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Vosough M, Shokouhian B, Sharbaf MA, Solhi R, Heidari Z, Seydi H, Hassan M, Devaraj E, Najimi M. Role of mitogens in normal and pathological liver regeneration. Hepatol Commun 2025; 9:e0692. [PMID: 40304568 PMCID: PMC12045551 DOI: 10.1097/hc9.0000000000000692] [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: 12/16/2024] [Accepted: 01/31/2025] [Indexed: 05/02/2025] Open
Abstract
The liver has a unique ability to regenerate to meet the body's metabolic needs, even following acute or chronic injuries. The cellular and molecular mechanisms underlying normal liver regeneration have been well investigated to improve organ transplantation outcomes. Once liver regeneration is impaired, pathological regeneration occurs, and the underlying cellular and molecular mechanisms require further investigations. Nevertheless, a plethora of cytokines and growth factor-mediated pathways have been reported to modulate physiological and pathological liver regeneration. Regenerative mitogens play an essential role in hepatocyte proliferation. Accelerator mitogens in synergism with regenerative ones promote liver regeneration following hepatectomy. Finally, terminator mitogens restore the proliferating status of hepatocytes to a differentiated and quiescent state upon completion of regeneration. Chronic loss of hepatocytes, which can manifest in chronic liver disorders of any etiology, often has undesired structural consequences, including fibrosis, cirrhosis, and liver neoplasia due to the unregulated proliferation of remaining hepatocytes. In fact, any impairment in the physiological function of the terminator mitogens results in the progression of pathological liver regeneration. In the current review, we intend to highlight the updated cellular and molecular mechanisms involved in liver regeneration and discuss the impairments in central regulating mechanisms responsible for pathological liver regeneration.
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Affiliation(s)
- Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Bahare Shokouhian
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mohammad Amin Sharbaf
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Roya Solhi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Zahra Heidari
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Homeyra Seydi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Ezhilarasan Devaraj
- Department of Pharmacology, Hepatology and Molecular Medicine Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai, India
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
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2
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Ayala I, Hebbale SK, Mononen J, Brearley-Sholto MC, Shannon CE, Valdez I, Fourcaudot M, Bakewell TM, Zagorska A, Romero G, Asmis M, Musa FA, Sily JT, Smelter AA, Hinostroza EA, Freitas Lima LC, de Aguiar Vallim TQ, Heikkinen S, Norton L. The Spatial Transcriptional Activity of Hepatic TCF7L2 Regulates Zonated Metabolic Pathways that Contribute to Liver Fibrosis. Nat Commun 2025; 16:3408. [PMID: 40210847 PMCID: PMC11986045 DOI: 10.1038/s41467-025-58714-5] [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: 08/15/2023] [Accepted: 03/20/2025] [Indexed: 04/12/2025] Open
Abstract
The molecular mechanisms regulating the zonal distribution of metabolism in liver are incompletely understood. Here we use single nuclei genomics techniques to examine the spatial transcriptional function of transcription factor 7-like 2 (TCF7L2) in mouse liver, and determine the consequences of TCF7L2 transcriptional inactivation on the metabolic architecture of the liver and the function of zonated metabolic pathways. We report that while Tcf7l2 mRNA expression is ubiquitous across the liver lobule, accessibility of the consensus TCF/LEF DNA binding motif is restricted to pericentral (PC) hepatocytes in zone 3. In mice expressing functionally inactive TCF7L2 in liver, PC hepatocyte-specific gene expression is absent, which we demonstrate promotes hepatic cholesterol accumulation, impaired bile acid synthesis, disruption to glutamine/glutamate homeostasis and pronounced dietary-induced hepatic fibrosis. In summary, TCF7L2 is a key regulator of hepatic zonal gene expression and regulates several zonated metabolic pathways that may contribute to the development of fibrotic liver disease.
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Affiliation(s)
- Iriscilla Ayala
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Skanda K Hebbale
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Juho Mononen
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland
| | | | - Christopher E Shannon
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Ivan Valdez
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Marcel Fourcaudot
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Terry M Bakewell
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | | | - Giovanna Romero
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Mara Asmis
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Fatima A Musa
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Jonah T Sily
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Annie A Smelter
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Edgar A Hinostroza
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Leandro C Freitas Lima
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Thomas Q de Aguiar Vallim
- Department of Cardiology, School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Sami Heikkinen
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland
| | - Luke Norton
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
- Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, TX, USA.
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3
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Ma X, Huang T, Chen X, Li Q, Liao M, Fu L, Huang J, Yuan K, Wang Z, Zeng Y. Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics. Signal Transduct Target Ther 2025; 10:63. [PMID: 39920130 PMCID: PMC11806117 DOI: 10.1038/s41392-024-02104-8] [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: 11/08/2023] [Revised: 09/02/2024] [Accepted: 12/12/2024] [Indexed: 02/09/2025] Open
Abstract
Liver repair and regeneration are crucial physiological responses to hepatic injury and are orchestrated through intricate cellular and molecular networks. This review systematically delineates advancements in the field, emphasizing the essential roles played by diverse liver cell types. Their coordinated actions, supported by complex crosstalk within the liver microenvironment, are pivotal to enhancing regenerative outcomes. Recent molecular investigations have elucidated key signaling pathways involved in liver injury and regeneration. Viewed through the lens of metabolic reprogramming, these pathways highlight how shifts in glucose, lipid, and amino acid metabolism support the cellular functions essential for liver repair and regeneration. An analysis of regenerative variability across pathological states reveals how disease conditions influence these dynamics, guiding the development of novel therapeutic strategies and advanced techniques to enhance liver repair and regeneration. Bridging laboratory findings with practical applications, recent clinical trials highlight the potential of optimizing liver regeneration strategies. These trials offer valuable insights into the effectiveness of novel therapies and underscore significant progress in translational research. In conclusion, this review intricately links molecular insights to therapeutic frontiers, systematically charting the trajectory from fundamental physiological mechanisms to innovative clinical applications in liver repair and regeneration.
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Affiliation(s)
- Xiao Ma
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tengda Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xiangzheng Chen
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qian Li
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Mingheng Liao
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Fu
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jiwei Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Kefei Yuan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhen Wang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Yong Zeng
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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4
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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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5
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Oliva-Vilarnau N, Beusch CM, Sabatier P, Sakaraki E, Tjaden A, Graetz L, Büttner FA, Dorotea D, Nguyen M, Bergqvist F, Sundström Y, Müller S, Zubarev RA, Schulte G, Tredup C, Gramignoli R, Tietge UJ, Lauschke VM. Wnt/β-catenin and NFκB signaling synergize to trigger growth factor-free regeneration of adult primary human hepatocytes. Hepatology 2024; 79:1337-1351. [PMID: 37870288 PMCID: PMC11095891 DOI: 10.1097/hep.0000000000000648] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 09/18/2023] [Indexed: 10/24/2023]
Abstract
BACKGROUND AND AIMS The liver has a remarkable capacity to regenerate, which is sustained by the ability of hepatocytes to act as facultative stem cells that, while normally quiescent, re-enter the cell cycle after injury. Growth factor signaling is indispensable in rodents, whereas Wnt/β-catenin is not required for effective tissue repair. However, the molecular networks that control human liver regeneration remain unclear. METHODS Organotypic 3D spheroid cultures of primary human or murine hepatocytes were used to identify the signaling network underlying cell cycle re-entry. Furthermore, we performed chemogenomic screening of a library enriched for epigenetic regulators and modulators of immune function to determine the importance of epigenomic control for human hepatocyte regeneration. RESULTS Our results showed that, unlike in rodents, activation of Wnt/β-catenin signaling is the major mitogenic cue for adult primary human hepatocytes. Furthermore, we identified TGFβ inhibition and inflammatory signaling through NF-κB as essential steps for the quiescent-to-regenerative switch that allows Wnt/β-catenin-induced proliferation of human cells. In contrast, growth factors, but not Wnt/β-catenin signaling, triggered hyperplasia in murine hepatocytes. High-throughput screening in a human model confirmed the relevance of NFκB and revealed the critical roles of polycomb repressive complex 2, as well as of the bromodomain families I, II, and IV. CONCLUSIONS This study revealed a network of NFκB, TGFβ, and Wnt/β-catenin that controls human hepatocyte regeneration in the absence of exogenous growth factors, identified novel regulators of hepatocyte proliferation, and highlighted the potential of organotypic culture systems for chemogenomic interrogation of complex physiological processes.
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Affiliation(s)
- Nuria Oliva-Vilarnau
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Christian M. Beusch
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Pierre Sabatier
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Eirini Sakaraki
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Amelie Tjaden
- Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Frankfurt am Main, Germany
- Buchmann Institute for Molecular Life Sciences and Structural Genomics Consortium (SGC), Frankfurt am Main, Germany
| | - Lukas Graetz
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Florian A. Büttner
- Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
- University of Tübingen, Tübingen, Germany
| | - Debra Dorotea
- Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institutet, Stockholm, Sweden
| | - My Nguyen
- Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institutet, Stockholm, Sweden
| | - Filip Bergqvist
- Department of Medicine, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden
- The Structural Genomics Consortium (SGC), Karolinska Institutet, Stockholm, Sweden
| | - Yvonne Sundström
- Department of Medicine, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden
- The Structural Genomics Consortium (SGC), Karolinska Institutet, Stockholm, Sweden
| | - Susanne Müller
- Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Frankfurt am Main, Germany
- Buchmann Institute for Molecular Life Sciences and Structural Genomics Consortium (SGC), Frankfurt am Main, Germany
| | - Roman A. Zubarev
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Gunnar Schulte
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Claudia Tredup
- Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Frankfurt am Main, Germany
- Buchmann Institute for Molecular Life Sciences and Structural Genomics Consortium (SGC), Frankfurt am Main, Germany
| | - Roberto Gramignoli
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden
- Clinical Pathology and Cancer Diagnosis Unit, Karolinska University Hospital, Stockholm, Sweden
| | - Uwe J.F. Tietge
- Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institutet, Stockholm, Sweden
- Clinical Chemistry, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden
| | - Volker M. Lauschke
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
- Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
- University of Tübingen, Tübingen, Germany
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Matsumoto S, Kikuchi A. Wnt/β-catenin signaling pathway in liver biology and tumorigenesis. In Vitro Cell Dev Biol Anim 2024; 60:466-481. [PMID: 38379098 DOI: 10.1007/s11626-024-00858-7] [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: 11/13/2023] [Accepted: 01/16/2024] [Indexed: 02/22/2024]
Abstract
The Wnt/β-catenin pathway is an evolutionarily conserved signaling pathway that controls fundamental physiological and pathological processes by regulating cell proliferation and differentiation. The Wnt/β-catenin pathway enables liver homeostasis by inducing differentiation and contributes to liver-specific features such as metabolic zonation and regeneration. In contrast, abnormalities in the Wnt/β-catenin pathway promote the development and progression of hepatocellular carcinoma (HCC). Similarly, hepatoblastoma, the most common childhood liver cancer, is frequently associated with β-catenin mutations, which activate Wnt/β-catenin signaling. HCCs with activation of the Wnt/β-catenin pathway have unique gene expression patterns and pathological and clinical features. Accordingly, they are highly differentiated with retaining hepatocyte-like characteristics and tumorigenic. Activation of the Wnt/β-catenin pathway in HCC also alters the state of immune cells, causing "immune evasion" with inducing resistance to immune checkpoint inhibitors, which have recently become widely used to treat HCC. Activated Wnt/β-catenin signaling exhibits these phenomena in liver tumorigenesis through the expression of downstream target genes, and the molecular basis is still poorly understood. In this review, we describe the physiological roles of Wnt/b-catenin signaling and then discuss their characteristic changes by the abnormal activation of Wnt/b-catenin signaling. Clarification of the mechanism would contribute to the development of therapeutic agents in the future.
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Affiliation(s)
- Shinji Matsumoto
- Departments of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan.
