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He J, Li S, Yang Z, Ma J, Qian C, Huang Z, Li L, Yang Y, Chen J, Sun Y, Zhao T, Luo L. Gallbladder-derived retinoic acid signalling drives reconstruction of the damaged intrahepatic biliary ducts. Nat Cell Biol 2025; 27:39-47. [PMID: 39779943 DOI: 10.1038/s41556-024-01568-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 10/25/2024] [Indexed: 01/11/2025]
Abstract
Severe damage to the intrahepatic biliary duct (IHBD) network occurs in multiple human advanced cholangiopathies, such as primary sclerosing cholangitis, biliary atresia and end-stage primary biliary cholangitis. Whether and how a severely damaged IHBD network could reconstruct has remained unclear. Here we show that, although the gallbladder is not directly connected to the IHBD, there is a common hepatic duct (CHD) in between, and severe damage to the IHBD network induces migration of gallbladder smooth muscle cells (SMCs) to coat the CHD in mouse and zebrafish models. These gallbladder-derived, CHD-coating SMCs produce retinoic acid to activate Sox9b in the CHD, which drives proliferation and ingrowth of CHD cells into the inner liver to reconstruct the IHBD network. This study reveals a hitherto unappreciated function of the gallbladder in the recovery of injured liver, and characterizes mechanisms involved in how the gallbladder and liver communicate through inter-organ cell migration to drive tissue regeneration. Carrying out cholecystectomy will thus cause previously unexpected impairments to liver health.
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Affiliation(s)
- Jianbo He
- State Key laboratory of Genetic Engineering, School of Life Sciences, Liver Cancer Institute of Zhongshan Hospital, Fudan University, Shanghai, China
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, China
| | - Shuang Li
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, China
| | - Zhuolin Yang
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, China
| | - Jianlong Ma
- State Key laboratory of Genetic Engineering, School of Life Sciences, Liver Cancer Institute of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chuanfang Qian
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, China
| | - Zhuofu Huang
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, China
| | - Linke Li
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, China
| | - Yun Yang
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, China
| | - Jingying Chen
- State Key laboratory of Genetic Engineering, School of Life Sciences, Liver Cancer Institute of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yunfan Sun
- State Key laboratory of Genetic Engineering, School of Life Sciences, Liver Cancer Institute of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tianyu Zhao
- State Key laboratory of Genetic Engineering, School of Life Sciences, Liver Cancer Institute of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lingfei Luo
- State Key laboratory of Genetic Engineering, School of Life Sciences, Liver Cancer Institute of Zhongshan Hospital, Fudan University, Shanghai, China.
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, China.
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2
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Kim M, Park Y, Kim YS, Ko S. Cellular Plasticity in Gut and Liver Regeneration. Gut Liver 2024; 18:949-960. [PMID: 39081200 PMCID: PMC11565004 DOI: 10.5009/gnl240005] [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: 01/03/2024] [Revised: 06/07/2024] [Accepted: 06/21/2024] [Indexed: 11/16/2024] Open
Abstract
The intestine and liver share a unique regenerative property that sets them apart from other mammalian visceral organs. The intestinal epithelium exhibits rapid renewal, making it one of the fastest renewing tissues in humans. Under physiological conditions, intestinal stem cells within each intestinal crypt continuously differentiate into the different types of intestinal epithelial cells to maintain intestinal homeostasis. However, when exposed to tissue damage or stressful conditions such as inflammation, intestinal epithelial cells in the gastrointestinal tract exhibit plasticity, allowing fully differentiated cells to regain their stem cell properties. Likewise, hepatic epithelial cells possess a remarkable regenerative capacity to restore lost liver mass through proliferation-mediated liver regeneration. When the proliferation-mediated regenerative capacity is impaired, hepatocytes and biliary epithelial cells (BECs) can undergo plasticity-mediated regeneration and replenish each other. The transition of mammalian liver progenitor cells to hepatocytes/BECs can be observed under tightly controlled experimental conditions such as severe hepatocyte injury accompanied by the loss of regenerative capacity. In this review, we will discuss the mechanism by which cellular plasticity contributes to the regeneration process and the potential therapeutic implications of understanding and harnessing cellular plasticity in the gut and liver.
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Affiliation(s)
- Minwook Kim
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Yoojeong Park
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - You Sun Kim
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Sungjin Ko
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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3
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Chen Y, Yan Y, Li Y, Zhang L, Luo T, Zhu X, Qin D, Chen N, Huang W, Chen X, Wang L, Zhu X, Zhang L. Deletion of Tgm2 suppresses BMP-mediated hepatocyte-to-cholangiocyte metaplasia in ductular reaction. Cell Prolif 2024; 57:e13646. [PMID: 38623945 PMCID: PMC11471396 DOI: 10.1111/cpr.13646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 03/26/2024] [Accepted: 04/03/2024] [Indexed: 04/17/2024] Open
Abstract
Transglutaminase 2 (Tgm2) plays an essential role in hepatic repair following prolonged toxic injury. During cholestatic liver injury, the intrahepatic cholangiocytes undergo dynamic tissue expansion and remodelling, referred to as ductular reaction (DR), which is crucial for liver regeneration. However, the molecular mechanisms governing the dynamics of active cells in DR are still largely unclear. Here, we generated Tgm2-knockout mice (Tgm2-/-) and Tgm2-CreERT2-Rosa26-mTmG flox/flox (Tgm2CreERT2-R26T/Gf/f) mice and performed a three-dimensional (3D) collagen gel culture of mouse hepatocytes to demonstrate how Tgm2 signalling is involved in DR to remodel intrahepatic cholangiocytes. Our results showed that the deletion of Tgm2 adversely affected the functionality and maturity of the proliferative cholangiocytes in DR, thus leading to more severe cholestasis during DDC-induced liver injury. Additionally, Tgm2 hepatocytes played a crucial role in the regulation of DR through metaplasia. We unveiled that Tgm2 regulated H3K4me3Q5ser via serotonin to promote BMP signalling activation to participate in DR. Besides, we revealed that the activation or inhibition of BMP signalling could promote or suppress the development and maturation of cholangiocytes in DDC-induced DR. Furthermore, our 3D collagen gel culture assay indicated that Tgm2 was vital for the development of cholangiocytes in vitro. Our results uncovered a considerable role of BMP signalling in controlling metaplasia of Tgm2 hepatocytes in DR and revealed the phenotypic plasticity of mature hepatocytes.
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Affiliation(s)
- Yaqing Chen
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Yi Yan
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Yujing Li
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Liang Zhang
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Tingting Luo
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Xinlong Zhu
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Dan Qin
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Ning Chen
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Wendong Huang
- Department of Diabetes Complications and MetabolismDiabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical CenterDuarteCaliforniaUSA
| | - Xiangmei Chen
- Department of Nephrology, First Medical Center of Chinese PLA General HospitalNephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease ResearchBeijingChina
| | - Liqiang Wang
- Department of Nephrology, First Medical Center of Chinese PLA General HospitalNephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease ResearchBeijingChina
| | - Xianmin Zhu
- Department of Hepatobiliary and Pancreatic SurgeryCancer Hospital of Wuhan University (Hubei Cancer Hospital)WuhanChina
| | - Lisheng Zhang
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
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4
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Nishikawa Y. Aberrant differentiation and proliferation of hepatocytes in chronic liver injury and liver tumors. Pathol Int 2024; 74:361-378. [PMID: 38837539 PMCID: PMC11551836 DOI: 10.1111/pin.13441] [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: 03/09/2024] [Revised: 04/29/2024] [Accepted: 05/12/2024] [Indexed: 06/07/2024]
Abstract
Chronic liver injury induces liver cirrhosis and facilitates hepatocarcinogenesis. However, the effects of this condition on hepatocyte proliferation and differentiation are unclear. We showed that rodent hepatocytes display a ductular phenotype when they are cultured within a collagenous matrix. This process involves transdifferentiation without the emergence of hepatoblastic features and is at least partially reversible. During the ductular reaction in chronic liver diseases with progressive fibrosis, some hepatocytes, especially those adjacent to ectopic ductules, demonstrate ductular transdifferentiation, but the majority of increased ductules originate from the existing bile ductular system that undergoes extensive remodeling. In chronic injury, hepatocyte proliferation is weak but sustained, and most regenerative nodules in liver cirrhosis are composed of clonally proliferating hepatocytes, suggesting that a small fraction of hepatocytes maintain their proliferative capacity in chronic injury. In mouse hepatocarcinogenesis models, hepatocytes activate the expression of various fetal/neonatal genes, indicating that these cells undergo dedifferentiation. Hepatocyte-specific somatic integration of various oncogenes in mice demonstrated that hepatocytes may be the cells of origin for a broad spectrum of liver tumors through transdifferentiation and dedifferentiation. In conclusion, the phenotypic plasticity and heterogeneity of mature hepatocytes are important for understanding the pathogenesis of chronic liver diseases and liver tumors.
