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Berasain C. New Insights and Open Questions on the Molecular and Cellular Crosstalk Governing Hepatocyte Proliferation. Cell Mol Gastroenterol Hepatol 2025:101509. [PMID: 40245923 DOI: 10.1016/j.jcmgh.2025.101509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2025] [Accepted: 03/20/2025] [Indexed: 04/19/2025]
Affiliation(s)
- Carmen Berasain
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), Madrid, Spain.
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2
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Dhayanithy G, Radhakrishnan S, Ann Martin C, Caroline Martin J, Hakeem AR, Jothimani D, Kalkura SN, Rela M. Understanding immunological insights of liver transplantation: a practice for attaining operational tolerance. Clin Exp Immunol 2025; 219:uxae125. [PMID: 39973343 PMCID: PMC11878573 DOI: 10.1093/cei/uxae125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 11/15/2024] [Accepted: 02/19/2025] [Indexed: 02/21/2025] Open
Abstract
Liver transplantation has been at the forefront of medical research, with efforts concentrated on understanding the intricate cellular and molecular dynamics involved this complex procedure. This body of work has chronicled critical clinical advancements, identified challenges, and highlighted progressive improvements in surgical practices. These concerted efforts have significantly contributed to the evolution and enhancement of liver transplantation, elevating it to its current level of sophistication. A successful liver transplant now demands an integrated, multidisciplinary approach that includes not only expanding the donor pool from deceased to living donors but also embracing advances in surgical methods, efficiently managing post-transplant complications, and, importantly, achieving operational tolerance. The latter, operational tolerance, is a state wherein the recipient's immune system is coaxed into accepting the transplanted organ without the long-term use of immunosuppressive drugs, thereby minimizing potential side effects, and improving quality of life. Understanding the critical immune mechanisms that aim to prevent graft rejection is essential from an immunological perspective. This review aims to highlight the crucial areas of host versus graft immune responses, making a clear distinction between organs received from living and deceased donors. It examines how these immune responses, both innate and adaptive, are initiated and proposes the exploration of molecular docking sites as a strategy to curb unwanted immune reactions. Additionally, this review explores the promising potential of biomarkers in predicting graft rejection, and emphasizes the importance of achieving tolerance and the continuous quest for innovative strategies to enhance the success and longevity of liver transplants.
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Affiliation(s)
| | | | | | - Josette Caroline Martin
- Department of Pathology, Sri Venkateshwara Medical College Hospital and Research Institute, Pondicherry, India
| | | | - Dinesh Jothimani
- Dr. Rela Institute and Medical Centre, Chromepet, Chennai, India
| | - Subbaraya Narayana Kalkura
- Crystal Growth Centre, Anna University, Guindy, Chennai, India
- National Foundation for Liver Research, Chromepet, Chennai, India
| | - Mohamed Rela
- National Foundation for Liver Research, Chromepet, Chennai, India
- Dr. Rela Institute and Medical Centre, Chromepet, Chennai, India
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3
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Liang Y, Mei Q, He E, Ballar P, Wei C, Wang Y, Dong Y, Zhou J, Tao X, Qu W, Zhao M, Chhetri G, Wei L, Shao J, Shen Y, Liu J, Feng L, Shen Y. MANF serves as a novel hepatocyte factor to promote liver regeneration after 2/3 partial hepatectomy via doubly targeting Wnt/β-catenin signaling. Cell Death Dis 2024; 15:681. [PMID: 39289348 PMCID: PMC11408687 DOI: 10.1038/s41419-024-07069-8] [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: 04/23/2024] [Revised: 08/31/2024] [Accepted: 09/12/2024] [Indexed: 09/19/2024]
Abstract
Liver regeneration is an intricate pathophysiological process that has been a subject of great interest to the scientific community for many years. The capacity of liver regeneration is very critical for patients with liver diseases. Therefore, exploring the mechanisms of liver regeneration and finding good ways to improve it are very meaningful. Mesencephalic astrocyte-derived neurotrophic factor (MANF), a member of newly identified neurotrophic factors (NTFs) family, extensively expresses in the liver and has demonstrated cytoprotective effects during ER stress and inflammation. However, the role of MANF in liver regeneration remains unclear. Here, we used hepatocyte-specific MANF knockout (MANFHep-/-) mice to investigate the role of MANF in liver regeneration after 2/3 partial hepatectomy (PH). Our results showed that MANF expression was up-regulated in a time-dependent manner, and the peak level of mRNA and protein appeared at 24 h and 36 h after 2/3 PH, respectively. Notably, MANF knockout delayed hepatocyte proliferation, and the peak proliferation period was delayed by 24 h. Mechanistically, our in vitro results showed that MANF physically interacts with LRP5 and β-catenin, two essential components of Wnt/β-catenin pathway. Specifically, as a cofactor, MANF binds to the extracellular segment of LRP5 to activate Wnt/β-catenin signaling. On the other hand, MANF interacts with β-catenin to stabilize cytosolic β-catenin level and promote its nuclear translocation, which further enhance the Wnt/β-catenin signaling. We also found that MANF knockout does not affect the c-Met/β-catenin complex after 2/3 PH. In summary, our study confirms that MANF may serve as a novel hepatocyte factor that is closely linked to the activation of the Wnt/β-catenin pathway via intracellular and extracellular targets.
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Affiliation(s)
- Yanyan Liang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China
| | - Qiong Mei
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China
| | - Enguang He
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China
| | - Petek Ballar
- Department of Biochemistry, Faculty of Pharmacy, Ege University, Izmir, 35100, Turkey
| | - Chuansheng Wei
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China
| | - Yue Wang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China
| | - Yue Dong
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China
| | - Jie Zhou
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China
| | - Xiaofang Tao
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China
| | - Wenyan Qu
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China
| | - Mingxia Zhao
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China
| | - Goma Chhetri
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China
| | - Limeng Wei
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China
| | - Juntang Shao
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China
| | - Yujun Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China
| | - Jun Liu
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China
| | - Lijie Feng
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China
| | - Yuxian Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China.
- Department of General Surgery, The First Affiliated Hospital, Anhui Medical University, Hefei, 230022, China.
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Zaki P, Thonglert K, Apisarnthanarax S, Grassberger C, Bowen SR, Tsai J, Sham JG, Chiang BH, Nyflot MJ. Liver injury and recovery following radiation therapy for hepatocellular carcinoma: insights from functional liver imaging. HEPATOMA RESEARCH 2024; 10:36. [PMID: 40353184 PMCID: PMC12064179 DOI: 10.20517/2394-5079.2024.27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/14/2025]
Abstract
Aim A critical need for hepatocellular carcinoma (HCC) management is understanding how the liver recovers following radiotherapy (RT). We hypothesized that functional liver imaging with 99mTc-sulfur colloid (SC) SPECT/CT provides additional information on liver injury and recovery after RT compared to conventional imaging. Methods The liver function of patients with HCC was assessed using 99mTc-SC SPECT/CT imaging before and after definitive RT. The anatomical liver volume (ALV) was segmented on CT imaging. Liver function was measured as the total liver function (TLF) encompassing 30% of maximum SC uptake. Changes in ALV and TLF were compared to clinical characteristics. Results Of 31 patients with evaluable post-RT SC SPECT/CT scans (total of 32), 23 had pre-treatment Child-Pugh (CP)-A and 9 had CP-B/C scores. The median follow-up post-RT was 57 days. The median change in ALV was -1.7% with no significant difference between CP-A and CP-B/C patients (P = 0.26) or between short- (32-99 days) and long-term (271-1120 days) follow-up imaging groups (P = 0.28). The median change in TLF post-RT was -24% and was significantly different between short- and long-term groups (-39% vs. 2%, P = 0.001) and between CP-A and CP-B/C patients (-19% vs. -57%, P = 0.002). TLF significantly decreased following treatment at all radiation dose levels, with the decline correlating with the dose (P < 0.001). Conclusion Functional imaging provides additional information regarding liver injury and recovery following RT that conventional imaging cannot reveal. Patients with CP-A liver status showed less decline following RT and most had liver function near or above pre-treatment levels.
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Affiliation(s)
- Peter Zaki
- Department of Radiation Oncology, University of Washington, Seattle, WA 98195, USA
| | - Kanokphorn Thonglert
- Department of Radiology, Division of Radiation Oncology, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red C Society, Bangkok 10330, Thailand
| | | | - Clemens Grassberger
- Department of Radiation Oncology, University of Washington, Seattle, WA 98195, USA
| | - Stephen R. Bowen
- Department of Radiology, University of Washington, Seattle, WA 98195, USA
| | - Joseph Tsai
- Department of Radiation Oncology, University of Washington, Seattle, WA 98195, USA
| | - Jonathan G. Sham
- Department of Surgery, University of Washington, Seattle, WA 98195, USA
| | - Bing-Hao Chiang
- Department of Radiation Oncology, University of Washington, Seattle, WA 98195, USA
| | - Matthew J. Nyflot
- Department of Radiology, University of Washington, Seattle, WA 98195, USA
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5
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Karnawat K, Parthasarathy R, Sakhrie M, Karthik H, Krishna KV, Balachander GM. Building in vitro models for mechanistic understanding of liver regeneration in chronic liver diseases. J Mater Chem B 2024; 12:7669-7691. [PMID: 38973693 DOI: 10.1039/d4tb00738g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/09/2024]
Abstract
The liver has excellent regeneration potential and attains complete functional recovery from partial hepatectomy. The regenerative mechanisms malfunction in chronic liver diseases (CLDs), which fuels disease progression. CLDs account for 2 million deaths per year worldwide. Pathophysiological studies with clinical correlation have shown evidence of deviation of normal regenerative mechanisms and its contribution to fueling fibrosis and disease progression. However, we lack realistic in vitro models that can allow experimental manipulation for mechanistic understanding of liver regeneration in CLDs and testing of candidate drugs. In this review, we aim to provide the framework for building appropriate organotypic models for dissecting regenerative responses in CLDs, with the focus on non-alcoholic steatohepatitis (NASH). By drawing parallels with development and hepatectomy, we explain the selection of critical components such as cells, signaling, and, substrate-driven biophysical cues to build an appropriate CLD model. We highlight the organoid-based organotypic models available for NASH disease modeling, including organ-on-a-chip and 3D bioprinted models. With the focus on bioprinting as a fabrication method, we prescribe building in vitro CLD models and testing schemes for exploring the regenerative responses in the bioprinted model.
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Affiliation(s)
- Khushi Karnawat
- School of Biomedical Engineering, Indian Institute of Technology (BHU) Varanasi, Varanasi-221005, India.
| | - Rithika Parthasarathy
- School of Biomedical Engineering, Indian Institute of Technology (BHU) Varanasi, Varanasi-221005, India.
| | - Mesevilhou Sakhrie
- School of Biomedical Engineering, Indian Institute of Technology (BHU) Varanasi, Varanasi-221005, India.
| | - Harikeshav Karthik
- School of Biomedical Engineering, Indian Institute of Technology (BHU) Varanasi, Varanasi-221005, India.
| | - Konatala Vibhuvan Krishna
- School of Biomedical Engineering, Indian Institute of Technology (BHU) Varanasi, Varanasi-221005, India.
| | - Gowri Manohari Balachander
- School of Biomedical Engineering, Indian Institute of Technology (BHU) Varanasi, Varanasi-221005, India.
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Sun R, Fei F, Jin D, Yang H, Xu Z, Cao B, Li J. The integrated analysis of gut microbiota and metabolome revealed steroid hormone biosynthesis is a critical pathway in liver regeneration after 2/3 partial hepatectomy. Front Pharmacol 2024; 15:1407401. [PMID: 39188944 PMCID: PMC11345278 DOI: 10.3389/fphar.2024.1407401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 07/23/2024] [Indexed: 08/28/2024] Open
Abstract
Introduction: The liver is the only organ capable of full regeneration in mammals. However, the exact mechanism of gut microbiota and metabolites derived from them relating to liver regeneration has not been fully elucidated. Methods: To demonstrate how the gut-liver axis contributes to liver regeneration, using an LC-QTOF/MS-based metabolomics technique, we examine the gut microbiota-derived metabolites in the gut content of C57BL/6J mice at various points after 2/3 partial hepatectomy (PHx). Compound identification, multivariate/univariate data analysis and pathway analysis were performed subsequently. The diversity of the bacterial communities in the gastrointestinal content was measured using 16S rRNA gene sequencing. Then, the integration analysis of gut microbiota and metabolome was performed. Results: After 2/3 PHx, the residual liver proliferated quickly in the first 3 days and had about 90% of its initial weight by the seventh day. The results of PLS-DA showed that a significant metabolic shift occurred at 6 h and 36 h after 2/3 PHx that was reversed at the late phase of liver regeneration. The α and β-diversity of the gut microbiota significantly changed at the early stage of liver regeneration. Specifically, Escherichia Shigella, Lactobacillus, Akkermansia, and Muribaculaceae were the bacteria that changed the most considerably during liver regeneration. Further pathway analysis found the most influenced co-metabolized pathways between the host and gut bacteria including glycolysis, the TCA cycle, arginine metabolism, glutathione metabolism, tryptophan metabolism, and purine and pyrimidine metabolism. Specifically, steroid hormone biosynthesis is the most significant pathway of the host during liver regeneration. Discussion: These findings revealed that during liver regeneration, there was a broad modification of gut microbiota and systemic metabolism and they were strongly correlated. Targeting specific gut bacterial strains, especially increasing the abundance of Akkermansia and decreasing the abundance of Enterobacteriaceae, may be a promising beneficial strategy to modulate systemic metabolism such as amino acid and nucleotide metabolism and promote liver regeneration.