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan.
| | - Akira Kikuchi
- Departments of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
- Center of Infectious Disease Education and Research (CiDER), Osaka University, 2-8 Yamada-Oka, Suita, Osaka, 565-0871, Japan
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7
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Hu Y, Wang R, An N, Li C, Wang Q, Cao Y, Li C, Liu J, Wang Y. Unveiling the power of microenvironment in liver regeneration: an in-depth overview. Front Genet 2023; 14:1332190. [PMID: 38152656 PMCID: PMC10751322 DOI: 10.3389/fgene.2023.1332190] [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: 11/02/2023] [Accepted: 11/29/2023] [Indexed: 12/29/2023] Open
Abstract
The liver serves as a vital regulatory hub for various physiological processes, including sugar, protein, and fat metabolism, coagulation regulation, immune system maintenance, hormone inactivation, urea metabolism, and water-electrolyte acid-base balance control. These functions rely on coordinated communication among different liver cell types, particularly within the liver's fundamental hepatic lobular structure. In the early stages of liver development, diverse liver cells differentiate from stem cells in a carefully orchestrated manner. Despite its susceptibility to damage, the liver possesses a remarkable regenerative capacity, with the hepatic lobule serving as a secure environment for cell division and proliferation during liver regeneration. This regenerative process depends on a complex microenvironment, involving liver resident cells, circulating cells, secreted cytokines, extracellular matrix, and biological forces. While hepatocytes proliferate under varying injury conditions, their sources may vary. It is well-established that hepatocytes with regenerative potential are distributed throughout the hepatic lobules. However, a comprehensive spatiotemporal model of liver regeneration remains elusive, despite recent advancements in genomics, lineage tracing, and microscopic imaging. This review summarizes the spatial distribution of cell gene expression within the regenerative microenvironment and its impact on liver regeneration patterns. It offers valuable insights into understanding the complex process of liver regeneration.
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Affiliation(s)
- Yuelei Hu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Ruilin Wang
- Department of Cadre’s Wards Ultrasound Diagnostics, Ultrasound Diagnostic Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Ni An
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Chen Li
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- College of Life Science and Bioengineering, Faculty of Environmental and Life Sciences, Beijing University of Technology, Beijing, China
| | - Qi Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Yannan Cao
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Chao Li
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Juan Liu
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Yunfang Wang
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
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8
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Nejak-Bowen K, Monga SP. Wnt-β-catenin in hepatobiliary homeostasis, injury, and repair. Hepatology 2023; 78:1907-1921. [PMID: 37246413 PMCID: PMC10687322 DOI: 10.1097/hep.0000000000000495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 04/14/2023] [Indexed: 05/30/2023]
Abstract
Wnt-β-catenin signaling has emerged as an important regulatory pathway in the liver, playing key roles in zonation and mediating contextual hepatobiliary repair after injuries. In this review, we will address the major advances in understanding the role of Wnt signaling in hepatic zonation, regeneration, and cholestasis-induced injury. We will also touch on some important unanswered questions and discuss the relevance of modulating the pathway to provide therapies for complex liver pathologies that remain a continued unmet clinical need.
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Affiliation(s)
- Kari Nejak-Bowen
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA USA
| | - Satdarshan P. Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
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9
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Hashimoto T, Takayanagi D, Yonemaru J, Naka T, Nagashima K, Machida E, Kohno T, Yatabe Y, Kanemitsu Y, Hamamoto R, Takashima A, Shiraishi K, Sekine S. A comprehensive appraisal of HER2 heterogeneity in HER2-amplified and HER2-low colorectal cancer. Br J Cancer 2023; 129:1176-1183. [PMID: 37543670 PMCID: PMC10539373 DOI: 10.1038/s41416-023-02382-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 07/21/2023] [Accepted: 07/26/2023] [Indexed: 08/07/2023] Open
Abstract
BACKGROUND This study aimed to elucidate the clinicopathological and molecular features of HER2-amplified and HER2-low colorectal cancers (CRCs). We also characterised HER2 expression statuses in CRCs focusing on their intratumoral heterogeneity and alterations in metastatic lesions to establish practical HER2 status assessment. METHODS We evaluated 1009 CRCs for HER2 expression and HER2 amplification by immunohistochemistry and FISH, respectively, and correlated the results to clinicopathological and molecular data. For HER2-positive tumours, HER2 expression in metastatic lesions was also assessed. RESULTS Twenty-five HER2-amplified (2.5%) and 46 HER2-low tumours (4.6%) were identified. HER2-amplified tumours consistently lacked a mucinous component and HER2-low tumours tended to be in the right colon, but no other clinicopathological features were noted. KRAS, NRAS or BRAF mutations were detected in only two HER2-amplified tumours (8%), whereas 23 HER2-low tumours (50%) had one of these mutations. Most HER2-amplified and HER2-low tumours showed a homogeneous or mosaic HER2 expression pattern and a clustered heterogeneous expression pattern was rather rare. HER2 expression was maintained in most metastatic lesions in both HER2-amplified (93%) and HER2-low tumours (81%). CONCLUSIONS These results suggest that biopsy-based assessment of primary lesions is appropriate for the identification of CRC patients eligible for systemic HER2-targeted therapy.
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Affiliation(s)
- Taiki Hashimoto
- Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
| | - Daisuke Takayanagi
- Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan
- Department of Medicine, Division of Medical Oncology, Showa University School of Medicine, Tokyo, Japan
- Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo, Japan
| | - Junpei Yonemaru
- Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
| | - Tomoaki Naka
- Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
| | - Kengo Nagashima
- Biostatistics Unit, Clinical and Translational Research Center, Keio University Hospital, Tokyo, Japan
| | - Erika Machida
- Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan
| | - Takashi Kohno
- Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan
| | - Yasushi Yatabe
- Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
- Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Yukihide Kanemitsu
- Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Ryuji Hamamoto
- Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan
| | - Atsuo Takashima
- Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Kouya Shiraishi
- Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan
- Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Shigeki Sekine
- Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.
- Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
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10
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Purhonen J, Klefström J, Kallijärvi J. MYC-an emerging player in mitochondrial diseases. Front Cell Dev Biol 2023; 11:1257651. [PMID: 37731815 PMCID: PMC10507175 DOI: 10.3389/fcell.2023.1257651] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 08/21/2023] [Indexed: 09/22/2023] Open
Abstract
The mitochondrion is a major hub of cellular metabolism and involved directly or indirectly in almost all biological processes of the cell. In mitochondrial diseases, compromised respiratory electron transfer and oxidative phosphorylation (OXPHOS) lead to compensatory rewiring of metabolism with resemblance to the Warburg-like metabolic state of cancer cells. The transcription factor MYC (or c-MYC) is a major regulator of metabolic rewiring in cancer, stimulating glycolysis, nucleotide biosynthesis, and glutamine utilization, which are known or predicted to be affected also in mitochondrial diseases. Albeit not widely acknowledged thus far, several cell and mouse models of mitochondrial disease show upregulation of MYC and/or its typical transcriptional signatures. Moreover, gene expression and metabolite-level changes associated with mitochondrial integrated stress response (mt-ISR) show remarkable overlap with those of MYC overexpression. In addition to being a metabolic regulator, MYC promotes cellular proliferation and modifies the cell cycle kinetics and, especially at high expression levels, promotes replication stress and genomic instability, and sensitizes cells to apoptosis. Because cell proliferation requires energy and doubling of the cellular biomass, replicating cells should be particularly sensitive to defective OXPHOS. On the other hand, OXPHOS-defective replicating cells are predicted to be especially vulnerable to high levels of MYC as it facilitates evasion of metabolic checkpoints and accelerates cell cycle progression. Indeed, a few recent studies demonstrate cell cycle defects and nuclear DNA damage in OXPHOS deficiency. Here, we give an overview of key mitochondria-dependent metabolic pathways known to be regulated by MYC, review the current literature on MYC expression in mitochondrial diseases, and speculate how its upregulation may be triggered by OXPHOS deficiency and what implications this has for the pathogenesis of these diseases.
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Affiliation(s)
- Janne Purhonen
- Folkhälsan Research Center, Helsinki, Finland
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Juha Klefström
- Finnish Cancer Institute, FICAN South Helsinki University Hospital, Helsinki, Finland
- Translational Cancer Medicine, Medical Faculty, University of Helsinki, Helsinki, Finland
- Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, United States
| | - Jukka Kallijärvi
- Folkhälsan Research Center, Helsinki, Finland
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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11
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Shin YS, Hwang DB, Won DH, Kim SY, Kim C, Park JW, Jeon Y, Yun JW. The Wnt/β-catenin signaling pathway plays a role in drug-induced liver injury by regulating cytochrome P450 2E1 expression. Toxicol Res 2023; 39:443-453. [PMID: 37398564 PMCID: PMC10313641 DOI: 10.1007/s43188-023-00180-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/28/2023] [Accepted: 03/29/2023] [Indexed: 07/04/2023] Open
Abstract
Drug-induced liver injury (DILI) is a major cause of acute liver failure and drug withdrawal. Cytochrome P450 (CYP) 2E1 is involved in the metabolism of several drugs, and can induce liver injury through the production of toxic metabolites and the generation of reactive oxygen species. This study aimed to elucidate the role of Wnt/β-catenin signaling in CYP2E1 regulation for drug-induced hepatotoxicity. To achieve this, mice were administered cisplatin or acetaminophen (APAP) 1 h after treatment with the CYP2E1 inhibitor dimethyl sulfoxide (DMSO), and histopathological and serum biochemical analyses were performed. APAP treatment induced hepatotoxicity, as evidenced by an increase in liver weight and serum ALT levels. Moreover, histological analysis indicated severe injury, including apoptosis, in the liver tissue of APAP-treated mice, which was confirmed by TUNEL assay. Additionally, APAP treatment suppressed the antioxidant capacity of the mice and increased the expression of the DNA damage markers γ-H2AX and p53. However, these effects of APAP on hepatotoxicity were significantly attenuated by DMSO treatment. Furthermore, the activation of Wnt/β-catenin signaling using the Wnt agonist CHIR99021 (CHIR) increased CYP2E1 expression in rat liver epithelial cells (WB-F344), whereas treatment with the Wnt/β-catenin antagonist IWP-2 inhibited nuclear β-catenin and CYP2E1 expression. Interestingly, APAP-induced cytotoxicity in WB-F344 cells was exacerbated by CHIR treatment and suppressed by IWP-2 treatment. Overall, these results showed that the Wnt/β-catenin signaling is involved in DILI through the upregulation of CYP2E1 expression by directly binding the transcription factor β-cat/TCF to the Cyp2e1 promoter, thus exacerbating DILI. Supplementary Information The online version contains supplementary material available at 10.1007/s43188-023-00180-6.
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Affiliation(s)
- Yoo-Sub Shin
- Department of Research and Development, SML Genetree, Seoul, 05855 Republic of Korea
- Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662 Republic of Korea
| | - Da-Bin Hwang
- Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662 Republic of Korea
| | - Dong-Hoon Won
- Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662 Republic of Korea
| | - Shin-Young Kim
- Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662 Republic of Korea
| | - Changuk Kim
- Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662 Republic of Korea
| | - Jun Won Park
- Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, 24341 Republic of Korea
| | - Young Jeon
- Laboratory of Veterinary Toxicology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826 Republic of Korea
| | - Jun-Won Yun
- Laboratory of Veterinary Toxicology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826 Republic of Korea
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12
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Trinh VQH, Lee TF, Lemoinne S, Ray KC, Ybanez MD, Tsuchida T, Carter JK, Agudo J, Brown BD, Akat KM, Friedman SL, Lee YA. Hepatic stellate cells maintain liver homeostasis through paracrine neurotrophin-3 signaling that induces hepatocyte proliferation. Sci Signal 2023; 16:eadf6696. [PMID: 37253090 PMCID: PMC10367116 DOI: 10.1126/scisignal.adf6696] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 05/03/2023] [Indexed: 06/01/2023]
Abstract
Organ size is maintained by the controlled proliferation of distinct cell populations. In the mouse liver, hepatocytes in the midlobular zone that are positive for cyclin D1 (CCND1) repopulate the parenchyma at a constant rate to preserve liver mass. Here, we investigated how hepatocyte proliferation is supported by hepatic stellate cells (HSCs), pericytes that are in close proximity to hepatocytes. We used T cells to ablate nearly all HSCs in the murine liver, enabling the unbiased characterization of HSC functions. In the normal liver, complete loss of HSCs persisted for up to 10 weeks and caused a gradual reduction in liver mass and in the number of CCND1+ hepatocytes. We identified neurotrophin-3 (Ntf-3) as an HSC-produced factor that induced the proliferation of midlobular hepatocytes through the activation of tropomyosin receptor kinase B (TrkB). Treating HSC-depleted mice with Ntf-3 restored CCND1+ hepatocytes in the midlobular region and increased liver mass. These findings establish that HSCs form the mitogenic niche for midlobular hepatocytes and identify Ntf-3 as a hepatocyte growth factor.