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Affiliation(s)
- Yuji Nishikawa
- President's OfficeAsahikawa Medical UniversityAsahikawaHokkaidoJapan
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5
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Sun X, Nagahama Y, Singh SK, Kozakai Y, Nabeshima H, Fukushima K, Tanaka H, Motooka D, Fukui E, Vivier E, Diez D, Akira S. Deletion of the mRNA endonuclease Regnase-1 promotes NK cell anti-tumor activity via OCT2-dependent transcription of Ifng. Immunity 2024; 57:1360-1377.e13. [PMID: 38821052 DOI: 10.1016/j.immuni.2024.05.006] [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: 07/13/2023] [Revised: 12/31/2023] [Accepted: 05/07/2024] [Indexed: 06/02/2024]
Abstract
Limited infiltration and activity of natural killer (NK) and T cells within the tumor microenvironment (TME) correlate with poor immunotherapy responses. Here, we examined the role of the endonuclease Regnase-1 on NK cell anti-tumor activity. NK cell-specific deletion of Regnase-1 (Reg1ΔNK) augmented cytolytic activity and interferon-gamma (IFN-γ) production in vitro and increased intra-tumoral accumulation of Reg1ΔNK-NK cells in vivo, reducing tumor growth dependent on IFN-γ. Transcriptional changes in Reg1ΔNK-NK cells included elevated IFN-γ expression, cytolytic effectors, and the chemokine receptor CXCR6. IFN-γ induced expression of the CXCR6 ligand CXCL16 on myeloid cells, promoting further recruitment of Reg1ΔNK-NK cells. Mechanistically, Regnase-1 deletion increased its targets, the transcriptional regulators OCT2 and IκBζ, following interleukin (IL)-12 and IL-18 stimulation, and the resulting OCT2-IκBζ-NF-κB complex induced Ifng transcription. Silencing Regnase-1 in human NK cells increased the expression of IFNG and POU2F2. Our findings highlight NK cell dysfunction in the TME and propose that targeting Regnase-1 could augment active NK cell persistence for cancer immunotherapy.
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Affiliation(s)
- Xin Sun
- Laboratory of Host Defense, WPI Immunology Frontier Research Center (WPI-IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan; Quantitative Immunology Unit, WPI-IFReC, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan; Joint Research Chair of Innate Immunity for Drug Discovery, WPI-IFReC, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Yasuharu Nagahama
- Laboratory of Host Defense, WPI Immunology Frontier Research Center (WPI-IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan; Host Defense Laboratory, Immunology Unit, Department of Medical Innovations, Osaka Research Center for Drug Discovery, Otsuka Pharmaceutical Co. Ltd., 5-1-35 Saito-aokita, Minoh, Osaka 562-0029, Japan; Joint Research Chair of Innate Immunity for Drug Discovery, WPI-IFReC, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Shailendra Kumar Singh
- Laboratory of Host Defense, WPI Immunology Frontier Research Center (WPI-IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan; Joint Research Chair of Innate Immunity for Drug Discovery, WPI-IFReC, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Yuuki Kozakai
- Laboratory of Host Defense, WPI Immunology Frontier Research Center (WPI-IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Hiroshi Nabeshima
- Laboratory of Host Defense, WPI Immunology Frontier Research Center (WPI-IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan; Host Defense Laboratory, Immunology Unit, Department of Medical Innovations, Osaka Research Center for Drug Discovery, Otsuka Pharmaceutical Co. Ltd., 5-1-35 Saito-aokita, Minoh, Osaka 562-0029, Japan; Joint Research Chair of Innate Immunity for Drug Discovery, WPI-IFReC, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Kiyoharu Fukushima
- Laboratory of Host Defense, WPI Immunology Frontier Research Center (WPI-IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan; Joint Research Chair of Innate Immunity for Drug Discovery, WPI-IFReC, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan; Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Hiroki Tanaka
- Laboratory of Host Defense, WPI Immunology Frontier Research Center (WPI-IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Daisuke Motooka
- NGS Core Facility of the Genome Information Research Center, RIMD, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Eriko Fukui
- Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Eric Vivier
- Aix-Marseille Université, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Centre d'Immunologie de Marseille-Luminy, Marseille, France; Innate Pharma Research Laboratories, Marseille, France; APHM, Hôpital de la Timone, Marseille-Immunopole, Marseille, France
| | - Diego Diez
- Quantitative Immunology Unit, WPI-IFReC, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Shizuo Akira
- Laboratory of Host Defense, WPI Immunology Frontier Research Center (WPI-IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan; Joint Research Chair of Innate Immunity for Drug Discovery, WPI-IFReC, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan; Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan; Center for Advanced Modalities and Drug Delivery System (CAMaD), Osaka University, 2-8 Yamada-oka, Suita, Osaka 565-0871, Japan.
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Mavila N, Siraganahalli Eshwaraiah M, Kennedy J. Ductular Reactions in Liver Injury, Regeneration, and Disease Progression-An Overview. Cells 2024; 13:579. [PMID: 38607018 PMCID: PMC11011399 DOI: 10.3390/cells13070579] [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: 02/01/2024] [Revised: 03/11/2024] [Accepted: 03/22/2024] [Indexed: 04/13/2024] Open
Abstract
Ductular reaction (DR) is a complex cellular response that occurs in the liver during chronic injuries. DR mainly consists of hyper-proliferative or reactive cholangiocytes and, to a lesser extent, de-differentiated hepatocytes and liver progenitors presenting a close spatial interaction with periportal mesenchyme and immune cells. The underlying pathology of DRs leads to extensive tissue remodeling in chronic liver diseases. DR initiates as a tissue-regeneration mechanism in the liver; however, its close association with progressive fibrosis and inflammation in many chronic liver diseases makes it a more complicated pathological response than a simple regenerative process. An in-depth understanding of the cellular physiology of DRs and their contribution to tissue repair, inflammation, and progressive fibrosis can help scientists develop cell-type specific targeted therapies to manage liver fibrosis and chronic liver diseases effectively.
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Affiliation(s)
- Nirmala Mavila
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (M.S.E.); (J.K.)
- Division of Applied Cell Biology and Physiology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Mallikarjuna Siraganahalli Eshwaraiah
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (M.S.E.); (J.K.)
| | - Jaquelene Kennedy
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (M.S.E.); (J.K.)
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7
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Jiang M, Ren J, Belmonte JCI, Liu GH. Hepatocyte reprogramming in liver regeneration: Biological mechanisms and applications. FEBS J 2023; 290:5674-5688. [PMID: 37556833 DOI: 10.1111/febs.16930] [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: 05/15/2023] [Revised: 07/17/2023] [Accepted: 08/08/2023] [Indexed: 08/11/2023]
Abstract
The liver is one of the few organs that retain the capability to regenerate in adult mammals. This regeneration process is mainly facilitated by the dynamic behavior of hepatocytes, which are the major functional constituents in the liver. In response to liver injury, hepatocytes undergo remarkable alterations, such as reprogramming, wherein they lose their original identity and acquire properties from other cells. This phenomenon of hepatocyte reprogramming, coupled with hepatocyte expansion, plays a central role in liver regeneration, and its underlying mechanisms are complex and multifaceted. Understanding the fate of reprogrammed hepatocytes and the mechanisms of their conversion has significant implications for the development of innovative therapeutics for liver diseases. Herein, we review the plasticity of hepatocytes in response to various forms of liver injury, with a focus on injury-induced hepatocyte reprogramming. We provide a comprehensive summary of current knowledge on the molecular and cellular mechanisms governing hepatocyte reprogramming, specifically in the context of liver regeneration, providing insight into potential applications of this process in the treatment of liver disorders, including chronic liver diseases and liver cancer.
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Affiliation(s)
- Mengmeng Jiang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Jie Ren
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Key Laboratory of RNA Science and Engineering, CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, China
- Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China
- Aging Biomarker Consortium, Beijing, China
- School of Future Technology, University of Chinese Academy of Sciences, Beijing, China
| | | | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
- Aging Biomarker Consortium, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, China
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8
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Hrncir HR, Hantelys F, Gracz AD. Panic at the Bile Duct: How Intrahepatic Cholangiocytes Respond to Stress and Injury. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1440-1454. [PMID: 36870530 PMCID: PMC10548281 DOI: 10.1016/j.ajpath.2023.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 01/16/2023] [Accepted: 02/15/2023] [Indexed: 03/06/2023]
Abstract
In the liver, biliary epithelial cells (BECs) line intrahepatic bile ducts (IHBDs) and are primarily responsible for modifying and transporting hepatocyte-produced bile to the digestive tract. BECs comprise only 3% to 5% of the liver by cell number but are critical for maintaining choleresis through homeostasis and disease. To this end, BECs drive an extensive morphologic remodeling of the IHBD network termed ductular reaction (DR) in response to direct injury or injury to the hepatic parenchyma. BECs are also the target of a broad and heterogenous class of diseases termed cholangiopathies, which can present with phenotypes ranging from defective IHBD development in pediatric patients to progressive periductal fibrosis and cancer. DR is observed in many cholangiopathies, highlighting overlapping similarities between cell- and tissue-level responses by BECs across a spectrum of injury and disease. The following core set of cell biological BEC responses to stress and injury may moderate, initiate, or exacerbate liver pathophysiology in a context-dependent manner: cell death, proliferation, transdifferentiation, senescence, and acquisition of neuroendocrine phenotype. By reviewing how IHBDs respond to stress, this review seeks to highlight fundamental processes with potentially adaptive or maladaptive consequences. A deeper understanding of how these common responses contribute to DR and cholangiopathies may identify novel therapeutic targets in liver disease.
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Affiliation(s)
- Hannah R Hrncir
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia; Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia
| | - Fransky Hantelys
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia
| | - Adam D Gracz
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia; Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia.