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Affiliation(s)
- Runbin Sun
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Fei Fei
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Dandan Jin
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Haoyi Yang
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhi Xu
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Bei Cao
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Juan Li
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
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Sundaravadanan S, Welsh FK, Sethi P, Noorani S, Cresswell BA, Connell JJ, Knapp SK, Núñez L, Brady JM, Banerjee R, Rees M. Novel multiparametric MRI detects improved future liver remnant quality post-dual vein embolization. HPB (Oxford) 2024; 26:764-771. [PMID: 38480098 DOI: 10.1016/j.hpb.2024.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 02/11/2024] [Indexed: 06/02/2024]
Abstract
BACKGROUND Optimisation of the future liver remnant (FLR) is crucial to outcomes of extended liver resections. This study aimed to assess the quality of the FLR before and after dual vein embolization (DVE) by quantitative multiparametric MRI. METHODS Of 100 patients with liver metastases recruited in a clinical trial (Precision1:NCT04597710), ten consecutive patients with insufficient FLR underwent quantitative multiparametric MRI pre- and post-DVE (right portal and hepatic vein). FLR volume, liver fibro-inflammation (corrected T1) scores and fat percentage (proton density fat fraction, PDFF) were determined. Patient metrics were compared by Wilcoxon signed-rank test and statistical analysis done using R software. RESULTS All patients underwent uncomplicated DVE with improvement in liver remnant health, median 37 days after DVE: cT1 scores reduced from median (interquartile range) 790 ms (753-833 ms) to 741 ms (708-760 ms) p = 0.014 [healthy range <795 ms], as did PDFF from 11% (4-21%), to 3% (2-12%) p = 0.017 [healthy range <5.6%]. There was a significant increase in median (interquartile range) FLR volume from 33% (30-37%)% to 49% (44-52%), p = 0.002. CONCLUSION This non-invasive and reproducible MRI technique showed improvement in volume and quality of the FLR after DVE. This is a significant advance in our understanding of how to prevent liver failure in patients undergoing major liver surgery.
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Affiliation(s)
- Senthil Sundaravadanan
- Department of Hepatobiliary Surgery, Basingstoke and North Hampshire Hospital, Basingstoke, Hampshire, United Kingdom.
| | - Fenella Ks Welsh
- Department of Hepatobiliary Surgery, Basingstoke and North Hampshire Hospital, Basingstoke, Hampshire, United Kingdom
| | - Pulkit Sethi
- Department of Hepatobiliary Surgery, Basingstoke and North Hampshire Hospital, Basingstoke, Hampshire, United Kingdom
| | - Shaheen Noorani
- Department of Interventional Radiology, Basingstoke and North Hampshire Hospital, Basingstoke, Hampshire, United Kingdom
| | - Ben A Cresswell
- Department of Hepatobiliary Surgery, Basingstoke and North Hampshire Hospital, Basingstoke, Hampshire, United Kingdom
| | | | | | - Luis Núñez
- Perspectum, Gemini One, Oxford, United Kingdom
| | | | | | - Myrddin Rees
- Department of Hepatobiliary Surgery, Basingstoke and North Hampshire Hospital, Basingstoke, Hampshire, United Kingdom
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Watkins R, Gamo A, Choi SH, Kumar M, Buckarma E, McCabe C, Tomlinson J, Pereya D, Lupse B, Geravandi S, Werneburg NW, Wang C, Starlinger P, Zhu S, Li S, Yu S, Surakattula M, Baguley T, Ardestani A, Maedler K, Roland J, Nguyen-Tran V, Joseph S, Petrassi M, Rogers N, Gores G, Chatterjee A, Tremblay M, Shen W, Smoot R. A small molecule MST1/2 inhibitor accelerates murine liver regeneration with improved survival in models of steatohepatitis. PNAS NEXUS 2024; 3:pgae096. [PMID: 38528952 PMCID: PMC10962727 DOI: 10.1093/pnasnexus/pgae096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 02/20/2024] [Indexed: 03/27/2024]
Abstract
Dysfunctional liver regeneration following surgical resection remains a major cause of postoperative mortality and has no therapeutic options. Without targeted therapies, the current treatment paradigm relies on supportive therapy until homeostasis can be achieved. Pharmacologic acceleration of regeneration represents an alternative therapeutic avenue. Therefore, we aimed to generate a small molecule inhibitor that could accelerate liver regeneration with an emphasis on diseased models, which represent a significant portion of patients who require surgical resection and are often not studied. Utilizing a clinically approved small molecule inhibitor as a parent compound, standard medicinal chemistry approaches were utilized to generate a small molecule inhibitor targeting serine/threonine kinase 4/3 (MST1/2) with reduced off-target effects. This compound, mCLC846, was then applied to preclinical models of murine partial hepatectomy, which included models of diet-induced metabolic dysfunction-associated steatohepatitis (MASH). mCLC846 demonstrated on target inhibition of MST1/2 and reduced epidermal growth factor receptor inhibition. The inhibitory effects resulted in restored pancreatic beta-cell function and survival under diabetogenic conditions. Liver-specific cell-line exposure resulted in Yes-associated protein activation. Oral delivery of mCLC846 perioperatively resulted in accelerated murine liver regeneration and improved survival in diet-induced MASH models. Bulk transcriptional analysis of regenerating liver remnants suggested that mCLC846 enhanced the normal regenerative pathways and induced them following liver resection. Overall, pharmacological acceleration of liver regeneration with mCLC846 was feasible, had an acceptable therapeutic index, and provided a survival benefit in models of diet-induced MASH.
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Affiliation(s)
- Ryan Watkins
- Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Ana Gamo
- Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Seung Hyuk Choi
- Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Manoj Kumar
- Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - EeeLN Buckarma
- Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Chantal McCabe
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA
| | | | - David Pereya
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna 1090, Austria
| | - Blaz Lupse
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
| | - Shirin Geravandi
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
| | - Nathan W Werneburg
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA
| | - Chen Wang
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA
| | - Patrick Starlinger
- Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Center of Physiology and Pharmacology, Medical University of Vienna, Vienna 1090, Austria
| | - Siying Zhu
- Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Sijia Li
- Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Shan Yu
- Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Murali Surakattula
- Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Tyler Baguley
- Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Amin Ardestani
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
- Biomedical Institute for Multimorbidity (BIM), Centre for Biomedicine, Hull York Medical School, University of Hull, Hull YO10 5DD, UK
| | - Kathrin Maedler
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
| | - Jason Roland
- Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Van Nguyen-Tran
- Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Sean Joseph
- Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Mike Petrassi
- Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Nikki Rogers
- Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Gregory Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA
| | - Arnab Chatterjee
- Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Matthew Tremblay
- Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Weijun Shen
- Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Rory Smoot
- Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
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Wang ZY, Chen RX, Wang JF, Liu SC, Xu X, Zhou T, Chen YAL, Zhang YD, Li XC, Li CX. Apolipoprotein A-1 Accelerated Liver Regeneration Through Regulating Autophagy Via AMPK-ULK1 Pathway. Cell Mol Gastroenterol Hepatol 2023; 17:539-551. [PMID: 38122985 PMCID: PMC10883977 DOI: 10.1016/j.jcmgh.2023.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 12/12/2023] [Accepted: 12/12/2023] [Indexed: 12/23/2023]
Abstract
BACKGROUND & AIMS Apolipoprotein A-1 (ApoA-1), the main apolipoprotein of high-density lipoprotein, has been well studied in the area of lipid metabolism and cardiovascular diseases. In this project, we clarify the function and mechanism of ApoA-1 in liver regeneration. METHODS Seventy percent of partial hepatectomy was applied in male ApoA-1 knockout mice and wild-type mice to investigate the effects of ApoA-1 on liver regeneration. D-4F (ApoA-1 mimetic peptide), autophagy activator, and AMPK activator were used to explore the mechanism of ApoA-1 on liver regeneration. RESULTS We demonstrated that ApoA-1 levels were highly expressed during the early stage of liver regeneration. ApoA-1 deficiency greatly impaired liver regeneration after hepatectomy. Meanwhile, we found that ApoA-1 deficiency inhibited autophagy during liver regeneration. The activation of autophagy protected against ApoA-1 deficiency in inhibiting liver regeneration. Furthermore, ApoA-1 deficiency impaired autophagy through AMPK-ULK1 pathway, and AMPK activation significantly improved liver regeneration. The administration of D-4F could accelerated liver regeneration after hepatectomy. CONCLUSIONS These findings suggested that ApoA-1 played an essential role in liver regeneration through promoting autophagy in hepatocytes via AMPK-ULK1 pathway. Our findings enrich the understanding of the underlying mechanism of liver regeneration and provide a potential therapeutic strategy for liver injury.
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Affiliation(s)
- Zi Yi Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
| | - Rui Xiang Chen
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
| | - Ji Fei Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
| | - Shuo Chen Liu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
| | - Xiao Xu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
| | - Tao Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
| | - Yan An Lan Chen
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
| | - Yao Dong Zhang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
| | - Xiang Cheng Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.
| | - Chang Xian Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.
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10
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Muñoz-Hernández R, Gato S, Gil-Gómez A, Aller R, Rojas A, Morán L, Gallego J, Blázquez-López E, Gallego-Durán R, Montero-Vallejo R, García-Fernández V, Maya-Miles D, Rico MDC, Cubero FJ, Vaquero J, Ampuero J, Bañares R, Romero-Gómez M. Role of EpCAM+ CD133+ extracellular vesicles in steatosis to steatohepatitis transition in NAFLD. Liver Int 2023; 43:1909-1919. [PMID: 37288714 DOI: 10.1111/liv.15604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/30/2023] [Accepted: 04/23/2023] [Indexed: 06/09/2023]
Abstract
BACKGROUND AND AIMS Extracellular vesicles (EVs) have emerged as a potential source of circulating biomarkers in liver disease. We evaluated circulating AV+ EpCAM+ CD133+ EVs as a potential biomarker of the transition from simple steatosis to steatohepatitis. METHODS EpCAM and CD133 liver proteins and EpCAM+ CD133+ EVs levels were analysed in 31 C57BL/6J mice fed with a chow or high fat, high cholesterol and carbohydrates diet (HFHCC) for 52 weeks. The hepatic origin of MVs was addressed using AlbCrexmT/mG mice fed a Western (WD) or Dual diet for 23 weeks. Besides, we assessed plasma MVs in 130 biopsy-proven NAFLD patients. RESULTS Hepatic expression of EpCAM and CD133 and EpCAM+ CD133+ EVs increased during disease progression in HFHCC mice. GFP+ MVs were higher in AlbCrexmT/mG mice fed a WD (5.2% vs 12.1%) or a Dual diet (0.5% vs 7.3%). Most GFP+ MVs were also positive for EpCAM and CD133 (98.3% and 92.9% respectively), suggesting their hepatic origin. In 71 biopsy-proven NAFLD patients, EpCAM+ CD133+ EVs were significantly higher in those with steatohepatitis compare to those with simple steatosis (286.4 ± 61.9 vs 758.4 ± 82.3; p < 0.001). Patients with ballooning 367 ± 40.6 vs 532.0 ± 45.1; p = 0.01 and lobular inflammation (321.1 ± 74.1 vs 721.4 ± 80.1; p = 0.001), showed higher levels of these EVs. These findings were replicated in an independent cohort. CONCLUSIONS Circulating levels of EpCAM+ CD133+ MVs in clinical and experimental NAFLD were increased in the presence of steatohepatitis, showing high potential as a non-invasive biomarker for the evaluation and management of these patients.
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Affiliation(s)
- Rocío Muñoz-Hernández
- SeLiver Group, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Departamento de Medicina, Facultad de Medicina, Universidad de Sevilla, Seville, Spain
| | - Sheila Gato
- SeLiver Group, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Antonio Gil-Gómez
- SeLiver Group, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Rocío Aller
- Department of Medicine, Dermatology and Toxicology, Universidad de Valladolid / Gastroenterology Unit, Hospital Clínico Universitario de Valladolid / BioCritic, Group for Biomedical Research in Critical Care Medicine, Valladolid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
| | - Angela Rojas
- SeLiver Group, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Laura Morán
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
| | - Javier Gallego
- SeLiver Group, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
| | - Elena Blázquez-López
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Rocío Gallego-Durán
- SeLiver Group, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Rocío Montero-Vallejo
- SeLiver Group, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Vanessa García-Fernández
- SeLiver Group, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Departamento de Medicina, Facultad de Medicina, Universidad de Sevilla, Seville, Spain
| | - Douglas Maya-Miles
- SeLiver Group, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - María Del C Rico
- SeLiver Group, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- UCM Digestive diseases, Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | - Francisco J Cubero
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
| | - Javier Vaquero
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Javier Ampuero
- SeLiver Group, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Departamento de Medicina, Facultad de Medicina, Universidad de Sevilla, Seville, Spain
- UCM Digestive diseases, Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | - Rafael Bañares
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Manuel Romero-Gómez
- SeLiver Group, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Departamento de Medicina, Facultad de Medicina, Universidad de Sevilla, Seville, Spain
- UCM Digestive diseases, Hospital Universitario Virgen del Rocío, Sevilla, Spain
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11
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Klatt KC, Petviashvili EJ, Moore DD. LRH-1 induces hepatoprotective nonessential amino acids in response to acute liver injury. J Clin Invest 2023; 133:168805. [PMID: 37009899 PMCID: PMC10065065 DOI: 10.1172/jci168805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2023] Open
Abstract
Acute hepatic injury is observed in response to various stressors, including trauma, ingestion of hepatic toxins, and hepatitis. Investigations to date have focused on extrinsic and intrinsic signals required for hepatocytes to proliferate and regenerate the liver in response to injury, though there is a more limited understanding of induced stress responses promoting hepatocyte survival upon acute injury. In this issue of the JCI, Sun and colleagues detail a mechanism by which local activation of the nuclear receptor liver receptor homolog-1 (LRH-1; NR5A2) directly induces de novo asparagine synthesis and expression of asparagine synthetase (ASNS) in response to injury and show that this response restrains hepatic damage. This work opens up several avenues for inquiry, including the potential for asparagine supplementation to ameliorate acute hepatic injury.
