID: 26799921 PMCID: PMC4973669 DOI: 10.1002/hep.28469] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Revised: 12/25/2015] [Accepted: 01/17/2016] [Indexed: 12/14/2022]
Abstract
Adult liver cells have been considered restricted regarding their fate and lineage potential. That is, hepatocytes have been thought able only to generate hepatocytes and duct cells, only duct cells. While this may be the case for the majority of scenarios in a state of quiescence or homeostasis, evidence suggests that liver cells are capable of interconverting between cellular states of distinct phenotypic traits. This interconversion or plasticity had been suggested by classical studies using cellular markers, but recently lineage tracing approaches have proven that cells are highly plastic and retain an extraordinary ability to respond differently to normal tissue homeostasis, to tissue repair, or when challenged to expand ex vivo or to differentiate upon transplantation. Stemness, as "self-renewal and multipotency," seems not to be limited to a particular cell type but rather to a cellular state in which cells exhibit a high degree of plasticity and can move back and forth in different phenotypic states. For instance, upon damage cells can dedifferentiate to acquire stem cell potential that allows them to self-renew, repopulate a damaged tissue, and then undergo differentiation. In this review, we will discuss the evidence on cellular plasticity in the liver, focusing our attention on two markers, epithelial cell adhesion molecule and leucine-rich repeat-containing G protein-coupled receptor 5, which identify cells with stem cell potential. (Hepatology 2016;64:652-662).
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Affiliation(s)
- Meritxell Huch
- Wellcome Trust/Cancer Research UK‐Gurdon Institutethe Wellcome Trust‐Medical Research Council Stem Cell Institute, and Physiology, Development, and Neuroscience, University of CambridgeCambridgeUK
| | - Laurent Dollé
- Laboratory of Liver Cell BiologyDepartment of Basic Biomedical SciencesFaculty of Medicine and PharmacyFree University BrusselsBrusselsBelgium
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Pang YB, Zhong JH, Luo XL, Ou C, Guo Z, Xiang BD, Peng NF, Li LQ. Clinicopathological characteristics and liver stem cell marker expression in hepatocellular carcinoma involving bile duct tumor thrombi. Tumour Biol 2016; 37:5879-5884. [PMID: 26586401 DOI: 10.1007/s13277-015-4446-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 11/13/2015] [Indexed: 01/27/2023] Open
Abstract
The aim of this study was to analyze the clinicopathological characteristics and expression of liver stem cell markers of hepatocellular carcinoma (HCC) involving bile duct tumor thrombi (BDTT). A total of 35 patients with HCC and BDTT in a consecutive series of HCC patients who underwent surgical treatment were studied retrospectively and compared with 916 patients without BDTT from the same series. Clinicopathological characteristics, overall survival (OS), and tumor expression of liver stem cell markers CD133, CD90, EpCAM, CK19, VEGF, and C-kit were compared between the two patient groups. Analysis was performed for the entire patient groups as well as for 35 pairs of patients with or without BDTT matched by propensity score. HCC patients with BDTT tended to have smaller tumors than those without BDTT, as well as a higher probability of having poorly differentiated tumor, Child-Pugh class B, liver cirrhosis, and microvascular invasion. Tumor tissue in patients with BDTT showed significantly higher expression rates of all liver stem cell markers examined. OS was significantly lower for patients with BDTT at 1 year (69 vs 84 %), 3 years (37 vs 64 %), and 5 years (20 vs 55 %) (P < 0.001). Patients with HCC and BDTT show lower OS than patients without BDTT. The higher frequency of liver stem cell marker expression in the presence of BDTT suggests that such stem cells may play a role in the pathogenesis of this form of HCC.