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Affiliation(s)
| | - Ting-Fang Lee
- Department of Surgery, Vanderbilt University Medical Center; Nashville, TN, USA
| | - Sara Lemoinne
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai; New York, NY, USA
| | - Kevin C. Ray
- Department of Surgery, Vanderbilt University Medical Center; Nashville, TN, USA
| | - Maria D. Ybanez
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai; New York, NY, USA
| | - Takuma Tsuchida
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai; New York, NY, USA
| | - James K. Carter
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai; New York, NY, USA
| | - Judith Agudo
- Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School; Boston, MA, USA
| | - Brian D. Brown
- Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kemal M. Akat
- Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center; Nashville, TN, USA
| | - Scott L. Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai; New York, NY, USA
| | - Youngmin A. Lee
- Department of Surgery, Vanderbilt University Medical Center; Nashville, TN, USA
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13
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Grishanova AY, Klyushova LS, Perepechaeva ML. AhR and Wnt/β-Catenin Signaling Pathways and Their Interplay. Curr Issues Mol Biol 2023; 45:3848-3876. [PMID: 37232717 DOI: 10.3390/cimb45050248] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/27/2023] [Accepted: 04/28/2023] [Indexed: 05/27/2023] Open
Abstract
As evolutionarily conserved signaling cascades, AhR and Wnt signaling pathways play a critical role in the control over numerous vital embryonic and somatic processes. AhR performs many endogenous functions by integrating its signaling pathway into organ homeostasis and into the maintenance of crucial cellular functions and biological processes. The Wnt signaling pathway regulates cell proliferation, differentiation, and many other phenomena, and this regulation is important for embryonic development and the dynamic balance of adult tissues. AhR and Wnt are the main signaling pathways participating in the control of cell fate and function. They occupy a central position in a variety of processes linked with development and various pathological conditions. Given the importance of these two signaling cascades, it would be interesting to elucidate the biological implications of their interaction. Functional connections between AhR and Wnt signals take place in cases of crosstalk or interplay, about which quite a lot of information has been accumulated in recent years. This review is focused on recent studies about the mutual interactions of key mediators of AhR and Wnt/β-catenin signaling pathways and on the assessment of the complexity of the crosstalk between the AhR signaling cascade and the canonical Wnt pathway.
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Affiliation(s)
- Alevtina Y Grishanova
- Institute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, Timakova Str. 2, Novosibirsk 630117, Russia
| | - Lyubov S Klyushova
- Institute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, Timakova Str. 2, Novosibirsk 630117, Russia
| | - Maria L Perepechaeva
- Institute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, Timakova Str. 2, Novosibirsk 630117, Russia
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14
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Hu S, Cao C, Poddar M, Delgado E, Singh S, Singh-Varma A, Stolz DB, Bell A, Monga SP. Hepatocyte β-catenin loss is compensated by Insulin-mTORC1 activation to promote liver regeneration. Hepatology 2023; 77:1593-1611. [PMID: 35862186 PMCID: PMC9859954 DOI: 10.1002/hep.32680] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/13/2022] [Accepted: 07/16/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND AND AIMS Liver regeneration (LR) following partial hepatectomy (PH) occurs via activation of various signaling pathways. Disruption of a single pathway can be compensated by activation of another pathway to continue LR. The Wnt-β-catenin pathway is activated early during LR and conditional hepatocyte loss of β-catenin delays LR. Here, we study mechanism of LR in the absence of hepatocyte-β-catenin. APPROACH AND RESULTS Eight-week-old hepatocyte-specific Ctnnb1 knockout mice (β-catenin ΔHC ) were subjected to PH. These animals exhibited decreased hepatocyte proliferation at 40-120 h and decreased cumulative 14-day BrdU labeling of <40%, but all mice survived, suggesting compensation. Insulin-mediated mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) activation was uniquely identified in the β-catenin ΔHC mice at 72-96 h after PH. Deletion of hepatocyte regulatory-associated protein of mTOR (Raptor), a critical mTORC1 partner, in the β-catenin ΔHC mice led to progressive hepatic injury and mortality by 30 dys. PH on early stage nonmorbid Raptor ΔHC -β-catenin ΔHC mice led to lethality by 12 h. Raptor ΔHC mice showed progressive hepatic injury and spontaneous LR with β-catenin activation but died by 40 days. PH on early stage nonmorbid Raptor ΔHC mice was lethal by 48 h. Temporal inhibition of insulin receptor and mTORC1 in β-catenin ΔHC or controls after PH was achieved by administration of linsitinib at 48 h or rapamycin at 60 h post-PH and completely prevented LR leading to lethality by 12-14 days. CONCLUSIONS Insulin-mTORC1 activation compensates for β-catenin loss to enable LR after PH. mTORC1 signaling in hepatocytes itself is critical to both homeostasis and LR and is only partially compensated by β-catenin activation. Dual inhibition of β-catenin and mTOR may have notable untoward hepatotoxic side effects.
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Affiliation(s)
- Shikai Hu
- School of Medicine, Tsinghua University, Beijing, China
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
| | - Catherine Cao
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
| | - Minakshi Poddar
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
| | - Evan Delgado
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA USA
| | - Sucha Singh
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
| | - Anya Singh-Varma
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
| | - Donna Beer Stolz
- Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA USA
| | - Aaron Bell
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA USA
| | - Satdarshan P. Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
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15
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Gayden J, Hu S, Joseph PN, Delgado E, Liu S, Bell A, Puig S, Monga SP, Freyberg Z. A Spatial Atlas of Wnt Receptors in Adult Mouse Liver. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:558-566. [PMID: 36773785 PMCID: PMC10155265 DOI: 10.1016/j.ajpath.2023.01.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/13/2023] [Accepted: 01/30/2023] [Indexed: 02/12/2023]
Abstract
Hepatic zonation is critical for most metabolic functions in liver. Wnt signaling plays an important role in establishing and maintaining liver zonation. Yet, the anatomic expression of Wnt signaling components, especially all 10 Frizzled (Fzd) receptors, has not been characterized in adult liver. To address this, the spatial expression of Fzd receptors was quantitatively mapped in adult mouse liver via multiplex fluorescent in situ hybridization. Although all 10 Fzd receptors were expressed within a metabolic unit, Fzd receptors 1, 4, and 6 were the highest expressed. Although most Wnt signaling occurs in zone 3, expression of most Fzd receptors was not zonated. In contrast, Fzd receptor 6 was preferentially expressed in zone 1. Wnt2 and Wnt9b expression was highly zonated and primarily found in zone 3. Therefore, the current results suggest that zonated Wnt/β-catenin signaling at baseline occurs primarily due to Wnt2 and Wnt9b rather than zonation of Fzd mRNA expression. Finally, the study showed that Fzd receptors and Wnts are not uniformly expressed by all hepatic cell types. Instead, there is broad distribution among both hepatocytes and nonparenchymal cells, including endothelial cells. Overall, this establishment of a definitive mRNA expression atlas, especially of Fzd receptors, opens the door to future functional characterization in healthy and diseased liver states.
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Affiliation(s)
- Jenesis Gayden
- Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Shikai Hu
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Paul N Joseph
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Evan Delgado
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Silvia Liu
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Aaron Bell
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Stephanie Puig
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
| | - Satdarshan P Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania; Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania.
| | - Zachary Freyberg
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
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16
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Purhonen J, Banerjee R, Wanne V, Sipari N, Mörgelin M, Fellman V, Kallijärvi J. Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria. Nat Commun 2023; 14:2356. [PMID: 37095097 PMCID: PMC10126100 DOI: 10.1038/s41467-023-38027-1] [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: 10/18/2022] [Accepted: 04/12/2023] [Indexed: 04/26/2023] Open
Abstract
Accumulating evidence suggests mitochondria as key modulators of normal and premature aging, yet whether primary oxidative phosphorylation (OXPHOS) deficiency can cause progeroid disease remains unclear. Here, we show that mice with severe isolated respiratory complex III (CIII) deficiency display nuclear DNA damage, cell cycle arrest, aberrant mitoses, and cellular senescence in the affected organs such as liver and kidney, and a systemic phenotype resembling juvenile-onset progeroid syndromes. Mechanistically, CIII deficiency triggers presymptomatic cancer-like c-MYC upregulation followed by excessive anabolic metabolism and illicit cell proliferation against lack of energy and biosynthetic precursors. Transgenic alternative oxidase dampens mitochondrial integrated stress response and the c-MYC induction, suppresses the illicit proliferation, and prevents juvenile lethality despite that canonical OXPHOS-linked functions remain uncorrected. Inhibition of c-MYC with the dominant-negative Omomyc protein relieves the DNA damage in CIII-deficient hepatocytes in vivo. Our results connect primary OXPHOS deficiency to genomic instability and progeroid pathogenesis and suggest that targeting c-MYC and aberrant cell proliferation may be therapeutic in mitochondrial diseases.
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Affiliation(s)
- Janne Purhonen
- Folkhälsan Research Center, Haartmaninkatu 8, 00290, Helsinki, Finland
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, P.O.Box 63, 00014, Helsinki, Finland
| | - Rishi Banerjee
- Folkhälsan Research Center, Haartmaninkatu 8, 00290, Helsinki, Finland
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, P.O.Box 63, 00014, Helsinki, Finland
| | - Vilma Wanne
- Folkhälsan Research Center, Haartmaninkatu 8, 00290, Helsinki, Finland
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, P.O.Box 63, 00014, Helsinki, Finland
| | - Nina Sipari
- Viikki Metabolomics Unit, University of Helsinki, P.O.Box 65, Helsinki, Finland
| | - Matthias Mörgelin
- Division of Infection Medicine, Department of Clinical Sciences, Lund University, P.O.Box 117, 221 00, Lund, Sweden
- Colzyx AB, Scheelevägen 2, 22381, Lund, Sweden
| | - Vineta Fellman
- Folkhälsan Research Center, Haartmaninkatu 8, 00290, Helsinki, Finland
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, P.O.Box 63, 00014, Helsinki, Finland
- Department of Clinical Sciences, Lund, Pediatrics, Lund University, P.O.Box 117, 221 00, Lund, Sweden
- Children's Hospital, Clinicum, University of Helsinki, P.O. Box 22, 00014, Helsinki, Finland
| | - Jukka Kallijärvi
- Folkhälsan Research Center, Haartmaninkatu 8, 00290, Helsinki, Finland.
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, P.O.Box 63, 00014, Helsinki, Finland.
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17
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Zou G, Park JI. Wnt signaling in liver regeneration, disease, and cancer. Clin Mol Hepatol 2023; 29:33-50. [PMID: 35785913 PMCID: PMC9845677 DOI: 10.3350/cmh.2022.0058] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 06/30/2022] [Indexed: 02/02/2023] Open
Abstract
The liver exhibits the highest recovery rate from acute injuries. However, in chronic liver disease, the long-term loss of hepatocytes often leads to adverse consequences such as fibrosis, cirrhosis, and liver cancer. The Wnt signaling plays a pivotal role in both liver regeneration and tumorigenesis. Therefore, manipulating the Wnt signaling has become an attractive approach to treating liver disease, including cancer. Nonetheless, given the crucial roles of Wnt signaling in physiological processes, blocking Wnt signaling can also cause several adverse effects. Recent studies have identified cancer-specific regulators of Wnt signaling, which would overcome the limitation of Wnt signaling target approaches. In this review, we discussed the role of Wnt signaling in liver regeneration, precancerous lesion, and liver cancer. Furthermore, we summarized the basic and clinical approaches of Wnt signaling blockade and proposed the therapeutic prospects of cancer-specific Wnt signaling blockade for liver cancer treatment.
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Affiliation(s)
- Gengyi Zou
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,Corresponding author : Gengyi Zou Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd Unit 1054, Houston, TX 77030, USA Tel: +1-713-792-3659, Fax: +1-713-794-5369, E-mail:
| | - Jae-Il Park
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,Genetics and Epigenetics Program, The University of Texas MD Anderson Cancer Center Graduate School of Biomedical Sciences, Houston, TX, USA,Jae-Il Park Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd. Unit 1052, Houston, TX 77030, USA Tel: +1-713-792-3659, Fax: +1-713-794-5369, E-mail:
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18
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Hu S, Liu S, Bian Y, Poddar M, Singh S, Cao C, McGaughey J, Bell A, Blazer LL, Adams JJ, Sidhu SS, Angers S, Monga SP. Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b. Cell Rep Med 2022; 3:100754. [PMID: 36220068 PMCID: PMC9588996 DOI: 10.1016/j.xcrm.2022.100754] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 07/04/2022] [Accepted: 09/08/2022] [Indexed: 11/16/2022]
Abstract
The conclusive identity of Wnts regulating liver zonation (LZ) and regeneration (LR) remains unclear despite an undisputed role of β-catenin. Using single-cell analysis, we identified a conserved Wnt2 and Wnt9b expression in endothelial cells (ECs) in zone 3. EC-elimination of Wnt2 and Wnt9b led to both loss of β-catenin targets in zone 3, and re-appearance of zone 1 genes in zone 3, unraveling dynamicity in the LZ process. Impaired LR observed in the knockouts phenocopied models of defective hepatic Wnt signaling. Administration of a tetravalent antibody to activate Wnt signaling rescued LZ and LR in the knockouts and induced zone 3 gene expression and LR in controls. Administration of the agonist also promoted LR in acetaminophen overdose acute liver failure (ALF) fulfilling an unmet clinical need. Overall, we report an unequivocal role of EC-Wnt2 and Wnt9b in LZ and LR and show the role of Wnt activators as regenerative therapy for ALF.