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12
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Cinelli L, Muttillo EM, Felli E, Baiocchini A, Giannone F, Marescaux J, Mutter D, De Mathelin M, Gioux S, Felli E, Diana M. Surgical Models of Liver Regeneration in Pigs: A Practical Review of the Literature for Researchers. Cells 2023; 12:603. [PMID: 36831271 PMCID: PMC9954688 DOI: 10.3390/cells12040603] [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: 12/18/2022] [Revised: 02/01/2023] [Accepted: 02/10/2023] [Indexed: 02/15/2023] Open
Abstract
The remarkable capacity of regeneration of the liver is well known, although the involved mechanisms are far from being understood. Furthermore, limits concerning the residual functional mass of the liver remain critical in both fields of hepatic resection and transplantation. The aim of the present study was to review the surgical experiments regarding liver regeneration in pigs to promote experimental methodological standardization. The Pubmed, Medline, Scopus, and Cochrane Library databases were searched. Studies evaluating liver regeneration through surgical experiments performed on pigs were included. A total of 139 titles were screened, and 41 articles were included in the study, with 689 pigs in total. A total of 29 studies (71% of all) had a survival design, with an average study duration of 13 days. Overall, 36 studies (88%) considered partial hepatectomy, of which four were an associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Remnant liver volume ranged from 10% to 60%. Only 2 studies considered a hepatotoxic pre-treatment, while 25 studies evaluated additional liver procedures, such as stem cell application, ischemia/reperfusion injury, portal vein modulation, liver scaffold application, bio-artificial, and pharmacological liver treatment. Only nine authors analysed how cytokines and growth factors changed in response to liver resection. The most used imaging system to evaluate liver volume was CT-scan volumetry, even if performed only by nine authors. The pig represents one of the best animal models for the study of liver regeneration. However, it remains a mostly unexplored field due to the lack of experiments reproducing the chronic pathological aspects of the liver and the heterogeneity of existing studies.
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Affiliation(s)
- Lorenzo Cinelli
- Department of Gastrointestinal Surgery, San Raffaele Hospital IRCCS, 20132 Milan, Italy
- Research Institute against Digestive Cancer (IRCAD), 67000 Strasbourg, France
| | - Edoardo Maria Muttillo
- Division of General Surgery, Department of Medical and Surgical Sciences and Translational Medicine, Sant’Andrea University Hospital, Sapienza University of Rome, Via di Grottarossa 1035, 00189 Rome, Italy
| | - Emanuele Felli
- Service Chirurgie Digestive et Transplantation Hépatique, Hôpital Trousseau CHU, 37170 Tours, France
| | - Andrea Baiocchini
- Department of Pathology, San Camillo Forlanini Hospital, 00152 Rome, Italy
| | - Fabio Giannone
- Digestive and Endocrine Surgery, Nouvel Hopital Civil, University of Strasbourg, 67000 Strasbourg, France
| | - Jacques Marescaux
- Research Institute against Digestive Cancer (IRCAD), 67000 Strasbourg, France
| | - Didier Mutter
- Digestive and Endocrine Surgery, Nouvel Hopital Civil, University of Strasbourg, 67000 Strasbourg, France
- Institut de Chirurgie Guidée par L’image, University Hospital Institute (IHU), University of Strasbourg, 67000 Strasbourg, France
| | - Michel De Mathelin
- ICube Laboratory, Photonics Instrumentation for Health, 67400 Strasbourg, France
| | - Sylvain Gioux
- ICube Laboratory, Photonics Instrumentation for Health, 67400 Strasbourg, France
| | - Eric Felli
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
| | - Michele Diana
- Research Institute against Digestive Cancer (IRCAD), 67000 Strasbourg, France
- Digestive and Endocrine Surgery, Nouvel Hopital Civil, University of Strasbourg, 67000 Strasbourg, France
- ICube Laboratory, Photonics Instrumentation for Health, 67400 Strasbourg, France
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13
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Rigual MDM, Sánchez Sánchez P, Djouder N. Is liver regeneration key in hepatocellular carcinoma development? Trends Cancer 2023; 9:140-157. [PMID: 36347768 DOI: 10.1016/j.trecan.2022.10.005] [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: 07/13/2022] [Revised: 10/05/2022] [Accepted: 10/10/2022] [Indexed: 11/08/2022]
Abstract
The liver is the largest organ of the mammalian body and has the remarkable ability to fully regenerate in order to maintain tissue homeostasis. The adult liver consists of hexagonal lobules, each with a central vein surrounded by six portal triads localized in the lobule border containing distinct parenchymal and nonparenchymal cells. Because the liver is continuously exposed to diverse stress signals, several sophisticated regenerative processes exist to restore its functional status following impairment. However, these stress signals can affect the liver's capacity to regenerate and may lead to the development of hepatocellular carcinoma (HCC), one of the most aggressive liver cancers. Here, we review the mechanisms of hepatic regeneration and their potential to influence HCC development.
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Affiliation(s)
- María Del Mar Rigual
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain
| | - Paula Sánchez Sánchez
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain
| | - Nabil Djouder
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain.
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14
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Zang X, Wang Z, Li Y, Gao H, Guo J, Jin W, Chang C, Lin J, Zhu K, Xu C. Regulation of Hepatocytes in G0 and G1 Phases by NOTCH3 mRNA, miR-369-3p, and rno-Rmdn2_0006 during the Initial Stage of Rat Liver Regeneration. Genet Res (Camb) 2023; 2023:8779758. [PMID: 37153858 PMCID: PMC10159746 DOI: 10.1155/2023/8779758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 04/17/2023] [Accepted: 04/19/2023] [Indexed: 05/10/2023] Open
Abstract
The key event of liver regeneration initiation (LRI) is the switch of hepatocytes from the G0 phase to the G1 phase. This study aimed to use the data from large-scale quantitatively detecting and analyzing (LQDA) to reveal the regulation of hepatocytes in the G0 or G1 phase by competing endogenous RNAs (ceRNAs) during LRI. The hepatocytes of the rat liver right lobe were isolated 0, 6, and 24 h after partial hepatectomy. Their ceRNA expression level was measured using LQDA, and the correlation among their expression, interaction, and role was revealed by ceRNA comprehensive analysis. The expression of neurogenic loci notch homologous protein 3 (NOTCH3) mRNA was upregulated in 0 h, but the expression of miR-369-3p and rno-Rmdn2_0006 of hepatocytes did not change significantly. Meanwhile, the expression of the G0 phase-related gene CDKN1c was promoted by NOTCH3 upregulation, and the expression of the G1 phase-related gene PSEN2 was inhibited by NOTCH3 downregulation. On the contrary, the expression of NOTCH3 mRNA and rno-Rmdn2_0006 was upregulated at 6 h, but the expression of miR-136-3p was downregulated. The expression of the G1 phase-related genes CHUK, DDX24, HES1, NET1, and STAT3 was promoted by NOTCH3 upregulation, and the expression of the G0 phase-related gene CDKN1a was inhibited by NOTCH3 downregulation. These results suggested that the ceRNAs and the NOTCH3-regulated G0 phase- and G1 phase-related genes showed a correlation in expression, interaction, and role. They together regulated the hepatocytes in the G0 phase at 0 h and in the G1 phase at 6 h. These findings might help understand the mechanism by which ceRNA together regulated the hepatocytes in the G0 or G1 phase.
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Affiliation(s)
- Xiayan Zang
- College of Life Science, Henan Normal University, Xinxiang, China
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Xinxiang, China
| | - Zihui Wang
- College of Life Science, Henan Normal University, Xinxiang, China
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Xinxiang, China
| | - Yafei Li
- College of Life Science, Henan Normal University, Xinxiang, China
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Xinxiang, China
| | - Han Gao
- College of Life Science, Henan Normal University, Xinxiang, China
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Xinxiang, China
| | - Jianlin Guo
- College of Life Science, Henan Normal University, Xinxiang, China
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Xinxiang, China
| | - Wei Jin
- College of Life Science, Henan Normal University, Xinxiang, China
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Xinxiang, China
| | - Cuifang Chang
- College of Life Science, Henan Normal University, Xinxiang, China
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Xinxiang, China
| | - Juntang Lin
- Stem Cell and Biotherapy Technology Research Center, Xinxiang Medical University, Xinxiang, China
| | - Kuicheng Zhu
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Cunshuan Xu
- College of Life Science, Henan Normal University, Xinxiang, China
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Xinxiang, China
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15
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Pretzsch E, Nieß H, Khaled NB, Bösch F, Guba M, Werner J, Angele M, Chaudry IH. Molecular Mechanisms of Ischaemia-Reperfusion Injury and Regeneration in the Liver-Shock and Surgery-Associated Changes. Int J Mol Sci 2022; 23:12942. [PMID: 36361725 PMCID: PMC9657004 DOI: 10.3390/ijms232112942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/16/2022] [Accepted: 10/20/2022] [Indexed: 09/01/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (IRI) represents a major challenge during liver surgery, liver preservation for transplantation, and can cause hemorrhagic shock with severe hypoxemia and trauma. The reduction of blood supply with a concomitant deficit in oxygen delivery initiates various molecular mechanisms involving the innate and adaptive immune response, alterations in gene transcription, induction of cell death programs, and changes in metabolic state and vascular function. Hepatic IRI is a major cause of morbidity and mortality, and is associated with an increased risk for tumor growth and recurrence after oncologic surgery for primary and secondary hepatobiliary malignancies. Therapeutic strategies to prevent or treat hepatic IRI have been investigated in animal models but, for the most part, have failed to provide a protective effect in a clinical setting. This review focuses on the molecular mechanisms underlying hepatic IRI and regeneration, as well as its clinical implications. A better understanding of this complex and highly dynamic process may allow for the development of innovative therapeutic approaches and optimize patient outcomes.
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Affiliation(s)
- Elise Pretzsch
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Hanno Nieß
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Florian Bösch
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany
| | - Markus Guba
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Martin Angele
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Irshad H. Chaudry
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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16
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Lian YE, Bai YN, Lai JL, Huang AM. Aberrant regulation of autophagy disturbs fibrotic liver regeneration after partial hepatectomy. Front Cell Dev Biol 2022; 10:1030338. [PMID: 36393837 PMCID: PMC9644332 DOI: 10.3389/fcell.2022.1030338] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 10/13/2022] [Indexed: 01/04/2025] Open
Abstract
Reports indicate that autophagy is essential for maintaining hepatocyte proliferative capacity during liver regeneration. However, the role of autophagy in fibrotic liver regeneration is incompletely elucidated. We investigated the deregulation of autophagic activities in liver regeneration after partial hepatectomy using a CCl4-induced fibrosis mouse model. The baseline autophagic activity was significantly increased in the fibrotic liver. After 50% partial hepatectomy (PHx), liver regeneration was remarkably decreased, accompanied by increased hepatocyte size and binuclearity ratio. Moreover, the expression of autophagy-related proteins was functionally deregulated and resulted in a reduction in the number of autophagosome and autophagosome-lysosome fusions. We further showed upregulation of autophagy activities through verapamil administration, improved hepatocyte proliferation capacity, and restricted cellular hypertrophy and binuclearity ratio. In conclusion, we demonstrated that the impairment of liver regeneration is associated with aberrant autophagy in fibrotic liver and that enhancing autophagy with verapamil may partially restore the impaired liver regeneration following PHx.
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Affiliation(s)
- Yuan-E. Lian
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
- Department of Pathology, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, China
| | - Yan-Nan Bai
- Shengli Clinical Medical College of Fujian Medical University, Department of Hepatobiliary and Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Jian-Lin Lai
- Shengli Clinical Medical College of Fujian Medical University, Department of Hepatobiliary and Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Ai-Min Huang
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
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17
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Park ES, Dezhbord M, Lee AR, Park BB, Kim KH. Dysregulation of Liver Regeneration by Hepatitis B Virus Infection: Impact on Development of Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14153566. [PMID: 35892823 PMCID: PMC9329784 DOI: 10.3390/cancers14153566] [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] [Received: 06/29/2022] [Revised: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 02/04/2023] Open
Abstract
The liver is unique in its ability to regenerate in response to damage. The complex process of liver regeneration consists of multiple interactive pathways. About 2 billion people worldwide have been infected with hepatitis B virus (HBV), and HBV causes 686,000 deaths each year due to its complications. Long-term infection with HBV, which causes chronic inflammation, leads to serious liver-related diseases, including cirrhosis and hepatocellular carcinoma. HBV infection has been reported to interfere with the critical mechanisms required for liver regeneration. In this review, the studies on liver tissue characteristics and liver regeneration mechanisms are summarized. Moreover, the inhibitory mechanisms of HBV infection in liver regeneration are investigated. Finally, the association between interrupted liver regeneration and hepatocarcinogenesis, which are both triggered by HBV infection, is outlined. Understanding the fundamental and complex liver regeneration process is expected to provide significant therapeutic advantages for HBV-associated hepatocellular carcinoma.
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Affiliation(s)
- Eun-Sook Park
- Institute of Biomedical Science and Technology, School of Medicine, Konkuk University, Seoul 05029, Korea; (E.-S.P.); (B.B.P.)
| | - Mehrangiz Dezhbord
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Korea; (M.D.); (A.R.L.)
| | - Ah Ram Lee
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Korea; (M.D.); (A.R.L.)
| | - Bo Bae Park
- Institute of Biomedical Science and Technology, School of Medicine, Konkuk University, Seoul 05029, Korea; (E.-S.P.); (B.B.P.)
| | - Kyun-Hwan Kim
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Korea; (M.D.); (A.R.L.)