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Affiliation(s)
- Ye-Bin Pang
- Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd. #71, Nanning, 530021, People's Republic of China
- Research Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Jian-Hong Zhong
- Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd. #71, Nanning, 530021, People's Republic of China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, People's Republic of China
| | - Xiao-Ling Luo
- Research Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Chao Ou
- Research Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Zhe Guo
- Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd. #71, Nanning, 530021, People's Republic of China
| | - Bang-De Xiang
- Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd. #71, Nanning, 530021, People's Republic of China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, People's Republic of China
| | - Ning-Fu Peng
- Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd. #71, Nanning, 530021, People's Republic of China.
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, People's Republic of China.
| | - Le-Qun Li
- Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd. #71, Nanning, 530021, People's Republic of China.
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, People's Republic of China.
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Scheer MA, Schneider KJ, Finnigan RL, Maloney EP, Wells MA, Clemens DL. The Involvement of Acetaldehyde in Ethanol-Induced Cell Cycle Impairment. Biomolecules 2016; 6:biom6020017. [PMID: 27043646 PMCID: PMC4919912 DOI: 10.3390/biom6020017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 03/09/2016] [Accepted: 03/24/2016] [Indexed: 01/15/2023] Open
Abstract
Background: Hepatocytes metabolize the vast majority of ingested ethanol. This metabolic activity results in hepatic toxicity and impairs the ability of hepatocytes to replicate. Previous work by our group has shown that ethanol metabolism results in a G2/M cell cycle arrest. The intent of these studies was to discern the roles of acetaldehyde and reactive oxygen, two of the major by-products of ethanol metabolism, in the G2/M cell cycle arrest. Methods: To investigate the role of ethanol metabolites in the cell cycle arrest, VA-13 and VL-17A cells were used. These are recombinant Hep G2 cells that express alcohol dehydrogenase or alcohol dehydrogenase and cytochrome P450 2E1, respectively. Cells were cultured with or without ethanol, lacking or containing the antioxidants N-acetylcysteine (NAC) or trolox, for three days. Cellular accumulation was monitored by the DNA content of the cultures. The accumulation of the cyclin-dependent kinase, Cdc2 in the inactive phosphorylated form (p-Cdc2) and the cyclin-dependent kinase inhibitor p21 were determined by immunoblot analysis. Results: Cultures maintained in the presence of ethanol demonstrated a G2/M cell cycle arrest that was associated with a reduction in DNA content and increased levels of p-Cdc2 and p21, compared with cells cultured in its absence. Inclusion of antioxidants in the ethanol containing media was unable to rescue the cells from the cell cycle arrest or these ethanol metabolism-mediated effects. Additionally, culturing the cells in the presence of acetaldehyde alone resulted in increased levels of p-Cdc2 and p21. Conclusions: Acetaldehyde produced during ethanol oxidation has a major role in the ethanol metabolism-mediated G2/M cell cycle arrest, and the concurrent accumulation of p21 and p-Cdc2. Although reactive oxygen species are thought to have a significant role in ethanol-induced hepatocellular damage, they may have a less important role in the inability of hepatocytes to replace dead or damaged cells.
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Affiliation(s)
- Marc A Scheer
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA.
| | - Katrina J Schneider
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA.
- Nebraska and Western Iowa Veterans Administration Medical Center, University of Nebraska Medical Center, Omaha, NE 68105, USA.
| | - Rochelle L Finnigan
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA.
| | - Eamon P Maloney
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA.
| | - Mark A Wells
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA.
| | - Dahn L Clemens
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA.
- Nebraska and Western Iowa Veterans Administration Medical Center, University of Nebraska Medical Center, Omaha, NE 68105, USA.
- Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA.