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Affiliation(s)
- Shikai Hu
- School of Medicine, Tsinghua University, Beijing, China; Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Silvia Liu
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Yu Bian
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Minakshi Poddar
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Sucha Singh
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Catherine Cao
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jackson McGaughey
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Aaron Bell
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Levi L Blazer
- Donnelly Centre, University of Toronto, Toronto, ON, Canada
| | - Jarret J Adams
- Donnelly Centre, University of Toronto, Toronto, ON, Canada
| | | | - Stephane Angers
- Donnelly Centre, University of Toronto, Toronto, ON, Canada; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada
| | - Satdarshan P Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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19
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Khurana C, Bedi O. Proposed hypothesis of GSK-3 β inhibition for stimulating Wnt/β-catenin signaling pathway which triggers liver regeneration process. Naunyn Schmiedebergs Arch Pharmacol 2022; 395:377-380. [PMID: 35076714 DOI: 10.1007/s00210-022-02207-5] [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: 08/13/2021] [Accepted: 01/18/2022] [Indexed: 11/28/2022]
Abstract
Almost every human organ has a poor ability to regenerate, notable exceptions are liver, skin, gut, etc. Molecular and cellular underpinnings of liver regeneration might pave the way for novel treatments concerned with chronic liver disorder. Such treatments would eliminate the disadvantages of liver transplantation, such as a scarcity of donor organs, a lengthy waitlist, significant medical expenses, surgical complications, and the necessity for lifelong immunosuppressive medications. Advancement in the development of regenerative therapy is giving hope to those suffering from end-stage liver disorder. The regeneration process is unique, intricate, and well coordinated, which involve the interaction of numerous signaling pathways, cytokines, and growth factor. Various signaling pathways for liver regeneration are HO-1/BER pathway, Tweak/Fn14 signaling pathway, Hippo pathway, Wnt/beta-catenin pathway, Hedgehog signaling pathway, bile acids repairing pathway, serotonin (5HT) pathway, estrogen pathway, thyrotropin-releasing hormone (TRH) pathway, insulin repairing pathway, etc. The in vitro scientific literature revealed that numerous GSK-3 β inhibitors (LY 2090314, AR-A014418, Tideglusib, Solasodine, CHIR99021, 9-ING-41, SB-216763) play an important role in stimulating the liver regeneration process. Similarly, from the above discussion, the direction is highlighted to emphasize the proposed molecular Wnt/β-catenin signaling pathway which is associated with GSK-3 β inhibition for the induction of the repairing and regeneration process.
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Affiliation(s)
- Chirag Khurana
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Onkar Bedi
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
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20
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Hönes GS, Kerp H, Hoppe C, Kowalczyk M, Zwanziger D, Baba HA, Führer D, Moeller LC. Canonical Thyroid Hormone Receptor β Action Stimulates Hepatocyte Proliferation in Male Mice. Endocrinology 2022; 163:6509895. [PMID: 35038735 DOI: 10.1210/endocr/bqac003] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT 3,5,3'-L-triiodothyronine (T3) is a potent inducer of hepatocyte proliferation via the Wnt/β-catenin signaling pathway. Previous studies suggested the involvement of rapid noncanonical thyroid hormone receptor (TR) β signaling, directly activating hepatic Wnt/β-catenin signaling independent from TRβ DNA binding. However, the mechanism by which T3 increases Wnt/β-catenin signaling in hepatocytes has not yet been determined. OBJECTIVE We aimed to determine whether DNA binding of TRβ is required for stimulation of hepatocyte proliferation by T3. METHODS Wild-type (WT) mice, TRβ knockout mice (TRβ KO), and TRβ mutant mice with either specifically abrogated DNA binding (TRβ GS) or abrogated direct phosphatidylinositol 3 kinase activation (TRβ 147F) were treated with T3 for 6 hours or 7 days. Hepatocyte proliferation was assessed by Kiel-67 (Ki67) staining and apoptosis by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Activation of β-catenin signaling was measured in primary murine hepatocytes. Gene expression was analyzed by microarray, gene set enrichment analysis (GSEA), and quantitative reverse transcription polymerase chain reaction. RESULTS T3 induced hepatocyte proliferation with an increased number of Ki67-positive cells in WT and TRβ 147F mice (9.2% ± 6.5% and 10.1% ± 2.9%, respectively) compared to TRβ KO and TRβ GS mice (1.2% ± 1.1% and 1.5% ± 0.9%, respectively). Microarray analysis and GSEA showed that genes of the Wnt/β-catenin pathway-among them, Fzd8 (frizzled receptor 8) and Ctnnb1 (β-catenin)-were positively enriched only in T3-treated WT and TRβ 147F mice while B-cell translocation gene anti-proliferation factor 2 was repressed. Consequently, expression of Ccnd1 (CyclinD1) was induced. CONCLUSIONS Instead of directly activating Wnt signaling, T3 and TRβ induce key genes of the Wnt/β-catenin pathway, ultimately stimulating hepatocyte proliferation via CyclinD1. Thus, canonical transcriptional TRβ action is necessary for T3-mediated stimulation of hepatocyte proliferation.
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Affiliation(s)
- Georg Sebastian Hönes
- Department of Endocrinology, Diabetes and Metabolism and Division of Laboratory Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Helena Kerp
- Department of Endocrinology, Diabetes and Metabolism and Division of Laboratory Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Christoph Hoppe
- Department of Endocrinology, Diabetes and Metabolism and Division of Laboratory Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Manuela Kowalczyk
- Department of Endocrinology, Diabetes and Metabolism and Division of Laboratory Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Denise Zwanziger
- Department of Endocrinology, Diabetes and Metabolism and Division of Laboratory Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | | | - Dagmar Führer
- Department of Endocrinology, Diabetes and Metabolism and Division of Laboratory Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Lars Christian Moeller
- Department of Endocrinology, Diabetes and Metabolism and Division of Laboratory Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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21
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Chang YM, Chen PC, Hsu CP, Ma PF, Chen HL, Hsu SH. Loss of hepatic miR-194 promotes liver regeneration and protects from acetaminophen-induced acute liver injury. Biochem Pharmacol 2022; 195:114862. [PMID: 34843716 DOI: 10.1016/j.bcp.2021.114862] [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: 09/20/2021] [Revised: 11/23/2021] [Accepted: 11/24/2021] [Indexed: 11/26/2022]
Abstract
The two microRNAs miR-192 and miR-194 are abundantly expressed in the liver and are considered serum biomarkers of liver injury. However, their role in the development of liver injury has not yet been determined. In this study, we generated miR-192/194 mutant mice and determined the effect of miR-192/194 loss on acetaminophen (APAP)-induced acute liver injury. With genetic depletion of miR-192/194, mutant mice were fertile and normally developed. No spontaneous liver injuries were observed in mutant mice. After APAP administration, mutant mice developed less severe liver damage than control mice. Specifically, mutant mice exhibited significantly lower serum alanine transaminase (ALT) levels and pericentral necrosis/apoptosis than control mice receiving APAP. β-catenin signaling was activated during the early phase of liver injury. Activated β-catenin signaling led to faster cellular proliferation and higher expression of AXIN2 and glutamine synthetases. After partial hepatectomy, the miR-192/194 mutant hepatocytes were more regenerative than control hepatocytes (as shown by BrdU incorporation). Moreover, in vitro experiments indicated that miR-194, but not miR-192, specifically repressed β-catenin signaling, while animal experiments revealed that chemical-mediated knockdown of β-catenin signaling compromised APAP resistance that liver protected from miR-192/194 genetic depletion. Collectively, our data indicated that the loss of miR-194 promoted liver regeneration and protected the liver from APAP-induced injury.
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Affiliation(s)
- Yi-Ming Chang
- Department of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan
| | - Po-Chun Chen
- Department of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan; Division of Gastrointestinal Surgery, Department of Surgery, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan
| | - Chien-Peng Hsu
- Department of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan
| | - Peng-Fang Ma
- Department of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan; Department of Pediatrics, National Taiwan University College of Medicine and National Taiwan University Children's Hospital, Taipei, Taiwan
| | - Shu-Hao Hsu
- Department of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan.
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22
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Liu Z, Kuna VK, Xu B, Sumitran-Holgersson S. Wnt ligands 3a and 5a regulate proliferation and migration in human fetal liver progenitor cells. Transl Gastroenterol Hepatol 2021; 6:56. [PMID: 34805578 DOI: 10.21037/tgh.2020.01.12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 01/18/2020] [Indexed: 11/06/2022] Open
Abstract
Background Since human fetal liver progenitor cells (hFLPC) can differentiate into multiple liver cell types in vitro and in vivo, hFLPC may be a suitable source for cell therapy and regeneration strategies. Imperative for effective clinical applications of hFLPC is the enhanced knowledge of growth factors that mediate and improve migration and proliferation. The canonical wingless/int-1 (Wnt) signal transduction pathway is known to play a key role in proliferation and migration of stem cells. So, we investigated a role for Wnt3a and Wnt5a ligands in regulating the proliferation and migration of hFLPC. Methods We used alamarBlue assay and transwell migration assay and examined proliferation and migration of hFLPC to Wnt3a and Wnt5a. In addition, the target genes of Wnt signal transduction pathway was identified using microarray analysis and validated by quantitative real-time polymerase chain reaction (qPCR). Results We found that Wnt3a or Wnt5a independently significantly increased migration and proliferation in a dose-dependent manner which was significantly inhibited by Wnt inhibitors Wnt-C59 or KN-62. Addition of Wnt3a to hFLPC resulted in increased mRNA expression of the known Wnt target genes Axin-2, DKK2, while Wnt5a increased CXCR7, all of which are closely associated with an enhanced proliferation capacity of stem cells. Conclusions Thus, we report that Wnt3a and Wnt5a may play an important role in the proliferation and migration of hFLPC by possibly regulating key target genes-involved in these processes. Incorporating recombinant human Wnt3a and Wnt5a in regenerative strategies using liver stem/progenitor cells might improve the process of liver regeneration.
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Affiliation(s)
- Zhiwen Liu
- Laboratory for Transplantation and Regenerative Medicine, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Vijay Kumar Kuna
- Laboratory for Transplantation and Regenerative Medicine, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Bo Xu
- Laboratory for Transplantation and Regenerative Medicine, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Suchitra Sumitran-Holgersson
- Laboratory for Transplantation and Regenerative Medicine, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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23
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Liang R, Lin YH, Zhu H. Genetic and Cellular Contributions to Liver Regeneration. Cold Spring Harb Perspect Biol 2021; 14:a040832. [PMID: 34750173 PMCID: PMC9438780 DOI: 10.1101/cshperspect.a040832] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
The regenerative capabilities of the liver represent a paradigm for understanding tissue repair in solid organs. Regeneration after partial hepatectomy in rodent models is well understood, while regeneration in the context of clinically relevant chronic injuries is less studied. Given the growing incidence of fatty liver disease, cirrhosis, and liver cancer, interest in liver regeneration is increasing. Here, we will review the principles, genetics, and cell biology underlying liver regeneration, as well as new approaches being used to study heterogeneity in liver tissue maintenance and repair.
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Affiliation(s)
- Roger Liang
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Yu-Hsuan Lin
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Hao Zhu
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
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24
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Chen S, Tang Y, Fang W, He T, Chen X, Zhang P. CoQ10 promotes resolution of necrosis and liver regeneration after acetaminophen-induced liver injury. Toxicol Sci 2021; 185:19-27. [PMID: 34668565 DOI: 10.1093/toxsci/kfab123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Coenzyme Q10 (CoQ10) which acts as an electron transporter in the mitochondrial respiratory chain has many beneficial effects on liver diseases. In our previous research, CoQ10 has been found to attenuate acetaminophen (APAP) induced acute liver injury (ALI). However, whether CoQ10 administration is still effective at the late stage of APAP overdose is still unknown. In this study, we aimed to test CoQ10 efficacy at the late stage of APAP overdose. C57BL/6J mice were intraperitoneally treated with APAP to induce liver injury. CoQ10 (5 mg/kg) was given to mice at 16 hours after APAP treatment. The results showed that while CoQ10 treatment at 16 hours post-APAP overdose had no effects on the expression of ROS generated genes or scavenged genes, it still significantly decreased necrosis of hepatocytes following APAP-induced ALI. Moreover, CoQ10 increased MerTK+ macrophages accumulation in the APAP-overdose liver and inhibition of MerTK signaling partly abrogated the protective role of CoQ10 treatment on the hepatic necrosis. CoQ10 treatment also significantly enhanced hepatocytes proliferation as shown in the increased BrdU incorporation in the APAP-intoxicated mice liver section. In addition, CoQ10 treatment increased hepatic PCNA and Cyclin D1 expression and promoted activation of the β-catenin signaling in APAP-overdose mice. To conclude, these data provide evidence that CoQ10 treatment is still effective at the late stage of APAP-induced ALI and promotes resolution of necrosis and liver regeneration following ALI.