- Correspondence: ; Tel.: +82-31-299-6126
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Watkins RD, Buckarma EH, Tomlinson JL, McCabe CE, Yonkus JA, Werneburg NW, Bayer RL, Starlinger PP, Robertson KD, Wang C, Gores GJ, Smoot RL. SHP2 inhibition enhances Yes-associated protein mediated liver regeneration in murine partial hepatectomy models. JCI Insight 2022; 7:159930. [PMID: 35763355 PMCID: PMC9462473 DOI: 10.1172/jci.insight.159930] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 06/24/2022] [Indexed: 11/17/2022] Open
Abstract
Disrupted liver regeneration following hepatectomy represents an “undruggable” clinical challenge associated with poor patient outcomes. Yes-associated protein (YAP), a transcriptional coactivator that is repressed by the Hippo pathway, is instrumental in liver regeneration. We have previously described an alternative, Hippo-independent mechanism of YAP activation mediated by downregulation of protein tyrosine phosphatase nonreceptor type 11 (PTPN11, also known as SHP2) inhibition. Herein, we examined the effects of YAP activation with a selective SHP1/SHP2 inhibitor, NSC-87877, on liver regeneration in murine partial hepatectomy models. In our studies, NSC-87877 led to accelerated hepatocyte proliferation, improved liver regeneration, and decreased markers of injury following partial hepatectomy. The effects of NSC-87877 were lost in mice with hepatocyte-specific Yap/Taz deletion, and this demonstrated dependence on these molecules for the enhanced regenerative response. Furthermore, administration of NSC-87877 to murine models of nonalcoholic steatohepatitis was associated with improved survival and decreased markers of injury after hepatectomy. Evaluation of transcriptomic changes in the context of NSC-87877 administration revealed reduction in fibrotic signaling and augmentation of cell cycle signaling. Cytoprotective changes included downregulation of Nr4a1, an apoptosis inducer. Collectively, the data suggest that SHP2 inhibition induces a pro-proliferative and cytoprotective enhancement of liver regeneration dependent on YAP.
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Affiliation(s)
- Ryan D Watkins
- Department of Surgery, Mayo Clinic, Rochester, United States of America
| | - EeeLN H Buckarma
- Department of Surgery, Mayo Clinic, Rochester, United States of America
| | | | - Chantal E McCabe
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, United States of America
| | - Jennifer A Yonkus
- Department of Surgery, Mayo Clinic, Rochester, United States of America
| | - Nathan W Werneburg
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, United States of America
| | - Rachel L Bayer
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, United States of America
| | | | - Keith D Robertson
- Division of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America
| | - Chen Wang
- Department of Health Sciences Research, Mayo Clinic, Rochester, United States of America
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, United States of America
| | - Rory L Smoot
- Department of Surgery, Mayo Clinic, Rochester, United States of America
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19
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Hu Y, Zhang H, Xie N, Liu D, Jiang Y, Liu Z, Ye D, Liu S, Chen X, Li C, Wang Q, Huang X, Liu Y, Shi Y, Zhang X. Bcl-3 promotes TNF-induced hepatocyte apoptosis by regulating the deubiquitination of RIP1. Cell Death Differ 2022; 29:1176-1186. [PMID: 34853447 PMCID: PMC9177694 DOI: 10.1038/s41418-021-00908-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 11/16/2021] [Accepted: 11/16/2021] [Indexed: 11/09/2022] Open
Abstract
Tumor necrosis factor-α (TNF) is described as a main regulator of cell survival and apoptosis in multiple types of cells, including hepatocytes. Dysregulation in TNF-induced apoptosis is associated with many autoimmune diseases and various liver diseases. Here, we demonstrated a crucial role of Bcl-3, an IκB family member, in regulating TNF-induced hepatic cell death. Specifically, we found that the presence of Bcl-3 promoted TNF-induced cell death in the liver, while Bcl-3 deficiency protected mice against TNF/D-GalN induced hepatoxicity and lethality. Consistently, Bcl-3-depleted hepatic cells exhibited decreased sensitivity to TNF-induced apoptosis when stimulated with TNF/CHX. Mechanistically, the in vitro results showed that Bcl-3 interacted with the deubiquitinase CYLD to synergistically switch the ubiquitination status of RIP1 and facilitate the formation of death-inducing Complex II. This complex further resulted in activation of the caspase cascade to induce apoptosis. By revealing this novel role of Bcl-3 in regulating TNF-induced hepatic cell death, this study provides a potential therapeutic target for liver diseases caused by TNF-related apoptosis.
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Affiliation(s)
- Yiming Hu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Haohao Zhang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Ningxia Xie
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
| | - Dandan Liu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Yuhang Jiang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Zhi Liu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Deji Ye
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Sanhong Liu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 201203, Shanghai, China
| | - Xi Chen
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Cuifeng Li
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Qi Wang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Xingxu Huang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
| | - Yongzhong Liu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200032, Shanghai, China
| | - Yufang Shi
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Xiaoren Zhang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China.
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China.
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20
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Hazrati A, Malekpour K, Soudi S, Hashemi SM. Mesenchymal Stromal/Stem Cells and Their Extracellular Vesicles Application in Acute and Chronic Inflammatory Liver Diseases: Emphasizing on the Anti-Fibrotic and Immunomodulatory Mechanisms. Front Immunol 2022; 13:865888. [PMID: 35464407 PMCID: PMC9021384 DOI: 10.3389/fimmu.2022.865888] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 03/15/2022] [Indexed: 12/21/2022] Open
Abstract
Various factors, including viral and bacterial infections, autoimmune responses, diabetes, drugs, alcohol abuse, and fat deposition, can damage liver tissue and impair its function. These factors affect the liver tissue and lead to acute and chronic liver damage, and if left untreated, can eventually lead to cirrhosis, fibrosis, and liver carcinoma. The main treatment for these disorders is liver transplantation. Still, given the few tissue donors, problems with tissue rejection, immunosuppression caused by medications taken while receiving tissue, and the high cost of transplantation, liver transplantation have been limited. Therefore, finding alternative treatments that do not have the mentioned problems is significant. Cell therapy is one of the treatments that has received a lot of attention today. Hepatocytes and mesenchymal stromal/stem cells (MSCs) are used in many patients to treat liver-related diseases. In the meantime, the use of mesenchymal stem cells has been studied more than other cells due to their favourable characteristics and has reduced the need for liver transplantation. These cells increase the regeneration and repair of liver tissue through various mechanisms, including migration to the site of liver injury, differentiation into liver cells, production of extracellular vesicles (EVs), secretion of various growth factors, and regulation of the immune system. Notably, cell therapy is not entirely excellent and has problems such as cell rejection, undesirable differentiation, accumulation in unwanted locations, and potential tumorigenesis. Therefore, the application of MSCs derived EVs, including exosomes, can help treat liver disease and prevent its progression. Exosomes can prevent apoptosis and induce proliferation by transferring different cargos to the target cell. In addition, these vesicles have been shown to transport hepatocyte growth factor (HGF) and can promote the hepatocytes'(one of the most important cells in the liver parenchyma) growths.
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Affiliation(s)
- Ali Hazrati
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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21
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Martinez-Castillo M, León-Mancilla B, Ramírez-Rico G, Alfaro A, Pérez-Torres A, Díaz-Infante D, García-Loya J, Medina-Avila Z, Sanchez-Hernandez J, Piña-Barba C, Gutierrez-Reyes G. Xenoimplant of Collagen Matrix Scaffold in Liver Tissue as a Niche for Liver Cells. Front Med (Lausanne) 2022; 9:808191. [PMID: 35463025 PMCID: PMC9022037 DOI: 10.3389/fmed.2022.808191] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 02/23/2022] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus-induced liver damage, chronic liver damage due to alcohol, and non-alcoholic liver disease-induced cellular alterations promote fibrosis, cirrhosis, and/or hepatocellular carcinoma. The recommended therapeutic option for advanced liver damage is liver transplantation. Extracellular matrix scaffolds have been evaluated as an alternative for tissue restoration. Studies on the biocompatibility and rejection of synthetic and natural scaffolds as an alternative to organ transplantation have been evaluated. Our group has recently described the xenoimplant of collagen matrix scaffold (CMS) in a rat model. However, no complete macroscopic and histological description of the liver parenchyma at the initial (day 3), intermediate (day 14), and advanced (day 21) stages has been obtained. In this study, we described and compared liver tissue from the CMS zone (CZ, CMS, and liver parenchyma), liver tissue from the normal zone (liver parenchyma close to the CMS), and basal tissue (resected tissue from the CMS implantation site). Our data strongly suggest that the collagen matrix xenoimplant is a good niche for hepatocytes, with no rejection, and does not affect liver function tests. The liver can regenerate after damage, but this capacity is inhibited in a chronic injury. At present, the use of CMS after liver damage has not been reported. This biomaterial could be a novel alternative in the field of regenerative medicine for liver diseases.
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Affiliation(s)
- Moises Martinez-Castillo
- Liver, Pancreas and Motility Laboratory, Unit of Research in Experimental Medicine, School of Medicine, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Benjamín León-Mancilla
- Liver, Pancreas and Motility Laboratory, Unit of Research in Experimental Medicine, School of Medicine, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Gerardo Ramírez-Rico
- Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México (UNAM), Cuautitlán Izcalli, Mexico
| | - Ana Alfaro
- Department of Pathology, Hospital General de México, Mexico City, Mexico
| | - Armando Pérez-Torres
- Department of Cells and Tissue Biology, School of Medicine, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Daniela Díaz-Infante
- Liver, Pancreas and Motility Laboratory, Unit of Research in Experimental Medicine, School of Medicine, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Jorge García-Loya
- Liver, Pancreas and Motility Laboratory, Unit of Research in Experimental Medicine, School of Medicine, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Zaira Medina-Avila
- Liver, Pancreas and Motility Laboratory, Unit of Research in Experimental Medicine, School of Medicine, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Jaime Sanchez-Hernandez
- Liver, Pancreas and Motility Laboratory, Unit of Research in Experimental Medicine, School of Medicine, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Cristina Piña-Barba
- Materials Research Institute, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Gabriela Gutierrez-Reyes
- Liver, Pancreas and Motility Laboratory, Unit of Research in Experimental Medicine, School of Medicine, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
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22
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Hadjittofi C, Feretis M, Martin J, Harper S, Huguet E. Liver regeneration biology: Implications for liver tumour therapies. World J Clin Oncol 2021; 12:1101-1156. [PMID: 35070734 PMCID: PMC8716989 DOI: 10.5306/wjco.v12.i12.1101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.
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Affiliation(s)
- Christopher Hadjittofi
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Michael Feretis
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Jack Martin
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Simon Harper
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Huguet
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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23
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Rohan E, Camprová Turjanicová J, Liška V. Geometrical model of lobular structure and its importance for the liver perfusion analysis. PLoS One 2021; 16:e0260068. [PMID: 34855778 PMCID: PMC8638901 DOI: 10.1371/journal.pone.0260068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 11/02/2021] [Indexed: 11/18/2022] Open
Abstract
A convenient geometrical description of the microvascular network is necessary for computationally efficient mathematical modelling of liver perfusion, metabolic and other physiological processes. The tissue models currently used are based on the generally accepted schematic structure of the parenchyma at the lobular level, assuming its perfect regular structure and geometrical symmetries. Hepatic lobule, portal lobule, or liver acinus are considered usually as autonomous functional units on which particular physiological problems are studied. We propose a new periodic unit-the liver representative periodic cell (LRPC) and establish its geometrical parametrization. The LRPC is constituted by two portal lobulae, such that it contains the liver acinus as a substructure. As a remarkable advantage over the classical phenomenological modelling approaches, the LRPC enables for multiscale modelling based on the periodic homogenization method. Derived macroscopic equations involve so called effective medium parameters, such as the tissue permeability, which reflect the LRPC geometry. In this way, mutual influences between the macroscopic phenomena, such as inhomogeneous perfusion, and the local processes relevant to the lobular (mesoscopic) level are respected. The LRPC based model is intended for its use within a complete hierarchical model of the whole liver. Using the Double-permeability Darcy model obtained by the homogenization, we illustrate the usefulness of the LRPC based modelling to describe the blood perfusion in the parenchyma.
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Affiliation(s)
- Eduard Rohan
- Department of Mechanics, Faculty of Applied Sciences, NTIS – New Technologies for Information Society, University of West Bohemia, Pilsen, Czech Republic
- * E-mail:
| | - Jana Camprová Turjanicová
- Department of Mechanics, Faculty of Applied Sciences, NTIS – New Technologies for Information Society, University of West Bohemia, Pilsen, Czech Republic
| | - Václav Liška
- Biomedical Center, Faculty of Medicine, Charles University Pilsen, Pilsen, Czech Republic
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24
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Xu L, Ling J, Su C, Su YW, Xu Y, Jiang Z. Emerging Roles on Immunological Effect of Indoleamine 2,3-Dioxygenase in Liver Injuries. Front Med (Lausanne) 2021; 8:756435. [PMID: 34869457 PMCID: PMC8636938 DOI: 10.3389/fmed.2021.756435] [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] [Received: 09/10/2021] [Accepted: 10/22/2021] [Indexed: 11/13/2022] Open
Abstract
Indoleamine 2,3-dioxygenase (IDO) is one of the initial rate-limiting enzymes of the kynurenine pathway (KP), which causes immune suppression and induction of T cell anergy. It is associated with the imbalance of immune homeostasis in numerous diseases including cancer, chronic viral infection, allergy, and autoimmune diseases. Recently, IDO has extended its role to liver field. In this review, we summarize the dysregulation and potentials of IDO in the emerging field of liver injuries, as well as current challenges for IDO targets. In particular, we discuss unexpected conclusions against previous work published. IDO is induced by pro-inflammatory cytokines in liver dysfunction and exerts an immunosuppressive effect, whereas the improvement of liver injury may require consideration of multiple factors besides IDO.
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Affiliation(s)
- Lingyan Xu
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Jiawei Ling
- Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong, China
| | - Chang Su
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Yu-Wen Su
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
- School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Yan Xu
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Zhenzhou Jiang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China
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25
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Huang W, Han N, Du L, Wang M, Chen L, Tang H. A narrative review of liver regeneration-from models to molecular basis. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1705. [PMID: 34988214 PMCID: PMC8667151 DOI: 10.21037/atm-21-5234] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/04/2021] [Indexed: 12/11/2022]
Abstract
Objective To elucidate the characteristics of different liver regeneration animal models, understand the activation signals and mechanisms related to liver regeneration, and obtain a more comprehensive conception of the entire liver regeneration process. Background Liver regeneration is one of the most enigmatic and fascinating phenomena of the human organism. Despite suffering significant injuries, the liver still can continue to perform its complex functions through the regeneration system. Although advanced topics on liver regeneration have been proposed; unfortunately, complete regeneration of the liver has not been achieved until now. Therefore, increasing understanding of the liver regenerative process can help improve our treatment of liver failure. It will provide a new sight for the treatment of patients with liver injury in the clinic. Methods Literatures on liver regeneration animal models and involved basic research on molecular mechanisms were retrieved to analyze the characteristics of different models and those related to molecular basis. Conclusions The process of liver regeneration is complex and intricate, consisting of various and interactive pathways. There is sufficient evidence to demonstrate that liver regeneration is similar between humans and rodents. At the same time, many of the same cytokines, growth factors, and signaling pathways are relevant. There are many gaps in our current knowledge. Understanding of this knowledge will provide more supportive clinical treatment strategies, including small-scale liver transplantation and high-quality regenerative process after surgical resection, and offer possible targets to treat the dysregulation of regeneration that occurs in chronic hepatic diseases and tumors. Current research work, such as the use of animal models as in vivo vectors for high-quality human hepatocytes, represents a unique and significant cutting edge in the field of liver regeneration.