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Ma HY, Xu J, Liu X, Zhu Y, Gao B, Karin M, Tsukamoto H, Jeste DV, Grant I, Roberts AJ, Contet C, Geoffroy C, Zheng B, Brenner D, Kisseleva T. The role of IL-17 signaling in regulation of the liver-brain axis and intestinal permeability in Alcoholic Liver Disease. CURRENT PATHOBIOLOGY REPORTS 2016; 4:27-35. [PMID: 27239399 PMCID: PMC4878828 DOI: 10.1007/s40139-016-0097-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Alcoholic liver disease (ALD) progresses from a normal liver, to steatosis, steatohepatitis, fibrosis and hepatocellular carcinoma (HCC). Despite intensive studies, the pathogenesis of ALD is poorly understood, in part due to a lack of suitable animal models which mimic the stages of ALD progression. Furthermore, the role of IL-17 in ALD has not been evaluated. We and others have recently demonstrated that IL-17 signaling plays a critical role in development of liver fibrosis and cancer. Here we summarize the most recent evidence supporting the role of IL-17 in ALD. As a result of a collaborative effort of Drs. Karin, Gao, Tsukamoto and Kisseleva, we developed several improved models of ALD in mice: 1) chronic-plus-binge model that mimics early stages of steatohepatitis, 2) intragastric ethanol feeding model that mimics alcoholic steatohepatitis and fibrosis, and 3) diethylnitrosamine (DEN)+alcohol model that mimics alcoholic liver cancer. These models might provide new insights into the mechanism of IL-17 signaling in ALD and help identify novel therapeutic targets.
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Affiliation(s)
- Hsiao-Yen Ma
- Department of Medicine, UC San Diego, La Jolla, CA; Department of Surgery, UC San Diego, La Jolla, CA
| | - Jun Xu
- Department of Medicine, UC San Diego, La Jolla, CA; Department of Surgery, UC San Diego, La Jolla, CA
| | - Xiao Liu
- Department of Medicine, UC San Diego, La Jolla, CA; Department of Surgery, UC San Diego, La Jolla, CA
| | - Yunheng Zhu
- Department of Medicine, UC San Diego, La Jolla, CA; Department of Surgery, UC San Diego, La Jolla, CA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National, Institutes of Health, Bethesda, Maryland
| | - Michael Karin
- Department of Pharmacology, UC San Diego, La Jolla, CA
| | - Hidekazu Tsukamoto
- Southern California Research Center for ALPD & Cirrhosis Department of Pathology Keck School of Medicine of USC, University of Southern California, and Department of Veterans Affairs Great Los Angeles Healthcare System, Los Angeles, CA
| | - Dilip V Jeste
- Department of Psychiatry, UC San Diego, La Jolla, CA; Stein Institute for Research on Aging, UC San Diego, La Jolla, CA
| | - Igor Grant
- Department of Psychiatry, UC San Diego, La Jolla, CA
| | - Amanda J Roberts
- Department of Molecular & Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA
| | - Candice Contet
- Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA
| | | | - Binhai Zheng
- Department of Neurosciences, UC San Diego, La Jolla, CA
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Bashir S, Sadaf S, Ahmad S, Akhtar MW. Enhanced and Secretory Expression of Human Granulocyte Colony Stimulating Factor by Bacillus subtilis SCK6. BIOMED RESEARCH INTERNATIONAL 2015; 2015:636249. [PMID: 26881203 PMCID: PMC4735991 DOI: 10.1155/2015/636249] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Revised: 12/08/2015] [Accepted: 12/08/2015] [Indexed: 11/18/2022]
Abstract
This study describes a simplified approach for enhanced expression and secretion of a pharmaceutically important human cytokine, that is, granulocyte colony stimulating factor (GCSF), in the culture supernatant of Bacillus subtilis SCK6 cells. Codon optimized GCSF and pNWPH vector containing SpymwC signal sequence were amplified by prolonged overlap extension PCR to generate multimeric plasmid DNA, which was used directly to transform B. subtilis SCK6 supercompetent cells. Expression of GCSF was monitored in the culture supernatant for 120 hours. The highest expression, which corresponded to 17% of the total secretory protein, was observed at 72 hours of growth. Following ammonium sulphate precipitation, GCSF was purified to near homogeneity by fast protein liquid chromatography on a QFF anion exchange column. Circular dichroism spectroscopic analysis showed that the secondary structure contents of the purified GCSF are similar to the commercially available GCSF. Biological activity, as revealed by the regeneration of neutrophils in mice treated with ifosfamine, was also similar to the commercial preparation of GCSF. This, to our knowledge, is the first study that reports secretory expression of human GCSF in B. subtilis SCK6 with final recovery of up to 96 mg/L of the culture supernatant, without involvement of any chemical inducer.