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9
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Song Z, Lin S, Wu X, Ren X, Wu Y, Wen H, Qian B, Lin H, Huang Y, Zhao C, Wang N, Huang Y, Peng B, Li X, Peng H, Shen S. Hepatitis B virus-related intrahepatic cholangiocarcinoma originates from hepatocytes. Hepatol Int 2023; 17:1300-1317. [PMID: 37368186 PMCID: PMC10522522 DOI: 10.1007/s12072-023-10556-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 05/27/2023] [Indexed: 06/28/2023]
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is one of the most common risk factors for intrahepatic cholangiocarcinoma (ICC). However, there is no direct evidence of a causal relationship between HBV infection and ICC. In this study, we attempted to prove that ICC may originate from hepatocytes through a pathological study involving ICC tissue-derived organoids. METHOD The medical records and tumor tissue samples of 182 patients with ICC after hepatectomy were collected. The medical records of 182 patients with ICC were retrospectively analyzed to explore the prognostic factors. A microarray of 182 cases of ICC tumor tissue and 6 cases of normal liver tissue was made, and HBsAg was stained by immunohistochemistry (IHC) to explore the factors closely related to HBV infection. Fresh ICC tissues and corresponding adjacent tissues were collected to make paraffin sections and organoids. Immunofluorescence (IF) staining of factors including HBsAg, CK19, CK7, Hep-Par1 and Albumin (ALB) was performed on both fresh tissues and organoids. In addition, we collected adjacent nontumor tissues of 6 patients with HBV (+) ICC, from which biliary duct tissue and normal liver tissue were isolated and RNA was extracted respectively for quantitative PCR assay. In addition, the expression of HBV-DNA in organoid culture medium was detected by quantitative PCR and PCR electrophoresis. RESULTS A total of 74 of 182 ICC patients were HBsAg positive (40.66%, 74/182). The disease-free survival (DFS) rate of HBsAg (+) ICC patients was significantly lower than that of HBsAg (-) ICC patients (p = 0.0137). IF and IHC showed that HBsAg staining was only visible in HBV (+) ICC fresh tissues and organoids, HBsAg expression was negative in bile duct cells in the portal area. Quantitative PCR assay has shown that the expression of HBs antigen and HBx in normal hepatocytes were significantly higher than that in bile duct epithelial cells. Combined with the IF and IHC staining, it was confirmed that HBV does not infect normal bile duct epithelial cells. In addition, IF also showed that the staining of bile duct markers CK19 and CK7 were only visible in ICC fresh tissue and organoids, and the staining of hepatocyte markers Hep-Par1 and ALB was only visible in normal liver tissue fresh tissue. Real-time PCR and WB had the same results. High levels of HBV-DNA were detected in the culture medium of HBV (+) organoids but not in the culture medium of HBV (-) organoids. CONCLUSION HBV-related ICC might be derived from hepatocytes. HBV (+) ICC patients had shorter DFS than HBV (-) ICC patients.
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Affiliation(s)
- Zimin Song
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Shuirong Lin
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Xiwen Wu
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
- Department of Clinical Nutrition, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Xiaoxue Ren
- Department of Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Yifan Wu
- Department of Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Haoxiang Wen
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Baifeng Qian
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Haozhong Lin
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Yihao Huang
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Chenfeng Zhao
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Nian Wang
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510030, China
| | - Yan Huang
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510030, China
| | - Baogang Peng
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Xiaoxing Li
- Institute of Precision Medicine, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China.
| | - Hong Peng
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China.
| | - Shunli Shen
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China.
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10
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Lee SH, So J, Shin D. Hepatocyte-to-cholangiocyte conversion occurs through transdifferentiation independently of proliferation in zebrafish. Hepatology 2023; 77:1198-1210. [PMID: 36626626 PMCID: PMC10023500 DOI: 10.1097/hep.0000000000000016] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 10/10/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND AND AIMS Injury to biliary epithelial cells (BECs) lining the hepatic bile ducts leads to cholestatic liver diseases. Upon severe biliary damage, hepatocytes can convert to BECs, thereby contributing to liver recovery. Given a potential of augmenting this hepatocyte-to-BEC conversion as a therapeutic option for cholestatic liver diseases, it will be important to thoroughly understand the cellular and molecular mechanisms of the conversion process. APPROACH AND RESULTS Towards this aim, we have established a zebrafish model for hepatocyte-to-BEC conversion by employing Tg(fabp10a:CFP-NTR) zebrafish with a temporal inhibition of Notch signaling during regeneration. Cre/loxP-mediated permanent and H2B-mCherry-mediated short-term lineage tracing revealed that in the model, all BECs originate from hepatocytes. During the conversion, BEC markers are sequentially induced in the order of Sox9b, Yap/Taz, Notch activity/ epcam , and Alcama/ krt18 ; the expression of the hepatocyte marker Bhmt disappears between the Sox9b and Yap/Taz induction. Importantly, live time-lapse imaging unambiguously revealed transdifferentiation of hepatocytes into BECs: hepatocytes convert to BECs without transitioning through a proliferative intermediate state. In addition, using compounds and transgenic and mutant lines that modulate Notch and Yap signaling, we found that both Notch and Yap signaling are required for the conversion even in Notch- and Yap-overactivating settings. CONCLUSIONS Hepatocyte-to-BEC conversion occurs through transdifferentiation independently of proliferation, and Notch and Yap signaling control the process in parallel with a mutually positive interaction. The new zebrafish model will further contribute to a thorough understanding of the mechanisms of the conversion process.
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Affiliation(s)
- Seung-Hoon Lee
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Juhoon So
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Donghun Shin
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15260, USA
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11
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Huppert SS, Schwartz RE. Multiple Facets of Cellular Homeostasis and Regeneration of the Mammalian Liver. Annu Rev Physiol 2023; 85:469-493. [PMID: 36270290 PMCID: PMC9918695 DOI: 10.1146/annurev-physiol-032822-094134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Liver regeneration occurs in response to diverse injuries and is capable of functionally reestablishing the lost parenchyma. This phenomenon has been known since antiquity, encapsulated in the Greek myth where Prometheus was to be punished by Zeus for sharing the gift of fire with humanity by having an eagle eat his liver daily, only to have the liver regrow back, thus ensuring eternal suffering and punishment. Today, this process is actively leveraged clinically during living donor liver transplantation whereby up to a two-thirds hepatectomy (resection or removal of part of the liver) on a donor is used for transplant to a recipient. The donor liver rapidly regenerates to recover the lost parenchymal mass to form a functional tissue. This astonishing regenerative process and unique capacity of the liver are examined in further detail in this review.
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Affiliation(s)
- Stacey S Huppert
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA;
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Robert E Schwartz
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA;
- Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY, USA
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12
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Rigual MDM, Sánchez Sánchez P, Djouder N. Is liver regeneration key in hepatocellular carcinoma development? Trends Cancer 2023; 9:140-157. [PMID: 36347768 DOI: 10.1016/j.trecan.2022.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 10/05/2022] [Accepted: 10/10/2022] [Indexed: 11/08/2022]
Abstract
The liver is the largest organ of the mammalian body and has the remarkable ability to fully regenerate in order to maintain tissue homeostasis. The adult liver consists of hexagonal lobules, each with a central vein surrounded by six portal triads localized in the lobule border containing distinct parenchymal and nonparenchymal cells. Because the liver is continuously exposed to diverse stress signals, several sophisticated regenerative processes exist to restore its functional status following impairment. However, these stress signals can affect the liver's capacity to regenerate and may lead to the development of hepatocellular carcinoma (HCC), one of the most aggressive liver cancers. Here, we review the mechanisms of hepatic regeneration and their potential to influence HCC development.
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Affiliation(s)
- María Del Mar Rigual
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain
| | - Paula Sánchez Sánchez
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain
| | - Nabil Djouder
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain.
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13
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Kim M, Rizvi F, Shin D, Gouon-Evans V. Update on Hepatobiliary Plasticity. Semin Liver Dis 2023; 43:13-23. [PMID: 36764306 PMCID: PMC10005859 DOI: 10.1055/s-0042-1760306] [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] [Indexed: 02/12/2023]
Abstract
The liver field has been debating for decades the contribution of the plasticity of the two epithelial compartments in the liver, hepatocytes and biliary epithelial cells (BECs), to derive each other as a repair mechanism. The hepatobiliary plasticity has been first observed in diseased human livers by the presence of biphenotypic cells expressing hepatocyte and BEC markers within bile ducts and regenerative nodules or budding from strings of proliferative BECs in septa. These observations are not surprising as hepatocytes and BECs derive from a common fetal progenitor, the hepatoblast, and, as such, they are expected to compensate for each other's loss in adults. To investigate the cell origin of regenerated cell compartments and associated molecular mechanisms, numerous murine and zebrafish models with ability to trace cell fates have been extensively developed. This short review summarizes the clinical and preclinical studies illustrating the hepatobiliary plasticity and its potential therapeutic application.