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Affiliation(s)
- Shen Chen
- Department of Toxicology, School of Public Health, Sun Yat-sen University, People's Republic of China
| | - Yi Tang
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Wanjun Fang
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Taiping He
- Department of Nutrition, School of Public Health, Guangdong Medical University, People's Republic of China
| | - Xu Chen
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Peiwen Zhang
- Department of Nutrition, School of Public Health, Guangdong Medical University, People's Republic of China
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25
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Abstract
Significance: During aging, excessive production of reactive species in the liver leads to redox imbalance with consequent oxidative damage and impaired organ homeostasis. Nevertheless, slight amounts of reactive species may modulate several transcription factors, acting as second messengers and regulating specific signaling pathways. These redox-dependent alterations may impact the age-associated decline in liver regeneration. Recent Advances: In the last few decades, relevant findings related to redox alterations in the aging liver were investigated. Consistently, recent research broadened understanding of redox modifications and signaling related to liver regeneration. Other than reporting the effect of oxidative stress, epigenetic and post-translational modifications, as well as modulation of specific redox-sensitive cellular signaling, were described. Among them, the present review focuses on Wnt/β-catenin, the nuclear factor (erythroid-derived 2)-like 2 (NRF2), members of the Forkhead box O (FoxO) family, and the p53 tumor suppressor. Critical Issues: Even though alteration in redox homeostasis occurs both in aging and in impaired liver regeneration, the associative mechanisms are not clearly defined. Of note, antioxidants are not effective in slowing hepatic senescence, and do not clearly improve liver repopulation after hepatectomy or transplant in humans. Future Directions: Further investigations are needed to define mutual redox-dependent molecular pathways involved both in aging and in the decline of liver regeneration. Preclinical studies aimed at the characterization of these pathways would define possible therapeutic targets for human trials. Antioxid. Redox Signal. 35, 832-847.
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Affiliation(s)
- Francesco Bellanti
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gianluigi Vendemiale
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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26
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Frieg B, Görg B, Gohlke H, Häussinger D. Glutamine synthetase as a central element in hepatic glutamine and ammonia metabolism: novel aspects. Biol Chem 2021; 402:1063-1072. [PMID: 33962502 DOI: 10.1515/hsz-2021-0166] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/22/2021] [Indexed: 12/27/2022]
Abstract
Glutamine synthetase (GS) in the liver is expressed in a small perivenous, highly specialized hepatocyte population and is essential for the maintenance of low, non-toxic ammonia levels in the organism. However, GS activity can be impaired by tyrosine nitration of the enzyme in response to oxidative/nitrosative stress in a pH-sensitive way. The underlying molecular mechanism as investigated by combined molecular simulations and in vitro experiments indicates that tyrosine nitration can lead to a fully reversible and pH-sensitive regulation of protein function. This approach was also used to understand the functional consequences of several recently described point mutations of human GS with clinical relevance and to suggest an approach to restore impaired GS activity.
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Affiliation(s)
- Benedikt Frieg
- Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich GmbH, D-52425 Jülich, Germany
| | - Boris Görg
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany
| | - Holger Gohlke
- John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre (JSC), Institute of Biological Information Processing (IBI-7: Structural Biochemistry), and Institute of Bio- and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich GmbH, D-52425 Jülich, Germany
- Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany
| | - Dieter Häussinger
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany
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27
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Abstract
The liver is uniquely bestowed with an ability to regenerate following a surgical or toxicant insult. One of the most researched models to demonstrate the regenerative potential of this organ is the partial hepatectomy model, where two thirds of the liver is surgically resected. The remnant liver replenishes the lost mass within 1014 days in mice. The distinctive ability of the liver to regenerate has allowed living donor and split liver transplantation. One signaling pathway shown to be activated during the process of regeneration to contribute toward the mass and functional recovery of the liver is the Wnt/-catenin pathway. Very early after any insult to the liver, the cellmolecule circuitry of the Wnt/-catenin pathway is set into motion with the release of specific Wnt ligands from sinusoidal endothelial cells and macrophages, which, in a paracrine manner, engage Frizzled and LDL-related protein-5/6 coreceptors on hepatocytes to stabilize -catenin inducing its nuclear translocation. Nuclear -catenin interacts with T-cell factor family of transcription factors to induce target genes including cyclin D1 for proliferation, and others for regulating hepatocyte function. Working in collaboration with other signaling pathways, Wnt/-catenin signaling contributes to the restoration process without any compromise of function at any stage. Also, stimulation of this pathway through innovative means induces liver regeneration when this process is exhausted or compromised and thus has applications in the treatment of end-stage liver disease and in the field of liver transplantation. Thus, Wnt/-catenin signaling pathway is highly relevant in the discipline of hepatic regenerative medicine.
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Affiliation(s)
- Shikai Hu
- *School of Medicine, Tsinghua University, Beijing, China
- †Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Satdarshan P. Monga
- †Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- ‡Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- §Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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28
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β-Catenin Activation in Hepatocellular Cancer: Implications in Biology and Therapy. Cancers (Basel) 2021; 13:cancers13081830. [PMID: 33921282 PMCID: PMC8069637 DOI: 10.3390/cancers13081830] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/08/2021] [Accepted: 04/09/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Liver cancer is a dreadful tumor which has gradually increased in incidence all around the world. One major driver of liver cancer is the Wnt–β-catenin pathway which is active in a subset of these tumors. While this pathway is normally important in liver development, regeneration and homeostasis, it’s excessive activation due to mutations, is detrimental and leads to tumor cell growth, making it an important therapeutic target. There are also some unique characteristics of this pathway activation in liver cancer. It makes the tumor addicted to specific amino acids and in turn to mTOR signaling, which can be treated by certain existing therapies. In addition, activation of the Wnt–β-catenin in liver cancer appears to alter the immune cell landscape making it less likely to respond to the new immuno-oncology treatments. Thus, Wnt–β-catenin active tumors may need to be treated differently than non-Wnt–β-catenin active tumors. Abstract Hepatocellular cancer (HCC), the most common primary liver tumor, has been gradually growing in incidence globally. The whole-genome and whole-exome sequencing of HCC has led to an improved understanding of the molecular drivers of this tumor type. Activation of the Wnt signaling pathway, mostly due to stabilizing missense mutations in its downstream effector β-catenin (encoded by CTNNB1) or loss-of-function mutations in AXIN1 (the gene which encodes for Axin-1, an essential protein for β-catenin degradation), are seen in a major subset of HCC. Because of the important role of β-catenin in liver pathobiology, its role in HCC has been extensively investigated. In fact, CTNNB1 mutations have been shown to have a trunk role. β-Catenin has been shown to play an important role in regulating tumor cell proliferation and survival and in tumor angiogenesis, due to a host of target genes regulated by the β-catenin transactivation of its transcriptional factor TCF. Proof-of-concept preclinical studies have shown β-catenin to be a highly relevant therapeutic target in CTNNB1-mutated HCCs. More recently, studies have revealed a unique role of β-catenin activation in regulating both tumor metabolism as well as the tumor immune microenvironment. Both these roles have notable implications for the development of novel therapies for HCC. Thus, β-catenin has a pertinent role in driving HCC development and maintenance of this tumor-type, and could be a highly relevant therapeutic target in a subset of HCC cases.
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29
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Jung YS, Stratton SA, Lee SH, Kim MJ, Jun S, Zhang J, Zheng B, Cervantes CL, Cha JH, Barton MC, Park JI. TMEM9-v-ATPase Activates Wnt/β-Catenin Signaling Via APC Lysosomal Degradation for Liver Regeneration and Tumorigenesis. Hepatology 2021; 73:776-794. [PMID: 32380568 PMCID: PMC7647947 DOI: 10.1002/hep.31305] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 04/07/2020] [Accepted: 04/08/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS How Wnt signaling is orchestrated in liver regeneration and tumorigenesis remains elusive. Recently, we identified transmembrane protein 9 (TMEM9) as a Wnt signaling amplifier. APPROACH AND RESULTS TMEM9 facilitates v-ATPase assembly for vesicular acidification and lysosomal protein degradation. TMEM9 is highly expressed in regenerating liver and hepatocellular carcinoma (HCC) cells. TMEM9 expression is enriched in the hepatocytes around the central vein and acutely induced by injury. In mice, Tmem9 knockout impairs hepatic regeneration with aberrantly increased adenomatosis polyposis coli (Apc) and reduced Wnt signaling. Mechanistically, TMEM9 down-regulates APC through lysosomal protein degradation through v-ATPase. In HCC, TMEM9 is overexpressed and necessary to maintain β-catenin hyperactivation. TMEM9-up-regulated APC binds to and inhibits nuclear translocation of β-catenin, independent of HCC-associated β-catenin mutations. Pharmacological blockade of TMEM9-v-ATPase or lysosomal degradation suppresses Wnt/β-catenin through APC stabilization and β-catenin cytosolic retention. CONCLUSIONS Our results reveal that TMEM9 hyperactivates Wnt signaling for liver regeneration and tumorigenesis through lysosomal degradation of APC.
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Affiliation(s)
- Youn-Sang Jung
- Department of Experimental Radiation OncologyDivision of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonTX.,Department of Life ScienceChung-Ang UniversitySeoulSouth Korea
| | - Sabrina A Stratton
- Department of Epigenetics and Molecular CarcinogenesisThe University of Texas MD Anderson Cancer CenterHoustonTX
| | - Sung Ho Lee
- Department of Experimental Radiation OncologyDivision of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonTX
| | - Moon-Jong Kim
- Department of Experimental Radiation OncologyDivision of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonTX
| | - Sohee Jun
- Department of Experimental Radiation OncologyDivision of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonTX
| | - Jie Zhang
- Department of Experimental Radiation OncologyDivision of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonTX
| | - Biyun Zheng
- Department of Experimental Radiation OncologyDivision of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonTX
| | - Christopher L Cervantes
- Department of Experimental Radiation OncologyDivision of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonTX
| | - Jong-Ho Cha
- Department of Biomedical SciencesCollege of MedicineInha UniversityIncheonSouth Korea
| | - Michelle C Barton
- Department of Epigenetics and Molecular CarcinogenesisThe University of Texas MD Anderson Cancer CenterHoustonTX.,Graduate School of Biomedical SciencesThe University of Texas MD Anderson Cancer CenterHoustonTX
| | - Jae-Il Park
- Department of Experimental Radiation OncologyDivision of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonTX.,Graduate School of Biomedical SciencesThe University of Texas MD Anderson Cancer CenterHoustonTX.,Program in Genetics and EpigeneticsThe University of Texas MD Anderson Cancer CenterHoustonTX
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30
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Hendriks D, Artegiani B, Hu H, Chuva de Sousa Lopes S, Clevers H. Establishment of human fetal hepatocyte organoids and CRISPR-Cas9-based gene knockin and knockout in organoid cultures from human liver. Nat Protoc 2020; 16:182-217. [PMID: 33247284 DOI: 10.1038/s41596-020-00411-2] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 09/17/2020] [Indexed: 12/21/2022]
Abstract
The liver is composed of two epithelial cell types: hepatocytes and liver ductal cells. Culture conditions for expansion of human liver ductal cells in vitro as organoids were previously described in a protocol; however, primary human hepatocytes remained hard to expand, until recently. In this protocol, we provide full details of how we overcame this limitation, establishing culture conditions that facilitate long-term expansion of human fetal hepatocytes as organoids. In addition, we describe how to generate (multi) gene knockouts using CRISPR-Cas9 in both human fetal hepatocyte and adult liver ductal organoid systems. Using a CRISPR-Cas9 and homology-independent organoid transgenesis (CRISPR-HOT) approach, efficient gene knockin can be achieved in these systems. These gene knockin and knockout approaches, and their multiplexing, should be useful for a variety of applications, such as disease modeling, investigating gene functions and studying processes, such as cellular differentiation and cell division. The protocol to establish human fetal hepatocyte organoid cultures takes ~1-2 months. The protocols to genome engineer human liver ductal organoids and human fetal hepatocyte organoids take 2-3 months.
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Affiliation(s)
- Delilah Hendriks
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, the Netherlands. .,Oncode Institute, Utrecht, the Netherlands.
| | - Benedetta Artegiani
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, the Netherlands. .,Oncode Institute, Utrecht, the Netherlands. .,The Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands.
| | - Huili Hu
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, the Netherlands
| | | | - Hans Clevers
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, the Netherlands. .,Oncode Institute, Utrecht, the Netherlands. .,The Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands.