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Affiliation(s)
- Wei Huang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.,Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Ning Han
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.,Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Lingyao Du
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.,Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Ming Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.,Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Liyu Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.,Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.,Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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Feng L, Wang Y, Wang X, An S, Aizimuaji Z, Tao C, Zhang K, Cheng S, Wu J, Xiao T, Rong W. Integrated analysis of the rhesus monkey liver transcriptome during development and human primary HCC AFP-related gene expression. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 25:406-415. [PMID: 34484865 PMCID: PMC8403716 DOI: 10.1016/j.omtn.2021.06.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 06/16/2021] [Indexed: 01/10/2023]
Abstract
Embryonic development and tumorigenesis have a certain degree of similarity. Alpha-fetoprotein (AFP), a protein related to embryonic development, is a well-known biomarker for the diagnosis and prognosis of hepatocellular carcinoma (HCC). In this study, we analyzed the differences in gene expression profiles and molecular mechanisms in human HCC tissues from patients in AFPhigh (serum AFP level ≥ 25 ng/mL) and AFPlow (serum AFP level < 25 ng/mL) groups. The results indicated that AFPhigh HCC has more malignant biological characteristics. Single-sample gene set enrichment analysis (ssGSEA) showed significantly higher levels of genes expressed in dendritic cells, neutrophils, and natural killer cells in the AFPlow group than in the AFPhigh group. Then, we defined a rhesus monkey fetal liver developmental landscape and compared it to the HCC gene expression profile. The gene signatures of AFPhigh HCC tissues were similar to those of early embryonic liver tissues. In this study, we comprehensively analyzed the rhesus monkey liver transcriptome during development and human primary HCC AFP-related gene expression profiles and clarified the function of AFP in the occurrence and development of HCC from the perspective of developmental biology, which might provide a new perspective on the pathogenesis of HCC.
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Affiliation(s)
- Lin Feng
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yaru Wang
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xijun Wang
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Songlin An
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zulihumaer Aizimuaji
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Changcheng Tao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Kai Zhang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Shujun Cheng
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jianxiong Wu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Corresponding author: Dr. Jianxiong Wu, Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
| | - Ting Xiao
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Corresponding author: Dr. Ting Xiao, State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
| | - Weiqi Rong
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Corresponding author: Dr. Weiqi Rong, Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
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Elchaninov A, Lokhonina A, Vishnyakova P, Soboleva A, Poltavets A, Artemova D, Makarov A, Glinkina V, Goldshtein D, Bolshakova G, Sukhikh G, Fatkhudinov T. MARCO + Macrophage Dynamics in Regenerating Liver after 70% Liver Resection in Mice. Biomedicines 2021; 9:1129. [PMID: 34572315 PMCID: PMC8471044 DOI: 10.3390/biomedicines9091129] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 08/25/2021] [Accepted: 08/28/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Macrophages play a key role in liver regeneration. The fates of resident macrophages after 70% resection are poorly investigated. In this work, using the MARCO macrophage marker (abbreviated from macrophage receptor with collagenous structure), we studied the dynamics of mouse liver resident macrophages after 70% resection. METHODS In BALB/c male mice, a model of liver regeneration after 70% resection was reproduced. The dynamics of markers CD68, TIM4, and MARCO were studied immunohistochemically and by using a Western blot. RESULTS The number of MARCO- and CD68-positive macrophages in the regenerating liver increased 1 day and 3 days after resection, respectively. At the same time, the content of the MARCO protein increased in the sorted macrophages of the regenerating liver on the third day. CONCLUSIONS The data indicate that the number of MARCO-positive macrophages in the regenerating liver increases due to the activation of MARCO synthesis in the liver macrophages. The increased expression of MARCO by macrophages can be regarded as a sign of their activation. In the present study, stimulation with LPS led to an increase in the expression of the Marco gene in both Kupffer cells and macrophages of bone marrow origin.
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Affiliation(s)
- Andrey Elchaninov
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia; (A.L.); (P.V.); (A.P.); (G.S.)
- Histology Department, Medical Institute, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia; (A.M.); (T.F.)
| | - Anastasia Lokhonina
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia; (A.L.); (P.V.); (A.P.); (G.S.)
- Histology Department, Medical Institute, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia; (A.M.); (T.F.)
| | - Polina Vishnyakova
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia; (A.L.); (P.V.); (A.P.); (G.S.)
- Histology Department, Medical Institute, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia; (A.M.); (T.F.)
| | - Anna Soboleva
- Laboratory of Growth and Development, Scientific Research Institute of Human Morphology, 117418 Moscow, Russia; (A.S.); (D.A.); (G.B.)
| | - Anastasiya Poltavets
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia; (A.L.); (P.V.); (A.P.); (G.S.)
| | - Daria Artemova
- Laboratory of Growth and Development, Scientific Research Institute of Human Morphology, 117418 Moscow, Russia; (A.S.); (D.A.); (G.B.)
| | - Andrey Makarov
- Histology Department, Medical Institute, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia; (A.M.); (T.F.)
| | - Valeria Glinkina
- Histology Department, Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, 117997 Moscow, Russia;
| | - Dmitry Goldshtein
- Stem Cell Genetics Laboratory, Research Centre for Medical Genetics, 115522 Moscow, Russia;
| | - Galina Bolshakova
- Laboratory of Growth and Development, Scientific Research Institute of Human Morphology, 117418 Moscow, Russia; (A.S.); (D.A.); (G.B.)
| | - Gennady Sukhikh
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia; (A.L.); (P.V.); (A.P.); (G.S.)
| | - Timur Fatkhudinov
- Histology Department, Medical Institute, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia; (A.M.); (T.F.)
- Laboratory of Growth and Development, Scientific Research Institute of Human Morphology, 117418 Moscow, Russia; (A.S.); (D.A.); (G.B.)
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Gao Y, Lyu L, Feng Y, Li F, Hu Y. A review of cutting-edge therapies for hepatocellular carcinoma (HCC): Perspectives from patents. Int J Med Sci 2021; 18:3066-3081. [PMID: 34400877 PMCID: PMC8364461 DOI: 10.7150/ijms.59930] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 05/11/2021] [Indexed: 12/13/2022] Open
Abstract
Rationale: Hepatocellular carcinoma (HCC) is a challenging disease due to its heterogenous etiology. Several breakthroughs have occurred in treatment of HCC, associated with an enormous number of patent publications for a variety of HCC treatment modalities. As patents can provide valuable information for academic research and commercial development, this study aims to unravel the cutting-edge therapies for HCC by using patents as an indicator. The outcome from this analysis may offer meaningful insights for respective policymaking, strategic plan and research and development (R&D) prioritization. Methods: Derwent Innovation platform was employed to collect the sample data of patents related to HCC treatment technologies worldwide as of December 31, 2019. Data inclusion, screening and exclusion were according to the rules of preferred reporting items for systematic reviews and meta-analyses (PRISMA). Technologies were classified based on Barcelona Clinic Liver Cancer (BCLC) staging system and recent clinical publications. Patent citation network analysis was carried out to identify and understand HCC therapeutic technology flow. Results: A dataset of 2543 patent documents and 528 patent families was generated. 11 technological categories were classified. Numerous researches were focalized on refinements in technologies and innovations within the field of HCC therapy, and the major achievements are technology advancement on molecular target therapy, chemotherapy, locoregional therapy, combination therapy and immunotherapy with demonstrated clinical benefits. In patent citation network, Notch pathway investigation, antibody drug conjugate (ADC) technology development and drug eluting beads trans artery chemoembolization (DEB-TACE) advancement are the major technological communities involving patents with the greatest future exploratory potential. Conclusion: Numerous emerging technologies have been identified in this study, in which exploring novel therapeutic targets in molecular target therapy, more localized and visible locoregional therapy and combination of immunotherapy with target therapy or other traditional therapies are highlighted as the future trends in treating HCC.
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Affiliation(s)
| | | | | | | | - Yuanjia Hu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China
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Chen Y, Xu Z, Zeng Y, Liu J, Wang X, Kang Y. Altered metabolism by autophagy defection affect liver regeneration. PLoS One 2021; 16:e0250578. [PMID: 33914811 PMCID: PMC8084245 DOI: 10.1371/journal.pone.0250578] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 04/08/2021] [Indexed: 11/19/2022] Open
Abstract
Autophagy is the primary intracellular catabolic process for degrading and recycling long-lived proteins and damaged organelles, which maintains cellular homeostasis. Autophagy has key roles in development and differentiation. By using the mouse with liver specific knockout of autophagy related gene 5 (Atg5), a gene essential for autophagy, we investigated the possible role of autophagy in liver regeneration after 70% partial hepatectomy (PHx). Ablation of autophagy significantly impaired mouse liver regeneration, and this impairment was associated with reduced hepatocellular proliferation rate, down-regulated expression of cyclins and tumor suppressors, and increased hepatocellular apoptosis via the intrinsic apoptotic pathway. Ablation of autophagy does not affect IL-6 and TNF-α response after PHx, but the altered hepatic and systemic metabolic responses were observed in these mice, including reduced ATP and hepatic free fatty acid levels in the liver tissue, increased glucose level in the serum. Autophagy is required to promote hepatocellular proliferation by maintaining normal hepatic and systemic metabolism and suppress hepatocellular apoptosis in liver regeneration.
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Affiliation(s)
- Yi Chen
- Clinical Research Service Center, Henan Provincia People’s Hospital, Zhengzhou University People’s Hospital, Henan Province, Zhengzhou, China
| | - Zhiwei Xu
- Clinical Research Service Center, Henan Provincia People’s Hospital, Zhengzhou University People’s Hospital, Henan Province, Zhengzhou, China
| | - Yanli Zeng
- Department of Infectious Diseases, Henan Provincia People’s Hospital, Zhengzhou University People’s Hospital, Henan Province, Zhengzhou, China
| | - Junping Liu
- Department of Infectious Diseases, Henan Provincia People’s Hospital, Zhengzhou University People’s Hospital, Henan Province, Zhengzhou, China
| | - Xuemei Wang
- Department of Traditional Chinese Medicine, Henan Provincia People’s Hospital, Zhengzhou University People’s Hospital, Henan Province, Zhengzhou, China
| | - Yi Kang
- Department of Infectious Diseases, Henan Provincia People’s Hospital, Zhengzhou University People’s Hospital, Henan Province, Zhengzhou, China
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Transaminase Elevations during Treatment of Chronic Hepatitis B Infection: Safety Considerations and Role in Achieving Functional Cure. Viruses 2021; 13:v13050745. [PMID: 33922828 PMCID: PMC8146791 DOI: 10.3390/v13050745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/20/2021] [Accepted: 04/22/2021] [Indexed: 11/17/2022] Open
Abstract
While current therapies for chronic HBV infection work well to control viremia and stop the progression of liver disease, the preferred outcome of therapy is the restoration of immune control of HBV infection, allowing therapy to be removed while maintaining effective suppression of infection and reversal of liver damage. This “functional cure” of chronic HBV infection is characterized by the absence of detectable viremia (HBV DNA) and antigenemia (HBsAg) and normal liver function and is the goal of new therapies in development. Functional cure requires removal of the ability of infected cells in the liver to produce the hepatitis B surface antigen. The increased observation of transaminase elevations with new therapies makes understanding the safety and therapeutic impact of these flares an increasingly important issue. This review examines the factors driving the appearance of transaminase elevations during therapy of chronic HBV infection and the interplay of these factors in assessing the safety and beneficial nature of these flares.
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31
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Luo D, Jin B, Zhai X, Li J, Liu C, Guo W, Li J. Oxytocin promotes hepatic regeneration in elderly mice. iScience 2021; 24:102125. [PMID: 33659883 PMCID: PMC7895748 DOI: 10.1016/j.isci.2021.102125] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 12/15/2020] [Accepted: 01/26/2021] [Indexed: 12/23/2022] Open
Abstract
Liver aging impairs the ability of hepatocyte regeneration. Recent studies have found that oxytocin (OT) plays an important role in promoting tissue repair and maintaining differentiation and regeneration of stem cells. Here, we reported that OT receptors, which are specifically located in hepatocytes, decrease with aging in human and mice. Interestingly, the level of serum OT also decline with age. Notably, OT promotes hepatocyte regeneration only in aged mice but not in young mice in vitro and in vivo. Further studies reveal that OT promotes autophagy in either AML12 mouse hepatocytes or aged mice after partial hepatectomy or with CCl4-induced acute liver injury. In conclusion, OT promotes liver regeneration, especially in aged mice, which may be achieved by promoting autophagy. All these results support the possibility of OT and its analog being a potent anti-aging drug and promote liver rejuvenation.