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Affiliation(s)
- Minwook Kim
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Fatima Rizvi
- Department of Medicine, Gastroenterology Section, Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, Massachusetts
| | - Donghun Shin
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Valerie Gouon-Evans
- Department of Medicine, Gastroenterology Section, Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, Massachusetts
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14
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Kim M, Delgado E, Ko S. DNA methylation in cell plasticity and malignant transformation in liver diseases. Pharmacol Ther 2023; 241:108334. [PMID: 36535346 PMCID: PMC9841769 DOI: 10.1016/j.pharmthera.2022.108334] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/09/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
The liver possesses extraordinary regenerative capacity mainly attributable to the ability of hepatocytes (HCs) and biliary epithelial cells (BECs) to self-replicate. This ability is left over from their bipotent parent cell, the hepatoblast, during development. When this innate regeneration is compromised due to the absence of proliferative parenchymal cells, such as during cirrhosis, HCs and BEC can transdifferentiate; thus, adding another layer of complexity to the process of liver repair. In addition, dysregulated lineage maintenance in these two cell populations has been shown to promote malignant growth in experimental conditions. Here, malignant transformation, driven in part by insufficient maintenance of lineage reprogramming, contributes to end-stage liver disease. Epigenetic changes are key drivers for cell fate decisions as well as transformation by finetuning overall transcription and gene expression. In this review, we address how altered DNA methylation contributes to the initiation and progression of hepatic cell fate conversion and cancer formation. We also discussed the diagnostic and therapeutic potential of targeting DNA methylation in liver cancer, its current limitations, and what future research is necessary to facilitate its contribution to clinical translation.
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Affiliation(s)
- Minwook Kim
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
| | - Evan Delgado
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America; Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
| | - Sungjin Ko
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America; Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.
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15
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Chen Y, Gao WK, Shu YY, Ye J. Mechanisms of ductular reaction in non-alcoholic steatohepatitis. World J Gastroenterol 2022; 28:2088-2099. [PMID: 35664038 PMCID: PMC9134136 DOI: 10.3748/wjg.v28.i19.2088] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/18/2022] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disease spectrum caused in part by insulin resistance and genetic predisposition. This disease is primarily characterized by excessive lipid accumulation in hepatocytes in the absence of alcohol abuse and other causes of liver damage. Histologically, NAFLD is divided into several periods: simple steatosis, non-alcoholic steatohepatitis (NASH), hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. With the increasing prevalence of obesity and hyperlipidemia, NAFLD has become the main cause of chronic liver disease worldwide. As a result, the pathogenesis of this disease is drawing increasing attention. Ductular reaction (DR) is a reactive bile duct hyperplasia caused by liver injury that involves hepatocytes, cholangiocytes, and hepatic progenitor cells. Recently, DR is shown to play a pivotal role in simple steatosis progression to NASH or liver fibrosis, providing new research and treatment options. This study reviews several DR signaling pathways, including Notch, Hippo/YAP-TAZ, Wnt/β-catenin, Hedgehog, HGF/c-Met, and TWEAK/Fn14, and their role in the occurrence and development of NASH.
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Affiliation(s)
- Yue Chen
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Wen-Kang Gao
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Yan-Yun Shu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Jin Ye
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
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16
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Lan T, Qian S, Tang C, Gao J. Role of Immune Cells in Biliary Repair. Front Immunol 2022; 13:866040. [PMID: 35432349 PMCID: PMC9005827 DOI: 10.3389/fimmu.2022.866040] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 03/08/2022] [Indexed: 02/06/2023] Open
Abstract
The biliary system is comprised of cholangiocytes and plays an important role in maintaining liver function. Under normal conditions, cholangiocytes remain in the stationary phase and maintain a very low turnover rate. However, the robust biliary repair is initiated in disease conditions, and different repair mechanisms can be activated depending on the pathological changes. During biliary disease, immune cells including monocytes, lymphocytes, neutrophils, and mast cells are recruited to the liver. The cellular interactions between cholangiocytes and these recruited immune cells as well as hepatic resident immune cells, including Kupffer cells, determine disease outcomes. However, the role of immune cells in the initiation, regulation, and suspension of biliary repair remains elusive. The cellular processes of cholangiocyte proliferation, progenitor cell differentiation, and hepatocyte-cholangiocyte transdifferentiation during biliary diseases are reviewed to manifest the underlying mechanism of biliary repair. Furthermore, the potential role of immune cells in crucial biliary repair mechanisms is highlighted. The mechanisms of biliary repair in immune-mediated cholangiopathies, inherited cholangiopathies, obstructive cholangiopathies, and cholangiocarcinoma are also summarized. Additionally, novel techniques that could clarify the underlying mechanisms of biliary repair are displayed. Collectively, this review aims to deepen the understanding of the mechanisms of biliary repair and contributes potential novel therapeutic methods for treating biliary diseases.
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Affiliation(s)
- Tian Lan
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Shuaijie Qian
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Chengwei Tang
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhang Gao
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
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17
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Lin Y, Zhang F, Zhang L, Chen L, Zheng S. Characteristics of SOX9-positive progenitor-like cells during cholestatic liver regeneration in biliary atresia. Stem Cell Res Ther 2022; 13:114. [PMID: 35313986 PMCID: PMC8935712 DOI: 10.1186/s13287-022-02795-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 03/02/2022] [Indexed: 11/16/2022] Open
Abstract
Background The progression of Biliary Atresia (BA) is associated with the number of reactive ductular cells (RDCs) whose heterogeneity in origin and evolution in humans remains unknown. SOX9-positive liver progenitor-like cells (LPLCs) have been shown to participate in RDCs and new hepatocyte formation during cholestatic liver regeneration in an animal model, which implies the possibility that hepatocyte-reprogrammed LPLCs could be a source of RDCs in BA. The present study aimed to elucidate the characteristics of SOX9-positive LPLCs in BA for exploring new possible therapeutic targets by manipulating the bi-differentiation process of LPLCs to prevent disease progression. Methods Twenty-eight patients, including 24 patients with BA and 4 patients with Congenital Choledochal Cyst as the control group, were retrospectively recruited. Liver biopsy samples were classified histologically using a 4-point scale based on fibrosis severity. LPLCs were detected by SOX9 and HNF4A double positive staining. Single immunohistochemistry, double immunohistochemistry, and multiple immunofluorescence staining were used to determine the different cell types and characteristics of LPLCs. Results The prognostic predictors of BA, namely total bile acid (TBA), RDCs, and fibrosis, were correlated to the emergence of LPLCs. SOX9 and HNF4A double-positive LPLCs co-stained rarely with relevant markers of portal hepatic progenitor cells (portal-HPCs), including CK19, CK7, EPCAM, PROM1 (CD133), TROP2, and AFP. Under cholestasis conditions, LPLCs acquired superior proliferation and anti-senescence ability among hepatocytes. Moreover, LPLCs arranged as a pseudo-rosette structure appeared from the periportal parenchyma to the portal region, which implied the differentiation from hepatocyte-reprogrammed LPLCs to RDCs with the progression of cholestasis. Conclusions LPLCs are associated with disease progression and prognostic factors of BA. The bipotent characteristics of LPLCs are different from those of portal-HPCs. As cholestasis progresses, LPLCs appear to gain superior proliferation and anti-senescence ability and continually differentiate to RDCs. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02795-2.
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Affiliation(s)
- Yuting Lin
- Department of Pediatric Surgery, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, 399 Wan Yuan Road, Shanghai, 201102, China
| | - Fang Zhang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Ludi Zhang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Lian Chen
- Department of Pathology, Children's Hospital of Fudan University, National Children's Medical Center, 399 Wan Yuan Road, Shanghai, 201102, China
| | - Shan Zheng
- Department of Pediatric Surgery, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, 399 Wan Yuan Road, Shanghai, 201102, China.
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18
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Özdemir BH. Tumor Microenvironment: Necroptosis Switches the Subtype of Liver Cancer While Necrosis Promotes Tumor Recurrence and Progression. EXP CLIN TRANSPLANT 2022; 21:291-298. [PMID: 35297332 DOI: 10.6002/ect.2021.0457] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Liver cancer is a heterogeneous group of solid tumors that include mainly epithelial tumors. As with other solid carcinomas, tumor development results from an accumulation of genetic and epigenetic alterations. Hepatocellular carcinoma and intrahepatic cholangiocarcinoma, derived from malignant transformation of hepatocytes and cholangiocytes, respectively, are 2 primary types of liver cancers. However, it has been shown that the same kind of cell can give rise to different types of cancer, depending on manner of cell death in the tumor microenvironment. In a recent animal study, hepatocytes gave rise to both hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Oncogenically activated hepatocytes were shown to give rise to intrahepatic cholangiocarcinoma or hepatocellular carcinoma depending on cell death type of neighboring cells. Hepatocytes within the necroptotic microenvironment gave rise to intrahepatic cholangiocarcinoma; however, hepatocytes harboring the same oncogenic driver gave rise to hepatocellular carcinoma within the apoptotic microenvironment. The hepatic cytokine microenvironment structured by the necroptosis can also switch hepatocellular carcinoma to intrahepatic cholangiocarcinoma independently of the oncogenic drivers. Cell death by necrosis in damaged livers can also lead to development of carcinoma. Cancer cells are known to be resistant to apoptosis as a result of p53 mutation. Therefore, necrosis is the primary cell death pathway in cancer therapy. Necrosis is associated with high levels of angiogenesis, tumor-associated macrophages, and increased inflammation in the tumor microenvironment. Patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma characterized by necrosis and tumor-associated macrophages have reduced overall survival and recurrence-free survival. Cytotoxicity from anticancer therapy can also lead to accelerated necrosis. The content of cells undergoing necrosis triggers cytokine secretion, which designs cancer progression via inflammatory and noninflammatory pathways. Thus, the tumor microenvironment and manner of cell death (necrosis, apoptosis, or necroptosis) are crucial factors in the development of primary liver cancers and tumor progression.