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31
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Walesky CM, Kolb KE, Winston CL, Henderson J, Kruft B, Fleming I, Ko S, Monga SP, Mueller F, Apte U, Shalek AK, Goessling W. Functional compensation precedes recovery of tissue mass following acute liver injury. Nat Commun 2020; 11:5785. [PMID: 33214549 PMCID: PMC7677389 DOI: 10.1038/s41467-020-19558-3] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 10/12/2020] [Indexed: 12/11/2022] Open
Abstract
The liver plays a central role in metabolism, protein synthesis and detoxification. It possesses unique regenerative capacity upon injury. While many factors regulating cellular proliferation during liver repair have been identified, the mechanisms by which the injured liver maintains vital functions prior to tissue recovery are unknown. Here, we identify a new phase of functional compensation following acute liver injury that occurs prior to cellular proliferation. By coupling single-cell RNA-seq with in situ transcriptional analyses in two independent murine liver injury models, we discover adaptive reprogramming to ensure expression of both injury response and core liver function genes dependent on macrophage-derived WNT/β-catenin signaling. Interestingly, transcriptional compensation is most prominent in non-proliferating cells, clearly delineating two temporally distinct phases of liver recovery. Overall, our work describes a mechanism by which the liver maintains essential physiological functions prior to cellular reconstitution and characterizes macrophage-derived WNT signals required for this compensation. The liver possesses the ability to regenerate following sudden injury. Here, the authors use single-cell RNA-sequencing and in situ transcriptional analyses to identify a new phase of liver regeneration in mice aimed at maintaining essential functions throughout the regenerative process.
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Affiliation(s)
- Chad M Walesky
- Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Kellie E Kolb
- Institute of Medical Engineering & Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.,Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA
| | - Carolyn L Winston
- Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Jake Henderson
- Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Benjamin Kruft
- Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Ira Fleming
- Institute of Medical Engineering & Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.,Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA
| | - Sungjin Ko
- Department of Pathology, University of Pittsburgh, School of Medicine; and Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, 15261, USA
| | - Satdarshan P Monga
- Department of Pathology, University of Pittsburgh, School of Medicine; and Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, 15261, USA
| | - Florian Mueller
- Imaging and Modeling Unit, Institut Pasteur, UMR 3691CNRS, C3BI USR 3756 IP CNRS, Paris, France
| | - Udayan Apte
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Alex K Shalek
- Institute of Medical Engineering & Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. .,Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. .,Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA. .,Harvard-MIT Division of Health Sciences and Technology, Boston, MA, 02115, USA.
| | - Wolfram Goessling
- Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. .,Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. .,Harvard-MIT Division of Health Sciences and Technology, Boston, MA, 02115, USA. .,Dana-Farber Cancer Institute, Boston, MA, 02215, USA. .,Harvard Stem Cell Institute, Cambridge, MA, 02134, USA. .,Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
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32
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Mak KM, Shin DW. Hepatic sinusoids versus central veins: Structures, markers, angiocrines, and roles in liver regeneration and homeostasis. Anat Rec (Hoboken) 2020; 304:1661-1691. [PMID: 33135318 DOI: 10.1002/ar.24560] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 10/14/2020] [Accepted: 10/22/2020] [Indexed: 01/20/2023]
Abstract
The blood circulates through the hepatic sinusoids delivering nutrients and oxygen to the liver parenchyma and drains into the hepatic central vein, yet the structures and phenotypes of these vessels are distinctively different. Sinusoidal endothelial cells are uniquely fenestrated, lack basal lamina and possess organelles involved in endocytosis, pinocytosis, degradation, synthesis and secretion. Hepatic central veins are nonfenestrated but are also active in synthesis and secretion. Endothelial cells of sinusoids and central veins secrete angiocrines that play respective roles in hepatic regeneration and metabolic homeostasis. The list of markers for identifying sinusoidal endothelial cells is long and their terminologies are complex. Further, their uses vary in different investigations and, in some instances, could be confusing. Central vein markers are fewer but more distinctive. Here we analyze and categorize the molecular pathways/modules associated with the sinusoid-mediated liver regeneration in response to partial hepatectomy and chemical-induced acute or chronic injury. Similarly, we highlight the findings that central vein-derived angiocrines interact with Wnt/β-catenin in perivenous hepatocytes to direct gene expression and maintain pericentral metabolic zonation. The proposal that perivenous hepatocytes behave as stem/progenitor cells to provoke hepatic homeostatic cell renewal is reevaluated and newer concepts of broad zonal distribution of hepatocyte proliferation in liver homeostasis and regeneration are updated. Thus, this review integrates the structures, biology and physiology of liver sinusoids and central veins in mediating hepatic regeneration and metabolic homeostasis.
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Affiliation(s)
- Ki M Mak
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Da Wi Shin
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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33
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Activation of the Akt pathway by a constitutive androstane receptor agonist results in β-catenin activation. Eur J Pharmacol 2020; 879:173135. [DOI: 10.1016/j.ejphar.2020.173135] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 04/17/2020] [Accepted: 04/20/2020] [Indexed: 12/21/2022]
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34
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The Connection of Azole Fungicides with Xeno-Sensing Nuclear Receptors, Drug Metabolism and Hepatotoxicity. Cells 2020; 9:cells9051192. [PMID: 32403288 PMCID: PMC7290820 DOI: 10.3390/cells9051192] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 05/07/2020] [Accepted: 05/08/2020] [Indexed: 12/21/2022] Open
Abstract
Azole fungicides, especially triazole compounds, are widely used in agriculture and as pharmaceuticals. For a considerable number of agricultural azole fungicides, the liver has been identified as the main target organ of toxicity. A number of previous studies points towards an important role of nuclear receptors such as the constitutive androstane receptor (CAR), the pregnane-X-receptor (PXR), or the aryl hydrocarbon receptor (AHR), within the molecular pathways leading to hepatotoxicity of these compounds. Nuclear receptor-mediated hepatic effects may comprise rather adaptive changes such as the induction of drug-metabolizing enzymes, to hepatocellular hypertrophy, histopathologically detectable fatty acid changes, proliferation of hepatocytes, and the promotion of liver tumors. Here, we present a comprehensive review of the current knowledge of the interaction of major agricultural azole-class fungicides with the three nuclear receptors CAR, PXR, and AHR in vivo and in vitro. Nuclear receptor activation profiles of the azoles are presented and related to histopathological findings from classic toxicity studies. Important issues such as species differences and multi-receptor agonism and the consequences for data interpretation and risk assessment are discussed.
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35
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Stone TW. Dependence and Guidance Receptors-DCC and Neogenin-In Partial EMT and the Actions of Serine Proteases. Front Oncol 2020; 10:94. [PMID: 32117748 PMCID: PMC7010924 DOI: 10.3389/fonc.2020.00094] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Accepted: 01/17/2020] [Indexed: 12/19/2022] Open
Abstract
The Epithelial-Mesenchymal Transition (EMT) is an important concept in understanding the processes of oncogenesis, especially with respect to the relationship between cell proliferation and metastatic properties such as spontaneous cell motility, chemotaxic migration and tissue invasion. EMT is now recognized as a more complex phenomenon than an all-or-nothing event, in which different components of the EMT may have distinct roles in the physio-pathological regulation of cell function and which may in turn depend on differential interactions with cell constituents and metabolic products. This mini-review summarizes recent work on the induction of cancer properties in parallel with the presence of EMT activities in the presence of serine proteases, with the focus on those tumor suppressors known as "dependence" receptors such as neogenin and Deleted in Colorectal Cancer (DCC). It is concluded that various forms of partial EMT should be given more detailed investigation and consideration as the results could have valuable implications for the development of disease-specific and patient-specific therapies.
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36
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Regulation of expression of drug-metabolizing enzymes by oncogenic signaling pathways in liver tumors: a review. Acta Pharm Sin B 2020; 10:113-122. [PMID: 31993310 PMCID: PMC6976994 DOI: 10.1016/j.apsb.2019.06.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 05/23/2019] [Accepted: 06/24/2019] [Indexed: 02/06/2023] Open
Abstract
Mutations in genes encoding key players in oncogenic signaling pathways trigger specific downstream gene expression profiles in the respective tumor cell populations. While regulation of genes related to cell growth, survival, and death has been extensively studied, much less is known on the regulation of drug-metabolizing enzymes (DMEs) by oncogenic signaling. Here, a comprehensive review of the available literature is presented summarizing the impact of the most relevant genetic alterations in human and rodent liver tumors on the expression of DMEs with a focus on phases I and II of xenobiotic metabolism. Comparably few data are available with respect to DME regulation by p53-dependent signaling, telomerase expression or altered chromatin remodeling. By contrast, DME regulation by constitutive activation of oncogenic signaling via the RAS/RAF/mitogen-activated protein kinase (MAPK) cascade or via the canonical WNT/β-catenin signaling pathway has been analyzed in greater depth, demonstrating mostly positive-regulatory effects of WNT/β-catenin signaling and negative-regulatory effects of MAPK signaling. Mechanistic studies have revealed molecular interactions between oncogenic signaling and nuclear xeno-sensing receptors which underlie the observed alterations in DME expression in liver tumors. Observations of altered DME expression and inducibility in liver tumors with a specific gene expression profile may impact pharmacological treatment options.
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37
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Mak KM, Png CYM. The Hepatic Central Vein: Structure, Fibrosis, and Role in Liver Biology. Anat Rec (Hoboken) 2019; 303:1747-1767. [PMID: 31581357 DOI: 10.1002/ar.24273] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 08/11/2019] [Accepted: 08/14/2019] [Indexed: 12/19/2022]
Abstract
The hepatic central vein is a primary source of Wnt2, Wnt9b, and R-spondin3. These angiocrines activate ß-catenin signaling to regulate hepatic metabolic zonation and perivenous gene expression in mice. Little is known about the central vein ultrastructure. Here, we describe the morphological-functional correlates of the central vein and its draining and branching patterns. Central vein fibrosis occurs in liver disease and is often accompanied by perivenous perisinusoidal fibrosis, which may affect perivenous gene expression. We review the biological properties of perivenous hepatocytes and glutamine synthetase that serve as a biomarker of perivenous hepatocytes. Glutamine synthetase and P4502E1 are indicators of ß-catenin activity in centrilobular liver injury and regeneration. The Wnt/ß-catenin pathway is the master regulator of hepatic metabolic zonation and perivenous gene expression and is modulated by the R-spondin-LGR4/5-ZNRF3/RNF43 module. We examined the structures of the molecules of these pathways and their involvements in liver biology. Central vein-derived Wnts and R-spondin3 participate in the cellular-molecular circuitry of the Wnt/ß-catenin and R-spondin-LGR4/5-ZNRF3/RNF43 module. The transport and secretion of lipidated Wnts in Wnt-producing cells require Wntless protein. Secreted Wnts are carried on exosomes in the extracellular matrix to responder cells. The modes of release of Wnts and R-spondin3 from central veins and their transit in the venular wall toward perivenous hepatocytes are unknown. We hypothesize that central vein fibrosis may impact perivenous gene expression. The proposal that the central vein constitutes an anatomical niche of perivenous stem cells that subserve homeostatic hepatic renewal still needs studies using additional mouse models for validation. Anat Rec, 2019. © 2019 American Association for Anatomy Anat Rec, 303:1747-1767, 2020. © 2019 American Association for Anatomy.
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Affiliation(s)
- Ki M Mak
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - C Y Maximilian Png
- Division of Vascular Surgery, Massachusetts General Hospital, Boston, Massachusetts
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38
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Zhao L, Jin Y, Donahue K, Tsui M, Fish M, Logan CY, Wang B, Nusse R. Tissue Repair in the Mouse Liver Following Acute Carbon Tetrachloride Depends on Injury-Induced Wnt/β-Catenin Signaling. Hepatology 2019; 69:2623-2635. [PMID: 30762896 PMCID: PMC7043939 DOI: 10.1002/hep.30563] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 01/28/2019] [Indexed: 12/19/2022]
Abstract
In the liver, Wnt/β-catenin signaling is involved in regulating zonation and hepatocyte proliferation during homeostasis. We examined Wnt gene expression and signaling after injury, and we show by in situ hybridization that Wnts are activated by acute carbon tetrachloride (CCl4 ) toxicity. Following injury, peri-injury hepatocytes become Wnt-responsive, expressing the Wnt target gene axis inhibition protein 2 (Axin2). Lineage tracing of peri-injury Axin2+ hepatocytes shows that during recovery the injured parenchyma becomes repopulated and repaired by Axin2+ descendants. Using single-cell RNA sequencing, we show that endothelial cells are the major source of Wnts following acute CCl4 toxicity. Induced loss of β-catenin in peri-injury hepatocytes results in delayed repair and ultimately injury-induced lethality, while loss of Wnt production from endothelial cells leads to a delay in the proliferative response after injury. Conclusion: Our findings highlight the importance of the Wnt/β-catenin signaling pathway in restoring tissue integrity following acute liver toxicity and establish a role of endothelial cells as an important Wnt-producing regulator of liver tissue repair following localized liver injury.