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Affiliation(s)
- Dan Luo
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Bin Jin
- Department of general surgery, Qilu hospital of Shandong University, Jinan 250012, China
| | - Xiangyu Zhai
- Department of general surgery, Qilu hospital of Shandong University, Jinan 250012, China
| | - Jing Li
- Department of Pathology, Central Hospital of Zibo, Zibo 255036, China
| | - Chuanyong Liu
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Wei Guo
- Department of general surgery, Qilu hospital of Shandong University, Jinan 250012, China
| | - Jingxin Li
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
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32
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Zhu YX, Zhu L, Chen YF, Xu JM, Shne ZL, Liu RJ, Zou J, Yuan MQ, Ye F, Zeng QQ. Luteoloside Ameliorates Palmitic Acid-Induced in Vitro Model of Non-alcoholic Fatty Liver Disease via Activating STAT3-Triggered Hepatocyte Regeneration. Folia Biol (Praha) 2021; 67:126-133. [PMID: 35151246 DOI: 10.14712/fb2021067030126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Luteoloside (Lute), a bioactive natural ingredient, widely exists in nature and possesses hepatoprotective and hepatocyte proliferation-promoting properties. This study aimed to investigate whether Lute could counteract non-alcoholic fatty liver disease (NAFLD)-caused hepatocyte damage via its stimulation of hepatocyte regeneration efficacy and to explore the involved mechanism. LO2 cells and primary hepatocytes were used to examine the hepatocyte proliferation effects of Lute under physiological conditions and in the palmitic acid (PA)- induced in vitro model of NAFLD. STAT3 and cell cycle-related proteins (cyclin D1, c-myc and p21) were evaluated by Western blot. Under physiological conditions, LO2 cells and primary hepatocytes treated with various concentration of Lute for 12 and 24 h showed increased hepatocyte proliferation, especially with 20 μM treatment for 24 h. More notably, under the model conditions, co-incubation with 20 μM of Lute also markedly reversed PA-induced inhibition of cell proliferation and viability in primary hepatocytes. Mechanistically, Lute could activate STAT3 and subsequently increase cyclin D1 and cmyc expression, which positively regulates cell cycle progression, and decrease expression of p21, an inhibitor of cell cycle progression. Furthermore, Luteinduced hepatocyte proliferation-promoting efficacy was abolished by STAT3 inhibitor stattic. Collectively, Lute can alleviate PA-induced hepatocyte damage via activating STAT3-mediated hepatocyte regeneration.
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Affiliation(s)
- Y X Zhu
- Department of Pharmacy, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangshu, China
| | - L Zhu
- Department of Pharmacy, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangshu, China
| | - Y F Chen
- Department of Pharmacy, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangshu, China
| | - J M Xu
- Department of Pharmacy, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangshu, China
| | - Z L Shne
- Department of Pharmacy, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangshu, China
| | - R J Liu
- Department of Pharmacy, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangshu, China
| | - J Zou
- Department of Pharmacy, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangshu, China
| | - M Q Yuan
- Department of Pharmacy, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangshu, China
| | - F Ye
- Department of Pharmacy, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangshu, China
| | - Q Q Zeng
- Jiangsu Health Vocational College; Nanjing 210023, China
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Herranz-Itúrbide M, López-Luque J, Gonzalez-Sanchez E, Caballero-Díaz D, Crosas-Molist E, Martín-Mur B, Gut M, Esteve-Codina A, Jaquet V, Jiang JX, Török NJ, Fabregat I. NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice. Redox Biol 2020; 40:101841. [PMID: 33493901 PMCID: PMC7823210 DOI: 10.1016/j.redox.2020.101841] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/17/2020] [Accepted: 12/17/2020] [Indexed: 12/21/2022] Open
Abstract
Liver is a unique organ in displaying a reparative and regenerative response after acute/chronic damage or partial hepatectomy, when all the cell types must proliferate to re-establish the liver mass. The NADPH oxidase NOX4 mediates Transforming Growth Factor-beta (TGF-β) actions, including apoptosis in hepatocytes and activation of stellate cells to myofibroblasts. Aim of this work was to analyze the impact of NOX4 in liver regeneration by using two mouse models where Nox4 was deleted: 1) general deletion of Nox4 (NOX4-/-) and 2) hepatocyte-specific deletion of Nox4 (NOX4hepKO). Liver regeneration was analyzed after 2/3 partial hepatectomy (PH). Results indicated an earlier recovery of the liver-to-body weight ratio in both NOX4-/- and NOX4hepKO mice and an increased survival, when compared to corresponding WT mice. The regenerative hepatocellular fat accumulation and the parenchyma organization recovered faster in NOX4 deleted livers. Hepatocyte proliferation, analyzed by Ki67 and phospho-Histone3 immunohistochemistry, was accelerated and increased in NOX4 deleted mice, coincident with an earlier and increased Myc expression. Primary hepatocytes isolated from NOX4 deleted mice showed higher proliferative capacity and increased expression of Myc and different cyclins in response to serum. Transcriptomic analysis through RNA-seq revealed significant changes after PH in NOX4-/- mice and support a relevant role for Myc in a node of regulation of proliferation-related genes. Interestingly, RNA-seq also revealed changes in the expression of genes related to activation of the TGF-β pathway. In fact, levels of active TGF-β1, phosphorylation of Smads and levels of its target p21 were lower at 24 h in NOX4 deleted mice. Nox4 did not appear to be essential for the termination of liver regeneration in vivo, neither for the in vitro hepatocyte response to TGF-β1 in terms of growth inhibition, which suggest its potential as therapeutic target to improve liver regeneration, without adverse effects.
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Affiliation(s)
- M Herranz-Itúrbide
- TGF-β and Cancer Group. Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Spain
| | - J López-Luque
- TGF-β and Cancer Group. Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Spain
| | - E Gonzalez-Sanchez
- TGF-β and Cancer Group. Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Spain; Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Spain
| | - D Caballero-Díaz
- TGF-β and Cancer Group. Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Spain
| | - E Crosas-Molist
- TGF-β and Cancer Group. Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - B Martín-Mur
- CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
| | - M Gut
- CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain
| | - A Esteve-Codina
- CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
| | - V Jaquet
- Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland; RE.A.D.S Unit, Medical School, University of Geneva, Geneva, Switzerland
| | - J X Jiang
- Gastroenterology and Hepatology, UC Davis, Sacramento, CA, USA
| | - N J Török
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | - I Fabregat
- TGF-β and Cancer Group. Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Spain; Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Spain.
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Bayraktar B, Tekce E, Aksakal V, Gül M, Takma Ç, Bayraktar S, Bayraktar FG, Eser G. Effect of the addition of essential fatty acid mixture to the drinking water of the heat stress broilers on adipokine (Apelin, BDNF) response, histopathologic findings in liver and intestines, and some blood parameters. ITALIAN JOURNAL OF ANIMAL SCIENCE 2020. [DOI: 10.1080/1828051x.2020.1778548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Bülent Bayraktar
- Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation, Bayburt University, Bayburt, Turkey
| | - Emre Tekce
- Faculty of Applied Sciences, Department of Organic Agriculture Management, Bayburt University, Bayburt, Turkey
| | - Vecihi Aksakal
- Faculty of Applied Sciences, Department of Organic Agriculture Management, Bayburt University, Bayburt, Turkey
| | - Mehmet Gül
- Faculty of Veterinary Medicine, Animal Nutrition and Nutrition Disease, Atatürk University, Erzurum, Turkey
| | - Çiğdem Takma
- Faculty of Agriculture, Department of Animal Science, Biometry and Genetics Unit, Ege University, İzmir, Turkey
| | - Sevil Bayraktar
- Faculty of Veterinary Medicine, Department of physiology, Ondokuz Mayıs University, Samsun, Turkey
| | - Fatma Gülten Bayraktar
- Faculty of Veterinary Medicine, Department of pathology, Atatürk University, Erzurum, Turkey
| | - Gizem Eser
- Faculty of Veterinary Medicine, Department of pathology, Atatürk University, Erzurum, Turkey
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35
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Xu Y, Li W, Liang G, Peng J, Xu X. Platelet microparticles-derived miR-25-3p promotes the hepatocyte proliferation and cell autophagy via reducing B-cell translocation gene 2. J Cell Biochem 2020; 121:4959-4973. [PMID: 32692910 DOI: 10.1002/jcb.29825] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 05/07/2020] [Accepted: 06/23/2020] [Indexed: 12/26/2022]
Abstract
Platelets are critical regulators of liver regeneration, but the mechanisms are still not fully understood. Platelets have been shown to contain a wide variety of microRNAs (miRNAs) and play an important role in many diseases. However, the mechanism that how the platelet microparticles (PMPs)-derived miRNA regulate the hepatocyte proliferation is not very clear. In this study, we have successfully isolated and identified PMPs. We also found that PMPs, which could be well integrated into the HHL-5 cells, could upregulate the level of miR-25-3p in HHL-5 cells. Meanwhile, we found that PMPs-derived miR-25-3p promoted HHL-5 cells proliferation by accelerating cells into the S phase, and enhanced the autophagy by increasing the LC3II expression and reducing the P62 expression. Then, we proved that the miR-25-3p could target the B-cell translocation gene 2 (BTG2) and downregulate the expression levels of the BTG2 gene in HHL-5 cells. In addition, the overexpression of BTG2 significantly inhibited the proliferation and autophagy abilities of HHL-5 cells, while cotransfected miR-25-3p mimics or PMPs could partially rescue HHL-5 cells proliferation and autophagy. Furthermore, we proved that PMPs accelerated hepatocyte proliferation by regulating autophagy pathways. Therefore, PMPs-derived miR-25-3p promoted HHL-5 cell proliferation and autophagy by targeting BTG2, which may be a new therapeutic method for liver regeneration.
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Affiliation(s)
- Yuyuan Xu
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guandong, China
| | - Wenfei Li
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guandong, China
| | - Guangyu Liang
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guandong, China
| | - Jie Peng
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guandong, China
| | - Xuwen Xu
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guandong, China
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Peng YC, Lv TH, Du ZK, Cun XN, Yang KM. Liver Macrophages Stimulate the Expression of Hepatocyte Nuclear Factor-6 and Promote Hepatocyte Proliferation at the Early Stage of Liver Regeneration. Bull Exp Biol Med 2020; 170:40-45. [PMID: 33222081 DOI: 10.1007/s10517-020-05000-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Indexed: 01/09/2023]
Abstract
Hepatocyte nuclear factor (HNF-6) is a liver-specific protein and a key component in the differentiation process during the development of mature liver. The immunohistochemical staining and RT-PCR techniques were employed to examine the expression of HNF-6 and proliferation of Ki-67+ cells during the early regeneration of the liver on postsurgery in 3, 6, 12, and 24 h in original model of partial hepatectomy in rats. The earliest proliferating (Ki-67+) cells were observed in 3 h after surgery in liver sinusoids (liver macrophages) and then in liver parenchyma. Expression of HNF-6 in hepatocytes and epithelial cells of the bile ducts attained maximum in 6 h after surgery. At later terms, this parameter somewhat decreased, but still surpassed the control level.
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Affiliation(s)
- Y Ch Peng
- Department of Anatomy, School of Basic Medical Science, Dali University, Dali, PR China
| | - T H Lv
- Department of Surgery of Dali Prefecture People's Hospital, Dali, PR China
| | - Zh K Du
- Department of Anatomy, School of Basic Medical Science, Dali University, Dali, PR China
| | - X N Cun
- Department of Surgery of Affiliated Hospital of Dali University, Dali, PR China
| | - K M Yang
- Department of Anatomy, School of Basic Medical Science, Dali University, Dali, PR China.
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Yagi S, Hirata M, Miyachi Y, Uemoto S. Liver Regeneration after Hepatectomy and Partial Liver Transplantation. Int J Mol Sci 2020; 21:ijms21218414. [PMID: 33182515 PMCID: PMC7665117 DOI: 10.3390/ijms21218414] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/04/2020] [Accepted: 11/05/2020] [Indexed: 02/07/2023] Open
Abstract
The liver is a unique organ with an abundant regenerative capacity. Therefore, partial hepatectomy (PHx) or partial liver transplantation (PLTx) can be safely performed. Liver regeneration involves a complex network of numerous hepatotropic factors, cytokines, pathways, and transcriptional factors. Compared with liver regeneration after a viral- or drug-induced liver injury, that of post-PHx or -PLTx has several distinct features, such as hemodynamic changes in portal venous flow or pressure, tissue ischemia/hypoxia, and hemostasis/platelet activation. Although some of these changes also occur during liver regeneration after a viral- or drug-induced liver injury, they are more abrupt and drastic following PHx or PLTx, and can thus be the main trigger and driving force of liver regeneration. In this review, we first provide an overview of the molecular biology of liver regeneration post-PHx and -PLTx. Subsequently, we summarize some clinical conditions that negatively, or sometimes positively, interfere with liver regeneration after PHx or PLTx, such as marginal livers including aged or fatty liver and the influence of immunosuppression.
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38
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Yang H, Guo J, Jin W, Chang C, Guo X, Xu C. A combined proteomic and metabolomic analyses of the priming phase during rat liver regeneration. Arch Biochem Biophys 2020; 693:108567. [PMID: 32898568 DOI: 10.1016/j.abb.2020.108567] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 08/17/2020] [Accepted: 08/27/2020] [Indexed: 01/07/2023]
Abstract
By comparing differentially abundant proteins and metabolites, the protein expression, metabolic changes and metabolic regulation mechanisms during the priming phase of liver regeneration (LR) were investigated. We combined proteomic analysis via isobaric tags for relative and absolute quantification (iTRAQ) with metabolomic analysis via nontargeted liquid chromatography-mass spectrometry (LC-MS). LC-MS was used to examine 29 energy metabolites expression alterations in targeted metabolomics. A total number of 441 differentially expressed proteins and 65 metabolites were identified. PSMB10, PSMB5, RCG_63409, PSME4 and PSMB7 were key node proteins, these proteins are involved in the proteasome pathway. The most strongly enriched transcription factor motif was TP63. These results point out a critical role of the proteasome pathway (defense mechanisms) and of TP63 (metabolic regulator) as the key transcription factor during the priming phase of LR. Metabolomic and metabolite analysis showed that profiling indicates upregulation of arginine biosynthesis and glycolysis as the main ATP-delivering pathway. Integrative proteomic and metabolomic analysis showed that biomolecular changes were primarily related to the neurological disease, cell death and survival and cell morphology. What's more, neurotransmitters may play an important role in the regulation of LR.