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Affiliation(s)
- B Handan Özdemir
- From the Pathology Department, Baskent University, Ankara, Turkey
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19
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SOX9 contributes to the progression of ductular reaction for the protection from chronic liver injury. Hum Cell 2022; 35:721-734. [DOI: 10.1007/s13577-022-00683-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 01/30/2022] [Indexed: 11/26/2022]
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20
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Denk H, Pabst D, Abuja PM, Reihs R, Tessaro B, Zatloukal K, Lackner C. Senescence markers in focal nodular hyperplasia of the liver: pathogenic considerations on the basis of immunohistochemical results. Mod Pathol 2022; 35:87-95. [PMID: 34645984 DOI: 10.1038/s41379-021-00940-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/23/2021] [Accepted: 09/23/2021] [Indexed: 02/07/2023]
Abstract
Focal nodular hyperplasia (FNH) is a polyclonal tumour-like hepatic lesion characterised by parenchymal nodules, connective tissue septa without interlobular bile ducts, pronounced ductular reaction and inflammation. It may represent a response to local arterial hyperperfusion and hyperoxygenation resulting in oxidative stress. We aimed at obtaining closer insight into the pathogenesis of FNH with its characteristic morphologic features. Immunohistochemistry and immunofluorescence microscopy was performed on FNH specimens using antibodies against keratins (K) 7 and 19, neural cell adhesion molecule (NCAM), lamin B1, senescence markers (CDK inhibitor 1/p21Cip1, CDK inhibitor /p16Ink4a, senescence-associated (SA) β- galactosidase activity), proliferation markers (Ki-67, proliferating-cell nuclear antigen (PCNA)), and the abnormally phosphorylated histone γ-H2AX, indicating DNA double strand breaks; moreover SA β- galactosidase activity was determined histochemically. Ductular metaplasia of hepatocytes indicated by K7 expression in the absence of K19 plays a major role in the development of ductular reaction in FNH. Moreover, the expression of senescence markers (p21Cip1, p16Ink4a, γ-H2AX, SA β-galactosidase activity) in hepatocytes and cholangiocytes suggests that stress-induced cellular senescence contributes to fibrosis and inflammation via production of components of the senescence-associated secretory phenotype. Expression of proliferation markers (Ki-67, PCNA) was not enhanced in hepatocytes and biliary cells. Senescence and ductular metaplasia of hepatocytes may thus be involved in inflammation, fibrosis and apoptosis resistance. Hence, fibrosis, inflammation and reduced apoptotic cell death, rather than proliferation (hyperplasia) may be responsible for increased tissue mass and tumour-like appearance of FNH.
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Affiliation(s)
- Helmut Denk
- Diagnostic & Research Centre of Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria.
| | - Daniela Pabst
- Diagnostic & Research Centre of Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Peter M Abuja
- Diagnostic & Research Centre of Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Robert Reihs
- Diagnostic & Research Centre of Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Brigitte Tessaro
- Diagnostic & Research Centre of Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Kurt Zatloukal
- Diagnostic & Research Centre of Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Carolin Lackner
- Diagnostic & Research Centre of Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
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21
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Ohni S, Yamaguchi H, Hirotani Y, Nakanishi Y, Midorikawa Y, Sugitani M, Naruse H, Nakayama T, Makishima M, Esumi M. Direct molecular evidence for both multicentric and monoclonal carcinogenesis followed by transdifferentiation from hepatocellular carcinoma to cholangiocarcinoma in a case of metachronous liver cancer. Oncol Lett 2022; 23:22. [PMID: 34868359 PMCID: PMC8630812 DOI: 10.3892/ol.2021.13140] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 10/18/2021] [Indexed: 01/21/2023] Open
Abstract
Frequent recurrence is a major issue in liver cancer and histological heterogeneity frequently occurs in this cancer type. However, it has remained elusive whether such cancers are multicentric or monoclonal. To elucidate the clonal evolution of hepatocellular carcinoma (HCC) recurrence and combined hepatocellular-cholangiocarcinoma (cHCC-CCA) development, the somatic mutation frequency and signatures in a patient with triple occurrence of liver cancer every three years were examined, with samples designated as #1HCC, #2HCC and #3cHCC-CCA, respectively. A total of four tumor regions, including HCC (#3HCC) and intrahepatic CCA (#3iCCA) components of #3cHCC-CCA, and three nontumor regions (#1N, #2N and #3N) were precisely dissected from formalin-fixed paraffin-embedded tissues of each surgical specimen. DNA was extracted and subjected to tumor-specific somatic mutation determination. Of note, five nonsynonymous single-nucleotide variants (SNVs), namely those of KMT2D, TP53, DNMT3A, PKHD1 and TLR4, were identified in #3cHCC-CCA. All five SNVs were detected in both #3HCC and #3iCCA and #2HCC but not in #1HCC. The telomerase reverse transcriptase (TERT) promoter mutation C228T, but not C250T, was observed in all tumors. Digital PCR of C228T also indicated the presence of the TERT promoter mutation C228T in nontumorous liver tissues (#1N, #2N and #3N) at a frequency of 0.11-0.83% compared with normal liver and blood samples. These results suggest the following phylogenetic evolution of three metachronous liver cancers: #1HCC was not related to #2HCC, #3HCC and #3iCCA; both #3HCC and #3iCCA arose from #2HCC. From the above, three novel findings were deduced: i) Both multicentric occurrence and intrahepatic metastasis may be involved in liver cancer in a three-year interval; ii) transdifferentiation from HCC to iCCA is a possible pathogenic mechanism of cHCC-CCA; and iii) a nontumorous, noncirrhotic liver may contain a preneoplastic region with a cancer driver mutation in the TERT promoter.
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Affiliation(s)
- Sumie Ohni
- Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Hiromi Yamaguchi
- Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Yukari Hirotani
- Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Yoko Nakanishi
- Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Yutaka Midorikawa
- Department of Surgery, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Masahiko Sugitani
- Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Hiromu Naruse
- Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Tomohiro Nakayama
- Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Makoto Makishima
- Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Mariko Esumi
- Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo 173-8610, Japan
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22
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Zhou T, Kundu D, Robles-Linares J, Meadows V, Sato K, Baiocchi L, Ekser B, Glaser S, Alpini G, Francis H, Kennedy L. Feedback Signaling between Cholangiopathies, Ductular Reaction, and Non-Alcoholic Fatty Liver Disease. Cells 2021; 10:2072. [PMID: 34440841 PMCID: PMC8391272 DOI: 10.3390/cells10082072] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/03/2021] [Accepted: 08/04/2021] [Indexed: 12/12/2022] Open
Abstract
Fatty liver diseases, such as non-alcoholic fatty liver disease (NAFLD), are global health disparities, particularly in the United States, as a result of cultural eating habits and lifestyle. Pathological studies on NAFLD have been mostly focused on hepatocytes and other inflammatory cell types; however, the impact of other biliary epithelial cells (i.e., cholangiocytes) in the promotion of NAFLD is growing. This review article will discuss how cholestatic injury and cholangiocyte activity/ductular reaction influence NAFLD progression. Furthermore, this review will provide informative details regarding the fundamental properties of cholangiocytes and bile acid signaling that can influence NAFLD. Lastly, studies relating to the pathogenesis of NAFLD, cholangiopathies, and ductular reaction will be analyzed to help gain insight for potential therapies.
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Affiliation(s)
- Tianhao Zhou
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
| | - Debjyoti Kundu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
| | - Jonathan Robles-Linares
- Department of Graduate Studies, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - Vik Meadows
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
| | - Keisaku Sato
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
| | - Leonardo Baiocchi
- Liver Unit, Department of Medicine, University of Rome Tor Vergata, 00133 Rome, Italy;
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University, Indianapolis, IN 46202, USA;
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine Bryan, Bryan, TX 77807, USA;
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
- Richard L. Roudebush VA Medical Center, Department of Research, Indianapolis, IN 46202, USA
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
- Richard L. Roudebush VA Medical Center, Department of Research, Indianapolis, IN 46202, USA
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
- Richard L. Roudebush VA Medical Center, Department of Research, Indianapolis, IN 46202, USA
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23
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Liu Y, Xin B, Yamamoto M, Goto M, Ooshio T, Kamikokura Y, Tanaka H, Meng L, Okada Y, Mizukami Y, Nishikawa Y. Generation of combined hepatocellular-cholangiocarcinoma through transdifferentiation and dedifferentiation in p53-knockout mice. Cancer Sci 2021; 112:3111-3124. [PMID: 34051011 PMCID: PMC8353893 DOI: 10.1111/cas.14996] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 05/11/2021] [Accepted: 05/19/2021] [Indexed: 12/29/2022] Open
Abstract
The two principal histological types of primary liver cancers, hepatocellular carcinoma (HCC) and cholangiocarcinoma, can coexist within a tumor, comprising combined hepatocellular‐cholangiocarcinoma (cHCC‐CCA). Although the possible involvement of liver stem/progenitor cells has been proposed for the pathogenesis of cHCC‐CCA, the cells might originate from transformed hepatocytes that undergo ductular transdifferentiation or dedifferentiation. We previously demonstrated that concomitant introduction of mutant HRASV12 (HRAS) and Myc into mouse hepatocytes induced dedifferentiated tumors that expressed fetal/neonatal liver genes and proteins. Here, we examine whether the phenotype of HRAS‐ or HRAS/Myc‐induced tumors might be affected by the disruption of the Trp53 gene, which has been shown to induce biliary differentiation in mouse liver tumors. Hepatocyte‐derived liver tumors were induced in heterozygous and homozygous p53‐knockout (KO) mice by hydrodynamic tail vein injection of HRAS‐ or Myc‐containing transposon cassette plasmids, which were modified by deleting loxP sites, with a transposase‐expressing plasmid. The HRAS‐induced and HRAS/Myc‐induced tumors in the wild‐type mice demonstrated histological features of HCC, whereas the phenotype of the tumors generated in the p53‐KO mice was consistent with cHCC‐CCA. The expression of fetal/neonatal liver proteins, including delta‐like 1, was detected in the HRAS/Myc‐induced but not in the HRAS‐induced cHCC‐CCA tissues. The dedifferentiation in the HRAS/Myc‐induced tumors was more marked in the homozygous p53‐KO mice than in the heterozygous p53‐KO mice and was associated with activation of Myc and YAP and suppression of ERK phosphorylation. Our results suggest that the loss of p53 promotes ductular differentiation of hepatocyte‐derived tumor cells through either transdifferentiation or Myc‐mediated dedifferentiation.