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Affiliation(s)
- Ludan Zhao
- Institute for Stem Cell Biology and Regenerative Medicine,
Department of Developmental Biology, Howard Hughes Medical Institute, Stanford
School of Medicine, Stanford, CA 94305,Medical Scientist Training Program, Stanford School of
Medicine, Stanford, CA 94305
| | - Yinhua Jin
- Institute for Stem Cell Biology and Regenerative Medicine,
Department of Developmental Biology, Howard Hughes Medical Institute, Stanford
School of Medicine, Stanford, CA 94305
| | - Katie Donahue
- Institute for Stem Cell Biology and Regenerative Medicine,
Department of Developmental Biology, Howard Hughes Medical Institute, Stanford
School of Medicine, Stanford, CA 94305
| | - Margaret Tsui
- Department of Medicine and Liver Center, University of
California San Francisco, San Francisco, CA 94143
| | - Matt Fish
- Institute for Stem Cell Biology and Regenerative Medicine,
Department of Developmental Biology, Howard Hughes Medical Institute, Stanford
School of Medicine, Stanford, CA 94305
| | - Catriona Y. Logan
- Institute for Stem Cell Biology and Regenerative Medicine,
Department of Developmental Biology, Howard Hughes Medical Institute, Stanford
School of Medicine, Stanford, CA 94305
| | - Bruce Wang
- Institute for Stem Cell Biology and Regenerative Medicine,
Department of Developmental Biology, Howard Hughes Medical Institute, Stanford
School of Medicine, Stanford, CA 94305,Department of Medicine and Liver Center, University of
California San Francisco, San Francisco, CA 94143
| | - Roel Nusse
- Institute for Stem Cell Biology and Regenerative Medicine,
Department of Developmental Biology, Howard Hughes Medical Institute, Stanford
School of Medicine, Stanford, CA 94305
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39
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McNair K, Forrest CM, Vincenten MCJ, Darlington LG, Stone TW. Serine protease modulation of Dependence Receptors and EMT protein expression. Cancer Biol Ther 2018; 20:349-367. [PMID: 30403907 PMCID: PMC6370372 DOI: 10.1080/15384047.2018.1529109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 09/03/2018] [Accepted: 09/22/2018] [Indexed: 12/11/2022] Open
Abstract
Expression of the tumour suppressor Deleted in Colorectal Cancer (DCC) and the related protein neogenin is reduced by the mammalian serine protease chymotrypsin or the bacterial serine protease subtilisin, with increased cell migration. The present work examines whether these actions are associated with changes in the expression of cadherins, β-catenin and vimentin, established markers of the Epithelial-Mesenchymal Transition (EMT) which has been linked with cell migration and tumour metastasis. The results confirm the depletion of DCC and neogenin and show that chymotrypsin and subtilisin also reduce expression of β-catenin in acutely prepared tissue sections but not in human mammary adenocarcinoma MCF-7 or MDA-MB-231 cells cultured in normal media, or primary normal human breast cells. A loss of β-catenin was also seen in low serum media but transfecting cells with a dcc-containing plasmid induced resistance. E-cadherin was not consistently affected but vimentin was induced by low serum-containing media and was increased by serine proteases in MCF-7 and MDA-MB-231 cells in parallel with increased wound closure. Vimentin might contribute to the promotion of cell migration. The results suggest that changes in EMT proteins depend on the cells or tissues concerned and do not parallel the expression of DCC and neogenin. The increased cell migration induced by serine proteases is not consistently associated with the expression of the EMT proteins implying either that the increased migration may be independent of EMT or supporting the view that EMT is not itself consistently related to migration. (241).
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Affiliation(s)
- Kara McNair
- College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Caroline M. Forrest
- College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Maria C. J. Vincenten
- College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | | | - Trevor W. Stone
- College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
- The Kennedy Institute, University of Oxford, Oxford UK
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40
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Preziosi M, Okabe H, Poddar M, Singh S, Monga SP. Endothelial Wnts regulate β-catenin signaling in murine liver zonation and regeneration: A sequel to the Wnt-Wnt situation. Hepatol Commun 2018; 2:845-860. [PMID: 30027142 PMCID: PMC6049069 DOI: 10.1002/hep4.1196] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Revised: 03/18/2018] [Accepted: 03/26/2018] [Indexed: 12/29/2022] Open
Abstract
β-Catenin in hepatocytes, under the control of Wnts, regulates pericentral gene expression. It also contributes to liver regeneration (LR) after partial hepatectomy (PH) by regulating cyclin-D1 gene expression as shown in the β-catenin and Wnt coreceptors low-density lipoprotein receptor-related protein 5/6 conditional knockouts (KO). However, conditional deletion of Wntless (Wls), required for Wnt secretion, in hepatocytes, cholangiocytes, or macrophages lacked any impact on zonation, while Wls deletion in macrophages only marginally affected LR. Here, we address the contribution of hepatic endothelial cells (ECs) in zonation and LR by characterizing EC-Wls-KO generated by interbreeding Wls-floxed and lymphatic vessel endothelial hyaluronan receptor (Lyve1)-cre mice. These mice were also used to study LR after PH. While Lyve1 expression in adult liver is limited to sinusoidal ECs only, Lyve1-cre mice bred to ROSA26-Stopflox/flox-enhanced yellow fluorescent protein (EYFP) mice showed EYFP labeling in sinusoidal and central vein ECs. EC-Wls-KO mice showed decreased liver weights; lacked glutamine synthetase, cytochrome P450 2e1, and cytochrome P450 1a2; and were resistant to acetaminophen-induced liver injury. After PH, EC-Wls-KO showed quantitative and qualitative differences in cyclin-D1 expression at 24-72 hours, which led to a lower hepatocyte proliferation at 40 hours but a rebound increase by 72 hours. ECs and macrophages isolated from regenerating livers at 12 hours showed significant up-regulation of Wnt2 and Wnt9b messenger RNA; these are the same two Wnts involved in baseline β-catenin activity in pericentral hepatocytes. Conclusion: At baseline, ECs secrete Wnt proteins essential for β-catenin activation in pericentral hepatocytes. During LR, sinusoidal and central vein ECs and secondarily macrophages secrete Wnt2, while predominantly central vein ECs and secondarily macrophages are the likely source of Wnt9b. This process spatiotemporally regulates β-catenin activation in hepatocytes to induce cell proliferation. (Hepatology Communications 2018;2:845-860).
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Affiliation(s)
- Morgan Preziosi
- Department of PathologyUniversity of Pittsburgh Medical CenterPittsburghPA
- Pittsburgh Liver Research CenterUniversity of Pittsburgh and University of Pittsburgh Medical CenterPittsburghPA
| | - Hirohisa Okabe
- Department of Gastroenterological SurgeryKumamoto UniversityKumamotoJapan
| | - Minakshi Poddar
- Department of PathologyUniversity of Pittsburgh Medical CenterPittsburghPA
- Pittsburgh Liver Research CenterUniversity of Pittsburgh and University of Pittsburgh Medical CenterPittsburghPA
| | - Sucha Singh
- Department of PathologyUniversity of Pittsburgh Medical CenterPittsburghPA
- Pittsburgh Liver Research CenterUniversity of Pittsburgh and University of Pittsburgh Medical CenterPittsburghPA
| | - Satdarshan P. Monga
- Department of PathologyUniversity of Pittsburgh Medical CenterPittsburghPA
- Pittsburgh Liver Research CenterUniversity of Pittsburgh and University of Pittsburgh Medical CenterPittsburghPA
- Department of MedicineUniversity of PittsburghPittsburghPA
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41
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Kamimura K, Inoue R, Nagoya T, Sakai N, Goto R, Ko M, Niwa Y, Terai S. Autonomic nervous system network and liver regeneration. World J Gastroenterol 2018; 24:1616-1621. [PMID: 29686468 PMCID: PMC5910544 DOI: 10.3748/wjg.v24.i15.1616] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 04/01/2018] [Accepted: 04/16/2018] [Indexed: 02/06/2023] Open
Abstract
To date, various signal transducers, cytokines, growth factors, and hormones have been reported to play an important role in homeostasis of various organs. Various cells and organs are involved in the hepatic regeneration process, which proceeds as a result of the coordination of many factors. While these factors are well known to be involved in the liver regeneration after the liver injury, however, as the details of such mechanisms have not been sufficiently elucidated, the practical applicability of hepatic regeneration based on the action of these and cytokines growth factors is still unclear. In terms of the involvement of the autonomic nervous system in hepatic regeneration, cell proliferation resulting from direct signal transduction to the liver has also been reported and recent studies focusing on the inter-organ communication via neural network opened a novel aspect of this field for therapeutic applicability. Therefore, the appropriate understanding of the relationship between autonomic neural network and liver regeneration through various organs including brain, afferent nerve, efferent nerve, etc. is essential. This mini-review explains the principle of neural system involved in the inter-organ communication and its contribution on the liver regeneration upon the liver injury reviewing recent progress in this field.
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Affiliation(s)
- Kenya Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
| | - Ryosuke Inoue
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
| | - Takuro Nagoya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
| | - Norihiro Sakai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
| | - Ryo Goto
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
| | - Masayoshi Ko
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
| | - Yusuke Niwa
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
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Inoue R, Kamimura K, Nagoya T, Sakai N, Yokoo T, Goto R, Ogawa K, Shinagawa‐Kobayashi Y, Watanabe‐Mori Y, Sakamaki A, Abe S, Kamimura H, Miyamura N, Nishina H, Terai S. Effect of a neural relay on liver regeneration in mice: activation of serotonin release from the gastrointestinal tract. FEBS Open Bio 2018; 8:449-460. [PMID: 29511622 PMCID: PMC5832978 DOI: 10.1002/2211-5463.12382] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Revised: 01/04/2018] [Accepted: 01/06/2018] [Indexed: 12/15/2022] Open
Abstract
The development of therapeutic options to promote hepatic regeneration following severe liver injury is essential. While humoral factors have been reported as mechanisms of liver regeneration, the contributions of interorgan communication to liver regeneration have not been reported. In this study, we examined the effect of a neural relay on liver regeneration via activation of serotonin release from the gastrointestinal (GI) tract. Our results demonstrated that the afferent visceral nerve from the liver activates the efferent vagus nerve from the brain, leading to activation of serotonin release from the GI tract and contributing to liver regeneration. While it is difficult to apply these results directly to human health, we believe that this study may represent a step toward developing essential therapeutics to promote liver regeneration.
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Affiliation(s)
- Ryosuke Inoue
- Division of Gastroenterology and HepatologyGraduate School of Medical and Dental SciencesNiigata UniversityJapan
| | - Kenya Kamimura
- Division of Gastroenterology and HepatologyGraduate School of Medical and Dental SciencesNiigata UniversityJapan
| | - Takuro Nagoya
- Division of Gastroenterology and HepatologyGraduate School of Medical and Dental SciencesNiigata UniversityJapan
| | - Norihiro Sakai
- Division of Gastroenterology and HepatologyGraduate School of Medical and Dental SciencesNiigata UniversityJapan
| | - Takeshi Yokoo
- Division of Gastroenterology and HepatologyGraduate School of Medical and Dental SciencesNiigata UniversityJapan
| | - Ryo Goto
- Division of Gastroenterology and HepatologyGraduate School of Medical and Dental SciencesNiigata UniversityJapan
| | - Kohei Ogawa
- Division of Gastroenterology and HepatologyGraduate School of Medical and Dental SciencesNiigata UniversityJapan
| | - Yoko Shinagawa‐Kobayashi
- Division of Gastroenterology and HepatologyGraduate School of Medical and Dental SciencesNiigata UniversityJapan
| | - Yukari Watanabe‐Mori
- Division of Gastroenterology and HepatologyGraduate School of Medical and Dental SciencesNiigata UniversityJapan
| | - Akira Sakamaki
- Division of Gastroenterology and HepatologyGraduate School of Medical and Dental SciencesNiigata UniversityJapan
| | - Satoshi Abe
- Division of Gastroenterology and HepatologyGraduate School of Medical and Dental SciencesNiigata UniversityJapan
| | - Hiroteru Kamimura
- Division of Gastroenterology and HepatologyGraduate School of Medical and Dental SciencesNiigata UniversityJapan
| | - Norio Miyamura
- Department of Developmental and Regenerative BiologyMedical Research InstituteTokyo Medical and Dental UniversityJapan
| | - Hiroshi Nishina
- Department of Developmental and Regenerative BiologyMedical Research InstituteTokyo Medical and Dental UniversityJapan
| | - Shuji Terai
- Division of Gastroenterology and HepatologyGraduate School of Medical and Dental SciencesNiigata UniversityJapan
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43
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Lemberger UJ, Fuchs CD, Karer M, Haas S, Stojakovic T, Schöfer C, Marschall HU, Wrba F, Taketo MM, Egger G, Trauner M, Österreicher CH. Hepatocyte specific expression of an oncogenic variant of β-catenin results in cholestatic liver disease. Oncotarget 2018; 7:86985-86998. [PMID: 27895309 PMCID: PMC5349966 DOI: 10.18632/oncotarget.13521] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Accepted: 09/26/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The Wnt/β-catenin signaling pathway plays a crucial role in embryonic development, tissue homeostasis, wound healing and malignant transformation in different organs including the liver. The consequences of continuous β-catenin signaling in hepatocytes remain elusive. RESULTS Livers of Ctnnb1CA hep mice were characterized by disturbed liver architecture, proliferating cholangiocytes and biliary type of fibrosis. Serum ALT and bile acid levels were significantly increased in Ctnnb1CA hep mice. The primary bile acid synthesis enzyme Cyp7a1 was increased whereas Cyp27 and Cyp8b1 were reduced in Ctnnb1CA hep mice. Expression of compensatory bile acid transporters including Abcb1, Abcb4, Abcc2 and Abcc4 were significantly increased in Ctnnb1CA hep mice while Ntcp was reduced. Accompanying changes of bile acid transporters favoring excretion of bile acids were observed in intestine and kidneys of Ctnnb1CA hep mice. Additionally, disturbed bile acid regulation through the FXR-FGF15-FGFR4 pathway was observed in mice with activated β-catenin. MATERIALS AND METHODS Mice with a loxP-flanked exon 3 of the Ctnnb1 gene were crossed to Albumin-Cre mice to obtain mice with hepatocyte-specific expression of a dominant stable form of β-catenin (Ctnnb1CA hep mice). Ctnnb1CA hep mice were analyzed by histology, serum biochemistry and mRNA profiling. CONCLUSIONS Expression of a dominant stable form of β-catenin in hepatocytes results in severe cholestasis and biliary type fibrosis.