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Affiliation(s)
- Shaista Bashir
- School of Biological Sciences, University of the Punjab, Lahore 54590, Pakistan
| | - Saima Sadaf
- Institute of Biochemistry and Biotechnology, University of the Punjab, Lahore 54590, Pakistan
| | - Sajjad Ahmad
- School of Biological Sciences, University of the Punjab, Lahore 54590, Pakistan
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Advances in Liver Regeneration: Revisiting Hepatic Stem/Progenitor Cells and Their Origin. Stem Cells Int 2015; 2016:7920897. [PMID: 26798363 PMCID: PMC4699025 DOI: 10.1155/2016/7920897] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 09/02/2015] [Indexed: 02/08/2023] Open
Abstract
The liver has evolved to become a highly plastic organ with extraordinary regenerative capabilities. What drives liver regeneration is still being debated. Adult liver stem/progenitor cells have been characterized and used to produce functional hepatocytes and biliary cells in vitro. However, in vivo, numerous studies have questioned whether hepatic progenitor cells have a significant role in liver regeneration. Mature hepatocytes have recently been shown to be more plastic than previously believed and give rise to new hepatocytes after acute and chronic injury. In this review, we discuss current knowledge in the field of liver regeneration and the importance of the serotonin pathway as a clinical target for patients with liver dysfunction.
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Chen YH, Chen HL, Chien CS, Wu SH, Ho YT, Yu CH, Chang MH. Contribution of Mature Hepatocytes to Biliary Regeneration in Rats with Acute and Chronic Biliary Injury. PLoS One 2015; 10:e0134327. [PMID: 26308208 PMCID: PMC4550468 DOI: 10.1371/journal.pone.0134327] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 07/08/2015] [Indexed: 12/14/2022] Open
Abstract
Whether hepatocytes can convert into biliary epithelial cells (BECs) during biliary injury is much debated. To test this concept, we traced the fate of genetically labeled [dipeptidyl peptidase IV (DPPIV)-positive] hepatocytes in hepatocyte transplantation model following acute hepato-biliary injury induced by 4,4’-methylene-dianiline (DAPM) and D-galactosamine (DAPM+D-gal) and in DPPIV-chimeric liver model subjected to acute (DAPM+D-gal) or chronic biliary injury caused by DAPM and bile duct ligation (DAPM+BDL). In both models before biliary injury, BECs are uniformly DPPIV-deficient and proliferation of DPPIV-deficient hepatocytes is restricted by retrorsine. We found that mature hepatocytes underwent a stepwise conversion into BECs after biliary injury. In the hepatocyte transplantation model, DPPIV-positive hepatocytes entrapped periportally proliferated, and formed two-layered plates along portal veins. Within the two-layered plates, the hepatocytes gradually lost their hepatocytic identity, proceeded through an intermediate state, acquired a biliary phenotype, and subsequently formed bile ducts along the hilum-to-periphery axis. In DPPIV-chimeric liver model, periportal hepatocytes expressing hepatocyte nuclear factor-1β (HNF-1β) were exclusively DPPIV-positive and were in continuity to DPPIV-positives bile ducts. Inhibition of hepatocyte proliferation by additional doses of retrorsine in DPPIV-chimeric livers prevented the appearance of DPPIV-positive BECs after biliary injury. Moreover, enriched DPPIV-positive BEC/hepatic oval cell transplantation produced DPPIV-positive BECs or bile ducts in unexpectedly low frequency and in mid-lobular regions. These results together suggest that mature hepatocytes but not contaminating BECs/hepatic oval cells are the sources of periportal DPPIV-positive BECs. We conclude that mature hepatocytes contribute to biliary regeneration in the environment of acute and chronic biliary injury through a ductal plate configuration without the need of exogenously genetic or epigenetic manipulation.