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Affiliation(s)
- Yang Liu
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan.,Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, China
| | - Bing Xin
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Masahiro Yamamoto
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Masanori Goto
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Takako Ooshio
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Yuki Kamikokura
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Hiroki Tanaka
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Lingtong Meng
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Yoko Okada
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Yusuke Mizukami
- Department of Medicine, Cancer Genomics and Precision Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Yuji Nishikawa
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
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24
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Meng L, Goto M, Tanaka H, Kamikokura Y, Fujii Y, Okada Y, Furukawa H, Nishikawa Y. Decreased Portal Circulation Augments Fibrosis and Ductular Reaction in Nonalcoholic Fatty Liver Disease in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:1580-1591. [PMID: 34119474 DOI: 10.1016/j.ajpath.2021.06.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 05/02/2021] [Accepted: 06/03/2021] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease often progresses to cirrhosis and causes liver cancer, but mechanisms of its progression are yet to be elucidated. Although nonalcoholic fatty liver disease is often associated with abnormal portal circulation, there have not been any experimental studies to test its pathogenic role. Here, whether decreased portal circulation affected the pathology of nonalcoholic steatohepatitis (NASH) was examined using congenital portosystemic shunt (PSS) in C57BL/6J mice. Whereas PSS significantly attenuated free radical-mediated carbon tetrachloride injury, it augmented pericellular fibrosis in the centrilobular area induced by a 0.1% methionine choline-deficient l-amino acid-defined high-fat diet (CDAHFD). PSS aggravated ductular reaction and increased the expression of connective tissue growth factor. Pimonidazole immunohistochemistry of the liver revealed that the centrilobular area of PSS-harboring mice was more hypoxic than that of control mice. Although tissue hypoxia was observed in the fibrotic area in CDAHFD-induced NASH in both control and PSS-harboring mice, it was more profound in the latter, which was associated with higher carbonic anhydrase 9 and vascular endothelial growth factor expression and neovascularization in the fibrotic area. Furthermore, partial ligation of the portal vein also augmented pericellular fibrosis and ductular reaction induced by a CDAHFD. These results demonstrate that decreased portal circulation, which induces hypoxia due to disrupted intralobular perfusion, is an important aggravating factor of liver fibrosis in NASH.
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Affiliation(s)
- Lingtong Meng
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan; Division of Gastroenterological and General Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Masanori Goto
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Hiroki Tanaka
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Yuki Kamikokura
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Yumiko Fujii
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Yoko Okada
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Hiroyuki Furukawa
- Division of Gastroenterological and General Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Yuji Nishikawa
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.
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25
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Ooshio T, Yamamoto M, Fujii K, Xin B, Watanabe K, Goto M, Okada Y, Suzuki A, Penninger JM, Nishina H, Nishikawa Y. Hepatocyte Mitogen-Activated Protein Kinase Kinase 7 Contributes to Restoration of the Liver Parenchyma Following Injury in Mice. Hepatology 2021; 73:2510-2526. [PMID: 32969030 PMCID: PMC8252741 DOI: 10.1002/hep.31565] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 08/14/2020] [Accepted: 09/02/2020] [Indexed: 01/23/2023]
Abstract
BACKGROUND AND AIMS Mitogen-activated protein kinase kinase (MKK) 7 and MKK4 are upstream activators of c-Jun NH2 -terminal kinases (JNKs) and have been shown to be required for the early development of the liver. Although it has been suggested that MKK7 might be involved in the regulation of hepatocyte proliferation, the functional role of MKK7 in the liver has remained unclear. APPROACH AND RESULTS Here, we examined phenotypic alterations in liver-specific or hepatocyte/hematopoietic cell-specific MKK7 knockout (KO) mice, which were generated by crossing MKK7LoxP/LoxP with albumin-cyclization recombination (Alb-Cre) or myxovirus resistance protein 1-Cre mice, respectively. The livers of Alb-Cre-/+ MKK7LoxP/LoxP mice developed without discernible tissue disorganization. MKK7 KO mice responded normally to liver injuries incurred by partial hepatectomy or injection of CCl4 . However, tissue repair following CCl4 -induced injury was delayed in MKK7 KO mice compared with that of control mice. Furthermore, after repeated injections of CCl4 for 8 weeks, the liver in MKK7 KO mice showed intense fibrosis with increased protractive hepatocyte proliferation, suggesting that MKK7 deficiency might affect regenerative responses of hepatocytes in the altered tissue microenvironment. MKK7 KO hepatocytes demonstrated normal proliferative activity when cultured in monolayers. However, MKK7 KO significantly suppressed branching morphogenesis of hepatocyte aggregates within a collagen gel matrix. Microarray analyses revealed that suppression of branching morphogenesis in MKK7 KO hepatocytes was associated with a reduction in mRNA expression of transgelin, glioma pathogenesis related 2, and plasminogen activator urokinase-type (Plau); and forced expression of these genes in MKK7 KO hepatocytes partially recovered the attenuated morphogenesis. Furthermore, hepatocyte-specific overexpression of Plau rescued the impaired tissue repair of MKK7 KO mice following CCl4 -induced injury. CONCLUSIONS MKK7 is dispensable for the regenerative proliferation of hepatocytes but plays important roles in repair processes following parenchymal destruction, possibly through modulation of hepatocyte-extracellular matrix interactions.
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Affiliation(s)
- Takako Ooshio
- Division of Tumor PathologyDepartment of PathologyAsahikawa Medical UniversityAsahikawaHokkaidoJapan
| | - Masahiro Yamamoto
- Division of Tumor PathologyDepartment of PathologyAsahikawa Medical UniversityAsahikawaHokkaidoJapan
| | - Kiyonaga Fujii
- Division of Tumor PathologyDepartment of PathologyAsahikawa Medical UniversityAsahikawaHokkaidoJapan
| | - Bing Xin
- Division of Tumor PathologyDepartment of PathologyAsahikawa Medical UniversityAsahikawaHokkaidoJapan
| | - Kenji Watanabe
- Division of Tumor PathologyDepartment of PathologyAsahikawa Medical UniversityAsahikawaHokkaidoJapan,Division of Gastroenterological and General SurgeryDepartment of SurgeryAsahikawa Medical UniversityAsahikawaHokkaidoJapan
| | - Masanori Goto
- Division of Tumor PathologyDepartment of PathologyAsahikawa Medical UniversityAsahikawaHokkaidoJapan
| | - Yoko Okada
- Division of Tumor PathologyDepartment of PathologyAsahikawa Medical UniversityAsahikawaHokkaidoJapan
| | - Akira Suzuki
- Division of Molecular and Cellular BiologyKobe University Graduate School of MedicineKobeHyogoJapan
| | - Josef M. Penninger
- Department of Medical GeneticsLife Sciences InstituteUniversity of British ColumbiaVancouverBCCanada,Institute of Molecular Biotechnology of the Austrian Academy of SciencesViennaAustria
| | - Hiroshi Nishina
- Department of Developmental and Regenerative BiologyMedical Research InstituteTokyo Medical and Dental UniversityBunkyo‐ku, TokyoJapan
| | - Yuji Nishikawa
- Division of Tumor PathologyDepartment of PathologyAsahikawa Medical UniversityAsahikawaHokkaidoJapan
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26
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Wang Z, Faria J, Penning LC, Masereeuw R, Spee B. Tissue-Engineered Bile Ducts for Disease Modeling and Therapy. Tissue Eng Part C Methods 2021; 27:59-76. [PMID: 33267737 DOI: 10.1089/ten.tec.2020.0283] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Recent biotechnical advances in the in vitro culture of cholangiocytes and generation of bioengineered biliary tissue have a high potential for creating biliary tissue to be used for disease modeling, drug screening, and transplantation. For the past few decades, scientists have searched for a source of cholangiocytes, focused on primary cholangiocytes or cholangiocytes derived from hepatocytes or stem cells. At the same time, the development of scaffolds for biliary tissue engineering for transplantation and modeling of cholangiopathies has been explored. In this review, we provide an overview on the current understanding of cholangiocytes sources, the effect of signaling molecules, and transcription factors on cell differentiation, along with the effects of extracellular matrix molecules and scaffolds on bioengineered biliary tissues, and their application in disease modeling and drug screening. Impact statement Over the past few decades, biliary tissue engineering has acquired significant attention, but currently a number of factors hinder this field to eventually generate bioengineered bile ducts that mimic in vivo physiology and are suitable for transplantation. In this review, we present the latest advances with respect to cell source selection, influence of growth factors and scaffolds, and functional characterization, as well as applications in cholangiopathy modeling and drug screening. This review is suited for a broad spectrum of readers, including fundamental liver researchers and clinicians with interest in the current state and application of bile duct engineering and disease modeling.