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Affiliation(s)
- Hui Yang
- College of Life Science, Henan Normal University, Xinxiang, 453007, China; State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, China
| | - Jianlin Guo
- College of Life Science, Henan Normal University, Xinxiang, 453007, China; State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, China
| | - Wei Jin
- College of Life Science, Henan Normal University, Xinxiang, 453007, China; State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, China
| | - Cuifang Chang
- College of Life Science, Henan Normal University, Xinxiang, 453007, China; State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, China
| | - Xueqiang Guo
- College of Life Science, Henan Normal University, Xinxiang, 453007, China; State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, China
| | - Cunshuan Xu
- College of Life Science, Henan Normal University, Xinxiang, 453007, China; State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, China.
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Tavares MR, de Castro RVG, Pieri NCG, Cruz NRN, Martins DS, Ambrósio CE, Garcia JM, Camplesi AC, Bressan FF, Toniollo GH. Identification of hepatic progenitor cells in the canine fetal liver. Res Vet Sci 2020; 133:239-245. [PMID: 33032111 DOI: 10.1016/j.rvsc.2020.09.012] [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: 03/10/2020] [Revised: 06/08/2020] [Accepted: 09/14/2020] [Indexed: 10/23/2022]
Abstract
The liver plays essential roles in human and animal organisms, such as the storage, release, metabolism, and elimination of various endogenous or exogenous substances. Although its vital importance, few treatments are yet available when a hepatic failure occurs, and hence, the use of stem cells has arisen as a possible solution for both human and veterinary medicines. Previous studies have shown the existence of hepatic progenitor cells in human fetuses that were positive for EpCAM and NCAM. There is limited evidence, however, further identification and characterization of these cells in other species. Considering the similarity between dogs and humans regarding physiology, and also the increasing importance of developing new treatments for both veterinary and translational medicine, this study attempted to identify hepatic progenitor cells in canine fetal liver. For that, livers from canine fetuses were collected, cells were isolated by enzymatic digestion and cultured. Cells were characterized regarding morphology and expression of EpCAM, NCAM, Nestin, and Thy-1/CD90 markers. Our results suggest that it is possible to identify hepatic progenitor cells in the canine fetal liver; however, for therapeutic use, further techniques for cellular isolation and culture are necessary to obtain enriched populations of hepatic progenitors from the canine fetal liver.
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Affiliation(s)
- M R Tavares
- Department of Preventive Veterinary Medicine and Animal Reproduction, Faculty of Agricultural and Animal Science, State University of São Paulo, Jaboticabal/SP, Brazil.
| | - R V G de Castro
- Department of Preventive Veterinary Medicine and Animal Reproduction, Faculty of Agricultural and Animal Science, State University of São Paulo, Jaboticabal/SP, Brazil; Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of São Paulo, Pirassununga/SP, Brazil
| | - N C G Pieri
- Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of São Paulo, Pirassununga/SP, Brazil
| | - N R N Cruz
- Department of Veterinary Clinical and Surgery, Faculty of Agricultural and Animal Science, State University of São Paulo, Jaboticabal/SP, Brazil
| | - D S Martins
- Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of São Paulo, Pirassununga/SP, Brazil; Post-Graduate Program in Anatomy of Domestic and Wild Animals, Faculty of Veterinary Medicine and Animal Sciences, University of São Paulo, São Paulo/SP, Brazil
| | - C E Ambrósio
- Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of São Paulo, Pirassununga/SP, Brazil; Post-Graduate Program in Anatomy of Domestic and Wild Animals, Faculty of Veterinary Medicine and Animal Sciences, University of São Paulo, São Paulo/SP, Brazil
| | - J M Garcia
- Department of Preventive Veterinary Medicine and Animal Reproduction, Faculty of Agricultural and Animal Science, State University of São Paulo, Jaboticabal/SP, Brazil
| | - A C Camplesi
- Department of Veterinary Clinical and Surgery, Faculty of Agricultural and Animal Science, State University of São Paulo, Jaboticabal/SP, Brazil
| | - F F Bressan
- Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of São Paulo, Pirassununga/SP, Brazil; Post-Graduate Program in Anatomy of Domestic and Wild Animals, Faculty of Veterinary Medicine and Animal Sciences, University of São Paulo, São Paulo/SP, Brazil..
| | - G H Toniollo
- Department of Preventive Veterinary Medicine and Animal Reproduction, Faculty of Agricultural and Animal Science, State University of São Paulo, Jaboticabal/SP, Brazil
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Svobodová J, Procházková J, Kabátková M, Krkoška M, Šmerdová L, Líbalová H, Topinka J, Kléma J, Kozubík A, Machala M, Vondráček J. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Disrupts Control of Cell Proliferation and Apoptosis in a Human Model of Adult Liver Progenitors. Toxicol Sci 2020; 172:368-384. [PMID: 31536130 DOI: 10.1093/toxsci/kfz202] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The aryl hydrocarbon receptor (AhR) activation has been shown to alter proliferation, apoptosis, or differentiation of adult rat liver progenitors. Here, we investigated the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated AhR activation on a human model of bipotent liver progenitors, undifferentiated HepaRG cells. We used both intact undifferentiated HepaRG cells, and the cells with silenced Hippo pathway effectors, yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which play key role(s) in tissue-specific progenitor cell self-renewal and expansion, such as in liver, cardiac, or respiratory progenitors. TCDD induced cell proliferation in confluent undifferentiated HepaRG cells; however, following YAP, and, in particular, double YAP/TAZ knockdown, TCDD promoted induction of apoptosis. These results suggested that, unlike in mature hepatocytes, or hepatocyte-like cells, activation of the AhR may sensitize undifferentiated HepaRG cells to apoptotic stimuli. Induction of apoptosis in cells with silenced YAP/TAZ was associated with upregulation of death ligand TRAIL, and seemed to involve both extrinsic and mitochondrial apoptosis pathways. Global gene expression analysis further suggested that TCDD significantly altered expression of constituents and/or transcriptional targets of signaling pathways participating in control of expansion or differentiation of liver progenitors, including EGFR, Wnt/β-catenin, or tumor growth factor-β signaling pathways. TCDD significantly upregulated cytosolic proapoptotic protein BMF (Bcl-2 modifying factor) in HepaRG cells, which could be linked with an enhanced sensitivity of TCDD-treated cells to apoptosis. Our results suggest that, in addition to promotion of cell proliferation and alteration of signaling pathways controlling expansion of human adult liver progenitors, AhR ligands may also sensitize human liver progenitor cells to apoptosis.
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Affiliation(s)
- Jana Svobodová
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno 61265, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno 61137, Czech Republic
| | - Jiřina Procházková
- Department of Chemistry and Toxicology, Veterinary Research Institute, Brno 62100, Czech Republic
| | - Markéta Kabátková
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno 61265, Czech Republic
| | - Martin Krkoška
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno 61265, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno 61137, Czech Republic
| | - Lenka Šmerdová
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno 61265, Czech Republic
| | - Helena Líbalová
- Department of Genetic Ecotoxicology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 14220, Czech Republic
| | - Jan Topinka
- Department of Genetic Ecotoxicology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 14220, Czech Republic
| | - Jiří Kléma
- Department of Computer Science, Czech Technical University, Prague 12135, Czech Republic
| | - Alois Kozubík
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno 61265, Czech Republic
| | - Miroslav Machala
- Department of Chemistry and Toxicology, Veterinary Research Institute, Brno 62100, Czech Republic
| | - Jan Vondráček
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno 61265, Czech Republic
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Bhushan B, Michalopoulos GK. Role of epidermal growth factor receptor in liver injury and lipid metabolism: Emerging new roles for an old receptor. Chem Biol Interact 2020; 324:109090. [PMID: 32283070 DOI: 10.1016/j.cbi.2020.109090] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 04/02/2020] [Indexed: 12/15/2022]
Abstract
Epidermal growth factor receptor (EGFR) is conventionally known to play a crucial role in hepatocyte proliferation, liver regeneration and is also associated with hepatocellular carcinogenesis. In addition to these proliferative roles, EGFR has also implicated in apoptotic cell death signaling in various hepatic cells, mitochondrial dysfunction and acute liver necrosis in a clinically relevant murine model of acetaminophen overdose, warranting further comprehensive exploration of this paradoxical role of EGFR in hepatotoxicity. Apart from ligand dependent activation, EGFR can also be activated in ligand-independent manner, which is mainly associated to liver injury. Recent evidence has also emerged demonstrating important role of EGFR in lipid and fatty acid metabolism in quiescent and regenerating liver. Based on these findings, EGFR has also been shown to play an important role in steatosis in clinically relevant murine NAFLD models via regulating master transcription factors governing fatty acid synthesis and lipolysis. Moreover, several lines of evidences indicate that EGFR is also involved in hepatocellular injury, oxidative stress, inflammation, direct stellate cell activation and fibrosis in chronic liver injury models, including repeated CCl4 exposure, high-fat diet and fast-food diet models. In addition to briefly summarizing role of EGFR in liver regeneration, this review comprehensively discusses all these non-conventional emerging roles of EGFR. Considering evidences of multi-facet role of EGFR at various levels in these pathophysiological process, EGFR can be a promising therapeutic target for various liver diseases, including acute liver failure and NAFLD, requiring further exploration. These roles of EGFR are relevant for alcoholic liver diseases (ALD) as well, thus providing a valid rationale for future investigations exploring a role of EGFR in ALD.
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Affiliation(s)
- Bharat Bhushan
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
| | - George K Michalopoulos
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
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42
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Hübbers A, Hennings J, Lambertz D, Haas U, Trautwein C, Nevzorova YA, Sonntag R, Liedtke C. Pharmacological Inhibition of Cyclin-Dependent Kinases Triggers Anti-Fibrotic Effects in Hepatic Stellate Cells In Vitro. Int J Mol Sci 2020; 21:ijms21093267. [PMID: 32380742 PMCID: PMC7246535 DOI: 10.3390/ijms21093267] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 04/28/2020] [Accepted: 05/02/2020] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis is a wound healing process in response to chronic liver injury, which is characterized by the accumulation of extracellular collagen produced by Hepatic Stellate Cells (HSCs). This process involves cell cycle re-entry and proliferation of normally quiescent HSCs controlled by cyclins and associated cyclin-dependent kinases (Cdks). Cdk2 mediates the entry and progression through S-phase in complex with E-and A-type cyclins. We have demonstrated that cyclin E1 is essential for liver fibrogenesis in mice, but it is not known if this is dependent on Cdk2 or related Cdks. Here, we aimed to evaluate the benefit of the pan-Cdk inhibitor CR8 for treatment of liver fibrosis in vitro. CR8-treatment reduced proliferation and survival in immortalized HSC lines and in addition attenuated pro-fibrotic properties in primary murine HSCs. Importantly, primary murine hepatocytes were much more tolerant against the cytotoxic and anti-proliferative effects of CR8. We identified CR8 dosages mediating anti-fibrotic effects in primary HSCs without affecting cell cycle activity and survival in primary hepatocytes. In conclusion, the pharmacological pan-Cdk inhibitor CR8 restricts the pro-fibrotic properties of HSCs, while preserving proliferation and viability of hepatocytes at least in vitro. Therefore, CR8 and related drugs might be beneficial for the treatment of liver fibrosis.
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Affiliation(s)
- Anna Hübbers
- Department of Internal Medicine III, University Hospital, RWTH Aachen University, D-52074 Aachen, Germany; (A.H.); (J.H.); (D.L.); (U.H.); (C.T.); (Y.A.N.)
| | - Julia Hennings
- Department of Internal Medicine III, University Hospital, RWTH Aachen University, D-52074 Aachen, Germany; (A.H.); (J.H.); (D.L.); (U.H.); (C.T.); (Y.A.N.)
| | - Daniela Lambertz
- Department of Internal Medicine III, University Hospital, RWTH Aachen University, D-52074 Aachen, Germany; (A.H.); (J.H.); (D.L.); (U.H.); (C.T.); (Y.A.N.)
| | - Ute Haas
- Department of Internal Medicine III, University Hospital, RWTH Aachen University, D-52074 Aachen, Germany; (A.H.); (J.H.); (D.L.); (U.H.); (C.T.); (Y.A.N.)
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital, RWTH Aachen University, D-52074 Aachen, Germany; (A.H.); (J.H.); (D.L.); (U.H.); (C.T.); (Y.A.N.)
| | - Yulia A. Nevzorova
- Department of Internal Medicine III, University Hospital, RWTH Aachen University, D-52074 Aachen, Germany; (A.H.); (J.H.); (D.L.); (U.H.); (C.T.); (Y.A.N.)
- Department of Genetics, Physiology, and Microbiology, Faculty of Biology, Complutense University Madrid, 28040 Madrid, Spain
| | - Roland Sonntag
- Department of Internal Medicine III, University Hospital, RWTH Aachen University, D-52074 Aachen, Germany; (A.H.); (J.H.); (D.L.); (U.H.); (C.T.); (Y.A.N.)
- Correspondence: (R.S.); (C.L.)
| | - Christian Liedtke
- Department of Internal Medicine III, University Hospital, RWTH Aachen University, D-52074 Aachen, Germany; (A.H.); (J.H.); (D.L.); (U.H.); (C.T.); (Y.A.N.)
- Correspondence: (R.S.); (C.L.)