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Affiliation(s)
- Ya-Hui Chen
- Department of Pediatrics, Taipei Tzu-Chi Hospital, The Buddhist Tzuchi Medical Foundation, Taipei, Taiwan
- Department of Pediatrics, Buddhist Tzu-Chi University College of Medicine, Hualien, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hui-Ling Chen
- Hepatitis Research Center, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chin-Sung Chien
- Graduate Institute of Clinical Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Shang-Hsin Wu
- Graduate Institute of Clinical Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yi-Tian Ho
- Hepatitis Research Center, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chun-Hsien Yu
- Department of Pediatrics, Taipei Tzu-Chi Hospital, The Buddhist Tzuchi Medical Foundation, Taipei, Taiwan
- Department of Pediatrics, Buddhist Tzu-Chi University College of Medicine, Hualien, Taiwan
- * E-mail: (MHC); (CHY)
| | - Mei-Hwei Chang
- Graduate Institute of Clinical Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
- * E-mail: (MHC); (CHY)
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Zúñiga-García V, Chávez-López MDG, Quintanar-Jurado V, Gabiño-López NB, Hernández-Gallegos E, Soriano-Rosas J, Pérez-Carreón JI, Camacho J. Differential Expression of Ion Channels and Transporters During Hepatocellular Carcinoma Development. Dig Dis Sci 2015; 60:2373-83. [PMID: 25842354 DOI: 10.1007/s10620-015-3633-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 03/13/2015] [Indexed: 12/09/2022]
Abstract
BACKGROUND Ion channels and transporters are potential markers and therapeutic targets for several cancers. However, their expression during hepatocellular carcinoma (HCC) development remains unclear. AIM To investigate the mRNA expression of Na(+), K(+) and Ca(2+) channels and ABC transporters during rat HCC development, as well as Abcc3 protein in human liver biopsies. METHODS Wistar rats were treated with diethylnitrosamine (DEN) and developed both cirrhosis (12 weeks of treatment) and either pre-neoplastic lesions (16 weeks of treatment) or multinodular HCC (16 weeks of treatment plus 2 weeks DEN-free). The mRNA expression of 12 ion channels and two ABC transporters was studied using real-time RT-PCR. Tumor-containing or tumor-free liver sections were isolated by laser-capture microdissection. Abcc3 protein expression was studied by immunohistochemistry in healthy, cirrhotic and HCC human biopsies. RESULTS We observed expression changes in seven genes. Kcna3, Kcnn4, Kcnrg and Kcnj11 potassium channel mRNA expression reached peak values at the end of DEN treatment, while Scn2a1 sodium channel, Trpc6 calcium channel and Abcc3 transporter mRNA expression reached their highest levels in the presence of HCC (18 weeks). Whereas Kcnn4 and Scn2a1 channel expression was similar in non-tumor and tumor tissue, the Abcc3 transporter and Kcna3 potassium channels were preferentially overexpressed in the tumor sections. We observed differential Abcc3 protein subcellular localization and expression in human samples. CONCLUSIONS The ion channel/transporter expression profile observed suggests that these genes are potential early markers or therapeutic targets of HCC. The differential localization of Abcc3 may be useful in the diagnosis of cirrhosis and HCC.