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Affiliation(s)
- Zhenguo Wang
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.,Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - João Faria
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Louis C Penning
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Rosalinde Masereeuw
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Bart Spee
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
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27
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Abstract
Following injury, the liver's epithelial cells regenerate efficiently with rapid proliferation of hepatocytes and biliary cells. However, when proliferation of resident epithelial cells is impaired, alternative regeneration mechanisms can occur. Intricate lineage-tracing strategies and experimental models of regenerative stress have revealed a degree of plasticity between hepatocytes and biliary cells. New technologies such as single-cell omics, in combination with functional studies, will be instrumental to uncover the remaining unknowns in the field. In this review, we evaluate the experimental and clinical evidence for epithelial plasticity in the liver and how this influences the development of therapeutic strategies for chronic liver disease.
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Affiliation(s)
- Victoria L Gadd
- Centre for Regenerative Medicine, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, EH16 4UU, UK
| | - Niya Aleksieva
- Centre for Regenerative Medicine, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, EH16 4UU, UK
| | - Stuart J Forbes
- Centre for Regenerative Medicine, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, EH16 4UU, UK.
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28
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Kamimoto K, Nakano Y, Kaneko K, Miyajima A, Itoh T. Multidimensional imaging of liver injury repair in mice reveals fundamental role of the ductular reaction. Commun Biol 2020; 3:289. [PMID: 32503996 PMCID: PMC7275065 DOI: 10.1038/s42003-020-1006-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 05/12/2020] [Indexed: 02/07/2023] Open
Abstract
Upon severe and/or chronic liver injury, ectopic emergence and expansion of atypical biliary epithelial-like cells in the liver parenchyma, known as the ductular reaction, is typically induced and implicated in organ regeneration. Although this phenomenon has long been postulated to represent activation of facultative liver stem/progenitor cells that give rise to new hepatocytes, recent lineage-tracing analyses have challenged this notion, thereby leaving the pro-regenerative role of the ductular reaction enigmatic. Here, we show that the expanded and remodelled intrahepatic biliary epithelia in the ductular reaction constituted functional and complementary bile-excreting conduit systems in injured parenchyma where hepatocyte bile canalicular networks were lost. The canalicular collapse was an incipient defect commonly associated with hepatocyte injury irrespective of cholestatic statuses, and could sufficiently provoke the ductular reaction when artificially induced. We propose a unifying model for the induction of the ductular reaction, where compensatory biliary epithelial tissue remodeling ensures bile-excreting network homeostasis. Kenji Kamimoto et al. use multidimensional imaging technologies to study changes in the mouse biliary system following liver injury. They find an unexpected role of the ductular reaction – the process of ectopic expansion of biliary-like cells following liver injury – in restoring functional biliary structures in injured livers.
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Affiliation(s)
- Kenji Kamimoto
- Laboratory of Stem Cell Therapy, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.,Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
| | - Yasuhiro Nakano
- Laboratory of Stem Cell Therapy, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan
| | - Kota Kaneko
- Laboratory of Stem Cell Therapy, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.,Department of Pathology, University of California San Diego, La Jolla, CA, 92093, USA
| | - Atsushi Miyajima
- Laboratory of Stem Cell Therapy, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan
| | - Tohru Itoh
- Laboratory of Stem Cell Therapy, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
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29
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Wang G, Wang Q, Liang N, Xue H, Yang T, Chen X, Qiu Z, Zeng C, Sun T, Yuan W, Liu C, Chen Z, He X. Oncogenic driver genes and tumor microenvironment determine the type of liver cancer. Cell Death Dis 2020; 11:313. [PMID: 32366840 PMCID: PMC7198508 DOI: 10.1038/s41419-020-2509-x] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 04/10/2020] [Accepted: 04/14/2020] [Indexed: 02/06/2023]
Abstract
Primary liver cancer (PLC) may be mainly classified as the following four types: hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), hepatoblastoma (HB), and combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma (cHCC-ICC). The majority of PLC develops in the background of tumor microenvironment, such as inflammatory microenvironments caused by viral hepatitis, alcoholic or nonalcoholic steatohepatitis, carbon tetrachloride (CCl4), 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), and necroptosis-associated hepatic cytokine microenvironment caused by necroptosis of hepatocytes. However, the impact of different types of microenvironments on the phenotypes of PLC generated by distinct oncogenes is still unclear. In addition, the cell origin of different liver cancers have not been clarified, as far as we know. Recent researches show that mature hepatocytes retain phenotypic plasticity to differentiate into cholangiocytes. More importantly, our results initially demonstrated that HCC, ICC, and cHCC-ICC could originate from mature hepatocytes rather than liver progenitor cells (LPCs), hepatic stellate cells (HSCs) and cholangiocytes in AKT-driven, AKT/NICD-driven and AKT/CAT-driven mouse PLC models respectively by using hydrodynamic transfection methodology. Therefore, liver tumors originated from mature hepatocytes embody a wide spectrum of phenotypes from HCC to CC, possibly including cHCC-ICC and HB. However, the underlying mechanism determining the cancer phenotype of liver tumors has yet to be delineated. In this review, we will provide a summary of the possible mechanisms for directing the cancer phenotype of liver tumors (i.e., ICC, HCC, and cHCC-ICC) in terms of oncogenic driver genes and tumor microenvironment. Moreover, this study initially revealed the cell origin of different types of liver cancer.
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Affiliation(s)
- Gang Wang
- Department of General Surgery, The 74th Group Army Hospital, Guangzhou, 510220, China.,Department of General Surgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Qian Wang
- Department of General Surgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.,Department of Anorectal Surgery, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China
| | - Ning Liang
- Department of General Surgery, The 75th Group Army Hospital, Dali, 671000, China
| | - Hongyuan Xue
- Department of General Surgery, Huashan North Hospital, Fudan University, Shanghai, 201907, China
| | - Tao Yang
- Department of Pain Treatment, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710032, Shanxi, China
| | - Xuguang Chen
- Department of Dermatology, Dermatology Hospital of Southern Medical University, Guangzhou, 510091, China
| | - Zhaoyan Qiu
- Department of General Surgery, Chinese PLA General Hospital, Beijing, China
| | - Chao Zeng
- Department of Cardiology, The 74th Group Army Hospital, Guangzhou, 510318, China
| | - Tao Sun
- Departmentof Neurosurgery, First Affiliated Hospital, Zhengzhou University, Zheng zhou, 450052, China
| | - Weitang Yuan
- Department of Anorectal Surgery, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China
| | - Chaoxu Liu
- Department of General Surgery, Huashan North Hospital, Fudan University, Shanghai, 201907, China. .,Department of Anorectal Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, 310003, China.
| | - Zhangqian Chen
- Department of Infectious Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China. .,State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Xianli He
- Department of General Surgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.
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30
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Ko S, Russell JO, Molina LM, Monga SP. Liver Progenitors and Adult Cell Plasticity in Hepatic Injury and Repair: Knowns and Unknowns. ANNUAL REVIEW OF PATHOLOGY 2020; 15:23-50. [PMID: 31399003 PMCID: PMC7212705 DOI: 10.1146/annurev-pathmechdis-012419-032824] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The liver is a complex organ performing numerous vital physiological functions. For that reason, it possesses immense regenerative potential. The capacity for repair is largely attributable to the ability of its differentiated epithelial cells, hepatocytes and biliary epithelial cells, to proliferate after injury. However, in cases of extreme acute injury or prolonged chronic insult, the liver may fail to regenerate or do so suboptimally. This often results in life-threatening end-stage liver disease for which liver transplantation is the only effective treatment. In many forms of liver injury, bipotent liver progenitor cells are theorized to be activated as an additional tier of liver repair. However, the existence, origin, fate, activation, and contribution to regeneration of liver progenitor cells is hotly debated, especially since hepatocytes and biliary epithelial cells themselves may serve as facultative stem cells for one another during severe liver injury. Here, we discuss the evidence both supporting and refuting the existence of liver progenitor cells in a variety of experimental models. We also debate the validity of developing therapies harnessing the capabilities of these cells as potential treatments for patients with severe and chronic liver diseases.