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Laschinger M, Wang Y, Holzmann G, Wang B, Stöß C, Lu M, Brugger M, Schneider A, Knolle P, Wohlleber D, Schulze S, Steiger K, Tsujikawa K, Altmayr F, Friess H, Hartmann D, Hüser N, Holzmann B. The CGRP receptor component RAMP1 links sensory innervation with YAP activity in the regenerating liver. FASEB J 2020; 34:8125-8138. [PMID: 32329113 DOI: 10.1096/fj.201903200r] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 03/26/2020] [Accepted: 04/02/2020] [Indexed: 12/13/2022]
Abstract
The effectiveness of liver regeneration limits surgical therapies of hepatic disorders and determines patient outcome. Here, we investigated the role of the neuropeptide calcitonin gene-related peptide (CGRP) for liver regeneration after acute or chronic injury. Mice deficient for the CGRP receptor component receptor activity-modifying protein 1 (RAMP1) were subjected to a 70% partial hepatectomy or repeated intraperitoneal injections of carbon tetrachloride. RAMP1 deficiency severely impaired recovery of organ mass and hepatocyte proliferation after both acute and chronic liver injury. Mechanistically, protein expression of the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) was decreased in regenerating livers of RAMP1-deficient mice. Lack of RAMP1 was associated with hyperphosphorylation of YAP on Ser127 and Ser397, which regulates YAP functional activity and protein levels. Consequently, expression of various YAP-controlled cell cycle regulators and hepatocyte proliferation were severely reduced in the absence of RAMP1. In vitro, CGRP treatment caused increased YAP protein expression and a concomitant decline of YAP phosphorylation in liver tissue slice cultures of mouse and human origin and in primary human hepatocytes. Thus, our results indicate that sensory nerves represent a crucial control element of liver regeneration after acute and chronic injury acting through the CGRP-RAMP1 pathway, which stimulates YAP/TAZ expression and activity.
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Affiliation(s)
- Melanie Laschinger
- Department of Surgery, School of Medicine, Technical University of Munich, Munich, Germany
| | - Yang Wang
- Department of Surgery, School of Medicine, Technical University of Munich, Munich, Germany
| | - Gabriela Holzmann
- Department of Surgery, School of Medicine, Technical University of Munich, Munich, Germany
| | - Baocai Wang
- Department of Surgery, School of Medicine, Technical University of Munich, Munich, Germany
| | - Christian Stöß
- Department of Surgery, School of Medicine, Technical University of Munich, Munich, Germany
| | - Miao Lu
- Department of Surgery, School of Medicine, Technical University of Munich, Munich, Germany
| | - Marcus Brugger
- School of Medicine, Institute of Molecular Immunology & Experimental Oncology, Technical University of Munich, Munich, Germany
| | - Annika Schneider
- School of Medicine, Institute of Molecular Immunology & Experimental Oncology, Technical University of Munich, Munich, Germany
| | - Percy Knolle
- School of Medicine, Institute of Molecular Immunology & Experimental Oncology, Technical University of Munich, Munich, Germany
| | - Dirk Wohlleber
- School of Medicine, Institute of Molecular Immunology & Experimental Oncology, Technical University of Munich, Munich, Germany
| | - Sarah Schulze
- Department of Surgery, School of Medicine, Technical University of Munich, Munich, Germany
| | - Katja Steiger
- School of Medicine, Institute of Pathology, Technical University of Munich, Munich, Germany
| | - Kazutake Tsujikawa
- Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Felicitas Altmayr
- Department of Surgery, School of Medicine, Technical University of Munich, Munich, Germany
| | - Helmut Friess
- Department of Surgery, School of Medicine, Technical University of Munich, Munich, Germany
| | - Daniel Hartmann
- Department of Surgery, School of Medicine, Technical University of Munich, Munich, Germany
| | - Norbert Hüser
- Department of Surgery, School of Medicine, Technical University of Munich, Munich, Germany
| | - Bernhard Holzmann
- Department of Surgery, School of Medicine, Technical University of Munich, Munich, Germany
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Zhou J, Sun X, Yang L, Wang L, Ran G, Wang J, Cao Q, Wu L, Bryant A, Ling C, Pi L. Hepatocyte nuclear factor 4α negatively regulates connective tissue growth factor during liver regeneration. FASEB J 2020; 34:4970-4983. [PMID: 32057145 PMCID: PMC7722640 DOI: 10.1096/fj.201902382r] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 01/20/2020] [Accepted: 01/21/2020] [Indexed: 12/25/2022]
Abstract
Liver regeneration after injury requires fine-tune regulation of connective tissue growth factor (Ctgf). It also involves dynamic expression of hepatocyte nuclear factor (Hnf)4α, Yes-associated protein (Yap), and transforming growth factor (Tgf)-β. The upstream inducers of Ctgf, such as Yap, etc, are well-known. However, the negative regulator of Ctgf remains unclear. Here, we investigated the Hnf4α regulation of Ctgf post-various types of liver injury. Both wild-type animals and animals contained siRNA-mediated Hnf4α knockdown and Cre-mediated Ctgf conditional deletion were used. We observed that Ctgf induction was associated with Hnf4α decline, nuclear Yap accumulation, and Tgf-β upregulation during early stage of liver regeneration. The Ctgf promoter contained an Hnf4α binding sequence that overlapped with the cis-regulatory element for Yap and Tgf-β. Ctgf loss attenuated inflammation, hepatocyte proliferation, and collagen synthesis, whereas Hnf4α knockdown enhanced Ctgf induction and liver fibrogenesis. These findings provided a new mechanism about fine-tuned regulation of Ctgf through Hnf4α antagonism of Yap and Tgf-β activities to balance regenerative and fibrotic signals.
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Affiliation(s)
- Junmei Zhou
- Department of PediatricsUniversity of FloridaGainesvilleFLUSA
- Institute of Cardiovascular DiseaseKey Laboratory for Arteriosclerology of Hunan ProvinceUniversity of South ChinaHengyangChina
| | - Xiaowei Sun
- Department of PediatricsUniversity of FloridaGainesvilleFLUSA
- Institute of PathologySchool of Basic Medical SciencesLanzhou UniversityLanzhouChina
| | - Lu Yang
- Integrative Genomics CoreBeckman Research Institute of the City of HopeDuarteCAUSA
| | - Liqun Wang
- Department of MedicineUniversity of FloridaGainesvilleFLUSA
| | - Gai Ran
- Department of PediatricsUniversity of FloridaGainesvilleFLUSA
- State Key Laboratory of Genetic EngineeringSchool of Life SciencesZhongshan HospitalFudan UniversityShanghaiChina
| | - Jinhui Wang
- Integrative Genomics CoreBeckman Research Institute of the City of HopeDuarteCAUSA
| | - Qi Cao
- Department of Diagnostic Radiology and Nuclear MedicineUniversity of Maryland School of MedicineBaltimoreMDUSA
| | - Lizi Wu
- Department of Microbiology& Molecular GeneticsCollege of MedicineUniversity of FloridaGainesvilleFLUSA
| | - Andrew Bryant
- Department of MedicineUniversity of FloridaGainesvilleFLUSA
| | - Chen Ling
- Department of PediatricsUniversity of FloridaGainesvilleFLUSA
- State Key Laboratory of Genetic EngineeringSchool of Life SciencesZhongshan HospitalFudan UniversityShanghaiChina
| | - Liya Pi
- Department of PediatricsUniversity of FloridaGainesvilleFLUSA
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Méndez-Sánchez N, Valencia-Rodríguez A, Coronel-Castillo C, Vera-Barajas A, Contreras-Carmona J, Ponciano-Rodríguez G, Zamora-Valdés D. The cellular pathways of liver fibrosis in non-alcoholic steatohepatitis. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:400. [PMID: 32355844 PMCID: PMC7186641 DOI: 10.21037/atm.2020.02.184] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 02/29/2020] [Indexed: 12/12/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) is considered the advanced stage of non-alcoholic fatty liver disease (NAFLD). It is characterized by liver steatosis, inflammation and different degrees of fibrosis. Although the exact mechanisms by which fatty liver progresses to NASH are still not well understood, innate and adaptive immune responses seem to be essential key regulators in the establishment, progression, and chronicity of these disease. Diet-induced lipid overload of parenchymal and non-parenchymal liver cells is considered the first step for the development of fatty liver with the consequent organelle dysfunction, cellular stress and liver injury. These will generate the production of pro-inflammatory cytokines, chemokines and damage-associated molecular patterns (DAMPs) that will upregulate the activation of Kupffer cells (KCs) and monocyte-derived macrophages (MMs) favoring the polarization of the tolerogenic environment of the liver to an immunogenic phenotype with the resulting transdifferentiation of hepatic stellate cells (HSCs) into myofibroblasts developing fibrosis. In the long run, dendritic cells (DCs) will activate CD4+ T cells polarizing into the pro-inflammatory lymphocytes Th1 and Th17 worsening the liver damage and inflammation. Therefore, the objective of this review is to discuss in a systematic way the mechanisms known so far of the immune and non-proper immune liver cells in the development and progression of NASH.
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Affiliation(s)
- Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico
- Faculty of Medicine. National Autonomous University of Mexico, Mexico City, Mexico
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Abstract
The spiny mouse, Acomys spp., is a recently described model organism for regeneration studies. For a mammal, it displays surprising powers of regeneration because it does not fibrose (i.e. scar) in response to tissue injury as most other mammals, including humans, do. In this Primer article, we review these regenerative abilities, highlighting the phylogenetic position of the spiny mouse relative to other rodents. We also briefly describe the Acomys tissues that have been used for regeneration studies and the common features of their regeneration compared with the typical mammalian response. Finally, we discuss the contribution that Acomys has made in understanding the general principles of regeneration and elaborate hypotheses as to why this mammal is successful at regenerating.
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Affiliation(s)
- Malcolm Maden
- Department of Biology & UF Genetics Institute, University of Florida, PO Box 118525, Gainesville, FL 32611, USA
| | - Justin A Varholick
- Department of Biology & UF Genetics Institute, University of Florida, PO Box 118525, Gainesville, FL 32611, USA
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Baptista PM, Penning LC. Transplantable Liver Organoids, Too Many Cell Types to Choose: a Need for Scientific Self-Organization. CURRENT TRANSPLANTATION REPORTS 2020. [DOI: 10.1007/s40472-020-00266-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Abstract
Purpose of Review
Liver stem cells have been proposed as alternatives or additions for whole liver transplantations to accommodate the donor liver shortage. Various sources of liver stem cells have been described in experimental animal studies. Here we aim to compare the various studies.
Recent Findings
Irrespective of the experimental design, the percentage of long-lasting survival and functional recovery of transplanted cells is generally very low. An exception to this are the proliferating hepatocytes transplanted into Fah(-/-) Rag2−/−IL2rg−/− mice; here 4-month post-transplantation around 65% repopulation was observed, and 11/14 mice survived in contrast to zero survival in sham-treated animals.
Summary
Taking the different cellular sources for the organoids, the different maturation status of the transplanted cells, and the variable animal models into account, a paper-to-paper comparison is compromised. This lack of objective comparison restricts the translation of these model studies into clinical practice.
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48
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Chromatin dynamics during liver regeneration. Semin Cell Dev Biol 2020; 97:38-46. [DOI: 10.1016/j.semcdb.2019.03.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 03/12/2019] [Accepted: 03/28/2019] [Indexed: 12/15/2022]
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Bizzaro D, Russo FP, Burra P. New Perspectives in Liver Transplantation: From Regeneration to Bioengineering. Bioengineering (Basel) 2019; 6:81. [PMID: 31514475 PMCID: PMC6783848 DOI: 10.3390/bioengineering6030081] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 09/09/2019] [Accepted: 09/10/2019] [Indexed: 12/18/2022] Open
Abstract
Advanced liver diseases have very high morbidity and mortality due to associated complications, and liver transplantation represents the only current therapeutic option. However, due to worldwide donor shortages, new alternative approaches are mandatory for such patients. Regenerative medicine could be the more appropriate answer to this need. Advances in knowledge of physiology of liver regeneration, stem cells, and 3D scaffolds for tissue engineering have accelerated the race towards efficient therapies for liver failure. In this review, we propose an update on liver regeneration, cell-based regenerative medicine and bioengineering alternatives to liver transplantation.
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Affiliation(s)
- Debora Bizzaro
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology/Multivisceral Transplant Section, University/Hospital Padua, 35128 Padua, Italy.
| | - Francesco Paolo Russo
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology/Multivisceral Transplant Section, University/Hospital Padua, 35128 Padua, Italy.
| | - Patrizia Burra
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology/Multivisceral Transplant Section, University/Hospital Padua, 35128 Padua, Italy.
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Lv T, Kong L, Jiang L, Wu H, Wen T, Shi Y, Yang J. Dicer1 facilitates liver regeneration in a manner dependent on the inhibitory effect of miR-21 on Pten and Rhob expression. Life Sci 2019; 232:116656. [PMID: 31306658 DOI: 10.1016/j.lfs.2019.116656] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 07/07/2019] [Accepted: 07/12/2019] [Indexed: 02/06/2023]
Abstract
AIMS Tamoxifen-induced liver-specific Dicer1 deletion (iDicer1-/-) in mature mice may provide clues demonstrating the genuine effects of acute loss of Dicer1 and miRNAs in the liver regeneration process. MAIN METHODS In this study, mice with tamoxifen-induced Dicer1 deletion through the Cre/LoxP system were constructed and then underwent classic 70% partial hepatectomy or CCl4-induced liver injury. To rescue the inhibitory effect of Dicer1 ablation on liver regeneration, miR-21 agomir was injected into the tail vein of iDicer1-/- mice. KEY FINDINGS Unlike constitutive embryonic deletion of Dicer1, tamoxifen-induced Dicer1 deletion did not result in severe liver injury or lesions, providing an ideal model for investigating acute loss of Dicer1 and miRNAs in liver regeneration. Dicer1 deletion led to impaired liver regeneration through the inhibitory effect of miR-21 on PTEN and Rhob expression. SIGNIFICANCE In our previous study, we found that embryonic loss of Dicer1 impairs hepatocyte survival and leads to chronic inflammation and progenitor cell activation, while the role of Dicer1 in liver regeneration remains largely unknown. We clearly identified the promotion effect of Dicer1 on liver regeneration by increasing miR-21 expression, which inhibits the expression of two negative cell proliferation regulators, Pten and Rhob.
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Affiliation(s)
- Tao Lv
- Department of Hepato-Biliary-Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Lingxiang Kong
- Department of Hepato-Biliary-Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Li Jiang
- Department of Hepato-Biliary-Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Hong Wu
- Department of Hepato-Biliary-Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Tianfu Wen
- Department of Hepato-Biliary-Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Yujun Shi
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Chengdu 610041, China
| | - Jiayin Yang
- Department of Hepato-Biliary-Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu 610041, China.
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