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Affiliation(s)
- Violeta Zúñiga-García
- Department of Pharmacology, Centro de Investigación y Estudios Avanzados del Instituto Politécnico Nacional, Avenida Instituto Politécnico Nacional 2508, C.P. 07360, Mexico City, Mexico,
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Giri S, Acikgöz A, Bader A. Isolation and Expansion of Hepatic Stem-like Cells from a Healthy Rat Liver and their Efficient Hepatic Differentiation of under Well-defined Vivo Hepatic like Microenvironment in a Multiwell Bioreactor. J Clin Exp Hepatol 2015; 5:107-22. [PMID: 26155038 PMCID: PMC4491607 DOI: 10.1016/j.jceh.2015.03.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 03/20/2015] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Currently, undifferentiated cells are found in all tissue and term as local stem cells which are quiescent in nature and less in number under normal healthy conditions but activate upon injury and repair the tissue or organs via automated activating mechanism. Due to very scanty presence of local resident somatic local stem cells in healthy organs, isolation and expansion of these adult stems is an immense challenge for medical research and cell based therapy. Particularly organ like liver, there is an ongoing controversy about existence of liver stem cells. METHODS Herein, Hepatic stem cells population was identified during culture of primary hepatocyte cells upon immediate isolation of primary hepatocyte cells. These liver stem cells has been expanded extensively and differentiated into primary hepatocytes under defined culture conditions in a nanostructured self assembling peptides modular bioreactor that mimic the state of art of liver microenvironment and compared with Matrigel as a positive control. Nanostructured self assembling peptides were used a defined extracellular matrix and Matrigel was used for undefined extracellular matrix. Proliferation of hepatic stem cells was investigated by two strategies. First strategy is to provide high concentration of hepatocyte growth factor (HGF) and second strategy is to evaluate the role of recombinant human erythropoietin (rHuEPO) in presence of trauma/ischemia cytokines (IL-6, TNF-α). Expansion to hepatic differentiation is observed by morphological analysis and was evaluated for the expression of hepatocyte-specific genes using RT-PCR and biochemical methods. RESULTS Hepatocyte-specific genes are well expressed at final stage (day 21) of differentiation period. The differentiated hepatocytes exhibited functional hepatic characteristics such as albumin secretion, urea secretion and cytochrome P450 expression. Additionally, immunofluorescence analysis revealed that hepatic stem cells derived hepatocytes exhibited mature hepatocyte markers (albumin, CK-19, CPY3A1, alpha 1-antitrypsin). Expansion and hepatic differentiation was efficiently in nanostructured self assembling peptides without such batch to batch variation while there was much variation in Matrigel coated bioreactor. In conclusion, the results of the study suggest that the nanostructured self assembling peptides coated bioreactor supports expansion as well as hepatic differentiation of liver stem cells which is superior than Matrigel. CONCLUSION This defined microenvironment conditions in bioreactor module can be useful for research involving bioartificial liver system, stem cell research and engineered liver tissue which could contribute to regenerative cell therapies or drug discovery and development.
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Key Words
- A1AT, Alpha 1-antitrypsin
- AFP, α-fetoprotein
- CK 7, Cytokeratin 7
- CK-19, Cytokeratin 19
- CPY3A1, Cytochrome P450 3A 1
- EROD, Ethoxyresorufin O-deethylase
- GaIN, D-galactosamine
- HGF, Hepatocyte growth factor
- IL-6, Interleukin 6
- MROD, Methoxyresorufin O-demethylase
- Matrigel
- PROD, Pentoxyresorufin O-depentylase
- TNF-α, Tumor necrosis factor alpha
- Thy1, Thy-1 cell surface antigen
- bioreactor
- defined culture conditions
- hepatic stem cells
- nanostructured self assembling peptides
- rHuEPO, Recombinant human erythropoietin
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Affiliation(s)
- Shibashish Giri
- Department of Cell Techniques and Applied Stem Cell Biology, Center for Biotechnology and Biomedicine (BBZ), University of Leipzig, Deutscher Platz 5, 04103 Leipzig, Germany,Address for correspondence: Shibashish Giri, Department of Cell Techniques and Applied Stem Cell Biology, Center for Biotechnology and Biomedicine, Medical faculty, University of Leipzig, Deutscher Platz 5, D-04103 Leipzig, Germany.