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Affiliation(s)
- Ursula J Lemberger
- Institute of Pharmacology, Medical University of Vienna, Vienna, Austria.,Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.,Hans Popper Laboratory for Molecular Hepatology, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | - Claudia D Fuchs
- Hans Popper Laboratory for Molecular Hepatology, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | - Matthias Karer
- Institute of Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Stefanie Haas
- Institute of Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Tatjana Stojakovic
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Christian Schöfer
- Department of Cell and Developmental Biology, Medical University of Vienna, Vienna, Austria
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Fritz Wrba
- Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
| | - Makoto M Taketo
- Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Gerda Egger
- Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Hans Popper Laboratory for Molecular Hepatology, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
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44
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Deregulation of Frizzled Receptors in Hepatocellular Carcinoma. Int J Mol Sci 2018; 19:ijms19010313. [PMID: 29361730 PMCID: PMC5796257 DOI: 10.3390/ijms19010313] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 01/14/2018] [Accepted: 01/19/2018] [Indexed: 12/14/2022] Open
Abstract
G protein-coupled receptors (GPCRs) have a substantial role in tumorigenesis and are described as a “cancer driver”. Aberrant expression or activation of GPCRs leads to the deregulation of downstream signaling pathways, thereby promoting cancer progression. In hepatocellular carcinoma (HCC), the Wnt signaling pathway is frequently activated and it is associated with an aggressive HCC phenotype. Frizzled (FZD) receptors, a family member of GPCRs, are known to mediate Wnt signaling. Accumulating findings have revealed the deregulation of FZD receptors in HCC and their functional roles have been implicated in HCC progression. Given the important role of FZD receptors in HCC, we summarize here the expression pattern of FZD receptors in HCC and their corresponding functional roles during HCC progression. We also further review and highlight the potential targeting of FZD receptors as an alternative therapeutic strategy in HCC.
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45
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Tan SH, Barker N. Wnt Signaling in Adult Epithelial Stem Cells and Cancer. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2018; 153:21-79. [PMID: 29389518 DOI: 10.1016/bs.pmbts.2017.11.017] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Wnt/β-catenin signaling is integral to the homeostasis and regeneration of many epithelial tissues due to its critical role in adult stem cell regulation. It is also implicated in many epithelial cancers, with mutations in core pathway components frequently present in patient tumors. In this chapter, we discuss the roles of Wnt/β-catenin signaling and Wnt-regulated stem cells in homeostatic, regenerative and cancer contexts of the intestines, stomach, skin, and liver. We also examine the sources of Wnt ligands that form part of the stem cell niche. Despite the diversity in characteristics of various tissue stem cells, the role(s) of Wnt/β-catenin signaling is generally coherent in maintaining stem cell fate and/or promoting proliferation. It is also likely to play similar roles in cancer stem cells, making the pathway a salient therapeutic target for cancer. While promising progress is being made in the field, deeper understanding of the functions and signaling mechanisms of the pathway in individual epithelial tissues will expedite efforts to modulate Wnt/β-catenin signaling in cancer treatment and tissue regeneration.
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Affiliation(s)
- Si Hui Tan
- A*STAR Institute of Medical Biology, Singapore
| | - Nick Barker
- A*STAR Institute of Medical Biology, Singapore; Kanazawa University, Kanazawa, Japan; Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
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46
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Apte U, Bhushan B, Dadhania V. Hepatic Defenses Against Toxicity: Liver Regeneration and Tissue Repair. COMPREHENSIVE TOXICOLOGY 2018:368-396. [DOI: 10.1016/b978-0-12-801238-3.64918-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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47
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Bai L, Li J, Liu X, Li S, Li F, Chen Y, Yu Z. NH 4Cl affects the expression of Wnt/β-catenin pathway in hepatocytes. Can J Physiol Pharmacol 2017; 96:281-286. [PMID: 28977758 DOI: 10.1139/cjpp-2017-0604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We intended to explore whether NH4Cl influences the viability and regulates the expression of Wnt/β-catenin pathway in hepatocytes. The Chang liver cell line was used and cultured with different concentrations of NH4Cl (2.5, 5, 10, 20, 40, and 50 mmol/L) for 12, 24, and 48 h. The viability of hepatocytes was detected by MTT assay. The mRNA and protein expression level was analyzed with qRT-PCR and Western blotting, respectively. NH4Cl concentration significantly affects the viability of hepatocytes. With the increase of NH4Cl concentration, the viability of hepatocytes was decreased, accordingly. The mRNA and protein expression of Wnt1, β-catenin, and cyclin D was significantly increased after treatment with low concentrations of NH4Cl as compared with the control group, whereas their expression levels were decreased after treatment with high concentrations of NH4Cl. The mRNA and protein expression of Wnt1, β-catenin, and cyclin D was also significantly increased after treatment with NH4Cl for a short period as compared with the control group, whereas their expression levels were decreased after treatment with NH4Cl for a long period. In addition, we found NH4Cl treatment significantly reversed the results after RNA silencing of Wnt1 in hepatocytes. NH4Cl influences the viability of hepatocytes and affects the expression of Wnt/β-catenin pathway in hepatocytes.
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Affiliation(s)
- Lu Bai
- Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China.,Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Jingjing Li
- Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China.,Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Xiaorui Liu
- Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China.,Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Shasha Li
- Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China.,Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Fulei Li
- Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China.,Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Yanling Chen
- Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China.,Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Zujiang Yu
- Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China.,Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
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48
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Mills KM, Szczerkowski JLA, Habib SJ. Wnt ligand presentation and reception: from the stem cell niche to tissue engineering. Open Biol 2017; 7:rsob.170140. [PMID: 28814649 PMCID: PMC5577451 DOI: 10.1098/rsob.170140] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 07/21/2017] [Indexed: 02/06/2023] Open
Abstract
Stem cells reside in niches where spatially restricted signals maintain a delicate balance between stem cell self-renewal and differentiation. Wnt family proteins are particularly suited for this role as they are modified by lipids, which constrain and spatially regulate their signalling range. In recent years, Wnt/β-catenin signalling has been shown to be essential for the self-renewal of a variety of mammalian stem cells. In this review, we discuss Wnt-responsive stem cells in their niche, and mechanisms by which Wnt ligands are presented to responsive cells. We also highlight recent progress in molecular visualization that has allowed for the monitoring of Wnt signalling within the stem cell compartment and new approaches to recapitulate this niche signalling in vitro Indeed, new technologies that present Wnt in a localized manner and mimic the three-dimensional microenvironment of stem cells will advance our understanding of Wnt signalling in the stem cell niche. These advances will expand current horizons to exploit Wnt ligands in the rapidly evolving fields of tissue engineering and regenerative medicine.
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Affiliation(s)
- Kate M Mills
- Centre for Stem Cells and Regenerative Medicine, King's College London, London SE1 9RT, UK
| | - James L A Szczerkowski
- Centre for Stem Cells and Regenerative Medicine, King's College London, London SE1 9RT, UK
| | - Shukry J Habib
- Centre for Stem Cells and Regenerative Medicine, King's College London, London SE1 9RT, UK
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49
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Nejak-Bowen K, Moghe A, Cornuet P, Preziosi M, Nagarajan S, Monga SP. Role and Regulation of p65/β-Catenin Association During Liver Injury and Regeneration: A "Complex" Relationship. Gene Expr 2017; 17:219-235. [PMID: 28474571 PMCID: PMC5700461 DOI: 10.3727/105221617x695762] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
An important role for β-catenin in regulating p65 (a subunit of NF-κB) during acute liver injury has recently been elucidated through use of conditional β-catenin knockout mice, which show protection from apoptosis through increased activation of p65. Thus, we hypothesized that the p65/β-catenin complex may play a role in regulating processes such as cell proliferation during liver regeneration. We show through in vitro and in vivo studies that the p65/β-catenin complex is regulated through the TNF-α pathway and not through Wnt signaling. However, this complex is unchanged after partial hepatectomy (PH), despite increased p65 and β-catenin nuclear translocation as well as cyclin D1 activation. We demonstrate through both in vitro silencing experiments and chromatin immunoprecipitation after PH that β-catenin, and not p65, regulates cyclin D1 expression. Conversely, using reporter mice we show p65 is activated exclusively in the nonparenchymal (NPC) compartment during liver regeneration. Furthermore, stimulation of macrophages by TNF-α induces activation of NF-κB and subsequent secretion of Wnts essential for β-catenin activation in hepatocytes. Thus, we show that β-catenin and p65 are activated in separate cellular compartments during liver regeneration, with p65 activity in NPCs contributing to the activation of hepatocyte β-catenin, cyclin D1 expression, and subsequent proliferation.
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Affiliation(s)
- Kari Nejak-Bowen
- *Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
- †Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Akshata Moghe
- ‡Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Pamela Cornuet
- *Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Morgan Preziosi
- *Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Shanmugam Nagarajan
- *Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
- †Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Satdarshan P. Monga
- *Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
- †Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA
- ‡Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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50
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Bhushan B, Poudel S, Manley MW, Roy N, Apte U. Inhibition of Glycogen Synthase Kinase 3 Accelerated Liver Regeneration after Acetaminophen-Induced Hepatotoxicity in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:543-552. [PMID: 28068511 DOI: 10.1016/j.ajpath.2016.11.014] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 11/01/2016] [Accepted: 11/23/2016] [Indexed: 12/27/2022]
Abstract
Overdose of acetaminophen (APAP) is the leading cause of acute liver failure (ALF) in the United States. Timely initiation of compensatory liver regeneration after APAP hepatotoxicity is critical for final recovery, but the mechanisms of liver regeneration after APAP-induced ALF have not been extensively explored yet. Previous studies from our laboratory have demonstrated that activation of β-catenin signaling after APAP overdose is associated with timely liver regeneration. Herein, we investigated the role of glycogen synthase kinase 3 (GSK3) in liver regeneration after APAP hepatotoxicity using a pharmacological inhibition strategy in mice. Treatment with specific GSK3 inhibitor (L803-mts), starting from 4 hours after 600 mg/kg dose of APAP, resulted in early initiation of liver regeneration in a dose-dependent manner, without modifying the peak regenerative response. Acceleration of liver regeneration was not secondary to alteration of APAP-induced hepatotoxicity, which remained unchanged after GSK3 inhibition. Early cell cycle initiation in hepatocytes after GSK3 inhibition was because of rapid induction of cyclin D1 and phosphorylation of retinoblastoma protein. This was associated with increased activation of β-catenin signaling after GSK3 inhibition. Taken together, our study has revealed a novel role of GSK3 in liver regeneration after APAP overdose and identified GSK3 as a potential therapeutic target to improve liver regeneration after APAP-induced ALF.
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Affiliation(s)
- Bharat Bhushan
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Samikshya Poudel
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Michael W Manley
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Nairita Roy
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Udayan Apte
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
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