| | - Ali Acikgöz
- Department of Cell Techniques and Applied Stem Cell Biology, Center for Biotechnology and Biomedicine (BBZ), University of Leipzig, Deutscher Platz 5, 04103 Leipzig, Germany,Department of Gastroenterology and Hepatology, Klinikum St Georg, Delitzscher Straße, Leipzig, Germany
| | - Augustinus Bader
- Department of Cell Techniques and Applied Stem Cell Biology, Center for Biotechnology and Biomedicine (BBZ), University of Leipzig, Deutscher Platz 5, 04103 Leipzig, Germany
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Lee SY, Kim HJ, Choi D. Cell sources, liver support systems and liver tissue engineering: alternatives to liver transplantation. Int J Stem Cells 2015; 8:36-47. [PMID: 26019753 PMCID: PMC4445708 DOI: 10.15283/ijsc.2015.8.1.36] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2015] [Accepted: 05/04/2015] [Indexed: 12/11/2022] Open
Abstract
The liver is the largest organ in the body; it has a complex architecture, wide range of functions and unique regenerative capacity. The growing incidence of liver diseases worldwide requires increased numbers of liver transplant and leads to an ongoing shortage of donor livers. To meet the huge demand, various alternative approaches are being investigated including, hepatic cell transplantation, artificial devices and bioprinting of the organ itself. Adult hepatocytes are the preferred cell sources, but they have limited availability, are difficult to isolate, propagate poor and undergo rapid functional deterioration in vitro. There have been efforts to overcome these drawbacks; by improving culture condition for hepatocytes, providing adequate extracellular matrix, co-culturing with extra-parenchymal cells and identifying other cell sources. Differentiation of human stem cells to hepatocytes has become a major interest in the field of stem cell research and has progressed greatly. At the same time, use of decellularized organ matrices and 3 D printing are emerging cutting-edge technologies for tissue engineering, opening up new paths for liver regenerative medicine. This review provides a compact summary of the issues, and the locations of liver support systems and tissue engineering, with an emphasis on reproducible and useful sources of hepatocytes including various candidates formed by differentiation from stem cells.
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Affiliation(s)
- Soo Young Lee
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Han Joon Kim
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Dongho Choi
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
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Xu LB, Liu C. Role of liver stem cells in hepatocarcinogenesis. World J Stem Cells 2014; 6:579-590. [PMID: 25426254 PMCID: PMC4178257 DOI: 10.4252/wjsc.v6.i5.579] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Revised: 08/24/2014] [Accepted: 09/01/2014] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is an aggressive disease with a high mortality rate. Management of liver cancer is strongly dependent on the tumor stage and underlying liver disease. Unfortunately, most cases are discovered when the cancer is already advanced, missing the opportunity for surgical resection. Thus, an improved understanding of the mechanisms responsible for liver cancer initiation and progression will facilitate the detection of more reliable tumor markers and the development of new small molecules for targeted therapy of liver cancer. Recently, there is increasing evidence for the “cancer stem cell hypothesis”, which postulates that liver cancer originates from the malignant transformation of liver stem/progenitor cells (liver cancer stem cells). This cancer stem cell model has important significance for understanding the basic biology of liver cancer and has profound importance for the development of new strategies for cancer prevention and treatment. In this review, we highlight recent advances in the role of liver stem cells in hepatocarcinogenesis. Our review of the literature shows that identification of the cellular origin and the signaling pathways involved is challenging issues in liver cancer with pivotal implications in therapeutic perspectives. Although the dedifferentiation of mature hepatocytes/cholangiocytes in hepatocarcinogenesis cannot be excluded, neoplastic transformation of a stem cell subpopulation more easily explains hepatocarcinogenesis. Elimination of liver cancer stem cells in liver cancer could result in the degeneration of downstream cells, which makes them potential targets for liver cancer therapies. Therefore, liver stem cells could represent a new target for therapeutic approaches to liver cancer in the near future.
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Katoonizadeh A, Poustchi H, Malekzadeh R. Hepatic progenitor cells in liver regeneration: current advances and clinical perspectives. Liver Int 2014; 34:1464-1472. [PMID: 24750779 DOI: 10.1111/liv.12573] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Accepted: 04/17/2014] [Indexed: 12/12/2022]
Abstract
When there is a massive loss of hepatocytes and/or an inhibition in the proliferative capacity of the mature hepatocytes, activation of a dormant cell population of resident hepatic progenitor cells (HPCs) occurs. Depending on the type of liver damage HPCs generate new hepatocytes and biliary cells to repopulate the liver placing them as potential candidates for cell therapy in human liver failure. Liver injury specific mechanisms through which HPCs differentiate towards mature epithelial cell types are recently become understood. Such new insights will enable us not only to direct HPCs behaviour for therapeutic purposes, but also to develop clinically feasible methods for in vivo differentiation of other stem cell types towards functional hepatocytes. This review aimed to provide the current improved knowledge of the role of HPCs niche and its signals in directing the behaviour and fate of HPCs and to translate this basic knowledge of HPCs activation/differentiation into its clinical applications.
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Affiliation(s)
- Aezam Katoonizadeh
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran
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50
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Wang X, Lopategi A, Ge X, Lu Y, Kitamura N, Urtasun R, Leung TM, Fiel MI, Nieto N. Osteopontin induces ductular reaction contributing to liver fibrosis. Gut 2014; 63:1805-18. [PMID: 24496779 DOI: 10.1136/gutjnl-2013-306373] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE In human chronic liver disease, there is association between ductular reaction (DR) and fibrosis; yet, the mechanism triggering its onset and its role in scar formation remains unknown. Since we previously showed that osteopontin (OPN) is highly induced during drug-induced liver fibrosis, we hypothesised that OPN could drive oval cells (OC) expansion and DR and signal to hepatic stellate cells (HSC) to promote scarring. RESULTS In vivo studies demonstrated increased OPN expression in biliary epithelial cells (BEC) and in OC in thioacetamide (TAA)-treated mice. OPN ablation protected mice from TAA and bile duct ligation-induced liver injury, DR and scarring. This was associated with greater hepatocyte proliferation, lower OC expansion and DR along with less fibrosis, suggesting that OPN could activate the OC compartment to differentiate into BEC, which could then signal to HSC to enhance scarring. Since TAA-treated wild-type mice and cirrhotic patients showed TGF-β(+) BEC, which were lacking in TAA-treated Opn(-/-) mice and in healthy human explants, this suggested that OPN could regulate TGF-β, a profibrogenic factor. In vitro experiments confirmed that recombinant OPN (rOPN) decreases hepatocyte proliferation and increases OC and BEC proliferation. To evaluate how BEC regulate collagen-I production in HSC, co-cultures were established. Co-cultured BEC upregulated OPN and TGF-β expression and enhanced collagen-I synthesis by HSC. Lastly, recombinant TGF-β (rTGFβ) and rOPN promoted BEC proliferation and neutralisation of OPN and TGF-β reduced collagen-I expression in co-cultured HSC. CONCLUSIONS OPN emerges as a key matricellular protein driving DR and contributing to scarring and liver fibrosis via TGF-β.
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Affiliation(s)
- Xiaodong Wang
- Division of Liver Diseases, Department of Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA
| | - Aritz Lopategi
- Division of Liver Diseases, Department of Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA
| | - Xiaodong Ge
- Division of Liver Diseases, Department of Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA
| | - Yongke Lu
- Division of Liver Diseases, Department of Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA
| | - Naoto Kitamura
- Division of Liver Diseases, Department of Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA
| | - Raquel Urtasun
- Division of Liver Diseases, Department of Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA
| | - Tung-Ming Leung
- Division of Liver Diseases, Department of Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA
| | - Maria Isabel Fiel
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Natalia Nieto
- Division of Liver Diseases, Department of Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA
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