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Affiliation(s)
- Sungjin Ko
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
| | - Jacquelyn O Russell
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
| | - Laura M Molina
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
| | - Satdarshan P Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
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31
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Jia WJ, Tang QL, Jiang S, Sun SQ, Xue B, Qiu YD, Li CJ, Mao L. Conditional loss of geranylgeranyl diphosphate synthase alleviates acute obstructive cholestatic liver injury by regulating hepatic bile acid metabolism. FEBS J 2020; 287:3328-3345. [PMID: 31905247 DOI: 10.1111/febs.15204] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 10/31/2019] [Accepted: 01/04/2020] [Indexed: 12/12/2022]
Abstract
Previous studies have suggested that metabolites in the mevalonate pathway are involved in hepatic bile acid metabolism, yet the details of this relationship remain unknown. In this study, we found that the hepatic farnesyl pyrophosphate (FPP) level and the ratio of FPP to geranylgeranyl pyrophosphate (GGPP) were increased in mice with acute obstructive cholestasis compared with mice that underwent a sham operation. In addition, the livers of the mice with acute obstructive cholestasis showed lower expression of geranylgeranyl diphosphate synthase (GGPPS), which synthesizes GGPP from FPP. When Ggps1 was conditionally deleted in the liver, amelioration of liver injury, as shown by downregulation of the hepatic inflammatory response and decreased hepatocellular apoptosis, was found after ligation of the common bile duct and cholecystectomy (BDLC). Subsequently, liquid chromatography/mass spectrometry analysis showed that knocking out Ggps1 decreased the levels of hepatic bile acids, including hydrophobic bile acids. Mechanistically, the disruption of Ggps1 increased the levels of hepatic FPP and its metabolite farnesol, thereby resulting in farnesoid X receptor (FXR) activation, which modulated hepatic bile acid metabolism and reduced hepatic bile acids. It was consistently indicated that digeranyl bisphosphonate, a specific inhibitor of GGPPS, and GW4064, an agonist of FXR, could also alleviate acute obstructive cholestatic liver injury in vivo. In general, GGPPS is critical for modulating acute obstructive cholestatic liver injury, and the inhibition of GGPPS ameliorates acute obstructive cholestatic liver injury by decreasing hepatic bile acids, which is possibly achieved through the activation of FXR-induced bile acid metabolism.
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Affiliation(s)
- Wen-Jun Jia
- Department of General Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, China.,Ministry of Education Key Laboratory of Model Animal for Disease Study, the School of Medicine and Model Animal Research Center of Nanjing University, China.,Department of General Surgery, the Affiliated Drum Tower Hospital of Medical School of Nanjing University, China
| | - Qiao-Li Tang
- Ministry of Education Key Laboratory of Model Animal for Disease Study, the School of Medicine and Model Animal Research Center of Nanjing University, China
| | - Shan Jiang
- Ministry of Education Key Laboratory of Model Animal for Disease Study, the School of Medicine and Model Animal Research Center of Nanjing University, China
| | - Shi-Quan Sun
- Department of General Surgery, the Affiliated Drum Tower Hospital of Medical School of Nanjing University, China
| | - Bin Xue
- Core Laboratory, Sir Run Run Hospital, Nanjing Medical University, China.,State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Yu-Dong Qiu
- Department of General Surgery, the Affiliated Drum Tower Hospital of Medical School of Nanjing University, China
| | - Chao-Jun Li
- Ministry of Education Key Laboratory of Model Animal for Disease Study, the School of Medicine and Model Animal Research Center of Nanjing University, China
| | - Liang Mao
- Department of General Surgery, the Affiliated Drum Tower Hospital of Medical School of Nanjing University, China
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32
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Sasaki T, Suzuki Y, Kakisaka K, Wang T, Ishida K, Suzuki A, Abe H, Sugai T, Takikawa Y. IL-8 induces transdifferentiation of mature hepatocytes toward the cholangiocyte phenotype. FEBS Open Bio 2019; 9:2105-2116. [PMID: 31651102 PMCID: PMC6886300 DOI: 10.1002/2211-5463.12750] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 09/28/2019] [Accepted: 10/22/2019] [Indexed: 01/20/2023] Open
Abstract
The adult mammalian liver exhibits a remarkable regenerative capacity, with different modes of regeneration according to the type and extent of injury. Hepatocyte–cholangiocyte biphenotypic liver progenitor cell populations appear under conditions of excessive injury. It has been reported that mature hepatocytes can transdifferentiate toward a cholangiocyte phenotype and be a cellular source of progenitor cell populations. Here, we determined that among various plasma cytokines, interleukin (IL)‐8 levels were significantly elevated in acute liver failure and severe acute liver injury patients. In vitro assays revealed that administration of IL‐8 homologues increases the expression of Sry HMG box protein 9 (SOX9). In liver biopsies of acute liver injury patients, we observed the appearance of SOX9‐positive biphenotypic hepatocytes accompanied by elevation of plasma IL‐8 levels. Our results suggest that IL‐8 regulates the phenotypic conversion of mature hepatocytes toward a cholangiocyte phenotype. Interleukin (IL)‐8 treated mouse mature hepatocytes expressed Sry HMG box protein 9 (SOX9), a bile duct‐associated marker. In liver biopsies of acute liver injury patients, SOX9‐positive biphenotypic hepatocytes appeared in the liver parenchyma which is accompanied by elevation of plasma IL‐8 levels. Our results suggest that IL‐8 regulates the phenotypic conversion of mature hepatocytes toward a cholangiocyte phenotype.![]()
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Affiliation(s)
- Tokio Sasaki
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan
| | - Yuji Suzuki
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan
| | - Keisuke Kakisaka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan
| | - Ting Wang
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan
| | - Kazuyuki Ishida
- Department of Molecular Diagnostic Pathology, Iwate Medical University School of Medicine, Morioka, Japan
| | - Akiko Suzuki
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan
| | - Hiroaki Abe
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, Iwate Medical University School of Medicine, Morioka, Japan
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan
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33
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Kim HG, Huang M, Xin Y, Zhang Y, Zhang X, Wang G, Liu S, Wan J, Ahmadi AR, Sun Z, Liangpunsakul S, Xiong X, Dong XC. The epigenetic regulator SIRT6 protects the liver from alcohol-induced tissue injury by reducing oxidative stress in mice. J Hepatol 2019; 71:960-969. [PMID: 31295533 PMCID: PMC6801027 DOI: 10.1016/j.jhep.2019.06.019] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 05/29/2019] [Accepted: 06/24/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS As a nicotinamide adenine dinucleotide-dependent deacetylase and a key epigenetic regulator, sirtuin 6 (SIRT6) has been implicated in the regulation of metabolism, DNA repair, and inflammation. However, the role of SIRT6 in alcohol-related liver disease (ALD) remains unclear. The aim of this study was to investigate the function and mechanism of SIRT6 in ALD pathogenesis. METHODS We developed and characterized Sirt6 knockout (KO) and transgenic mouse models that were treated with either control or ethanol diet. Hepatic steatosis, inflammation, and oxidative stress were analyzed using biochemical and histological methods. Gene regulation was analyzed by luciferase reporter and chromatin immunoprecipitation assays. RESULTS The Sirt6 KO mice developed severe liver injury characterized by a remarkable increase of oxidative stress and inflammation, whereas the Sirt6 transgenic mice were protected from ALD via normalization of hepatic lipids, inflammatory response, and oxidative stress. Our molecular analysis has identified a number of novel Sirt6-regulated genes that are involved in antioxidative stress, including metallothionein 1 and 2 (Mt1 and Mt2). Mt1/2 genes were downregulated in the livers of Sirt6 KO mice and patients with alcoholic hepatitis. Overexpression of Mt1 in the liver of Sirt6 KO mice improved ALD by reducing hepatic oxidative stress and inflammation. We also identified a critical link between SIRT6 and metal regulatory transcription factor 1 (Mtf1) via a physical interaction and functional coactivation. Mt1/2 promoter reporter assays showed a strong synergistic effect of SIRT6 on the transcriptional activity of Mtf1. CONCLUSIONS Our data suggest that SIRT6 plays a critical protective role against ALD and it may serve as a potential therapeutic target for ALD. LAY SUMMARY The liver, the primary organ for ethanol metabolism, can be damaged by the byproducts of ethanol metabolism, including reactive oxygen species. In this study, we have identified a key epigenetic regulator SIRT6 that plays a critical role in protecting the liver from oxidative stress-induced liver injury. Thus, our data suggest that SIRT6 may be a potential therapeutic target for alcohol-related liver disease.
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Affiliation(s)
- Hyeong Geug Kim
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
| | - Menghao Huang
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.,Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
| | - Yue Xin
- School of Forensic Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, P.R. China,Xinxiang Key Laboratory of Metabolism and Integrative Physiology, Xinxiang Medical University, Xinxiang, Henan, 453003, P.R. China
| | - Yang Zhang
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
| | - Xinge Zhang
- School of Forensic Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, P.R. China,Xinxiang Key Laboratory of Metabolism and Integrative Physiology, Xinxiang Medical University, Xinxiang, Henan, 453003, P.R. China
| | - Gaihong Wang
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
| | - Sheng Liu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
| | - Jun Wan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.,Center of Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
| | - Ali Reza Ahmadi
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Zhaoli Sun
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.,Roudebush Veterans Administration Medical Center, Indianapolis, Indiana 46202, USA
| | - Xiwen Xiong
- School of Forensic Medicine, Xinxiang Medical University, Xinxiang, Henan 453003, PR China; Xinxiang Key Laboratory of Metabolism and Integrative Physiology, Xinxiang Medical University, Xinxiang, Henan 453003, PR China.
| | - Xiaocheng Charlie Dong
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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Shiojiri N, Tanaka S, Kawakami H. The hepatic architecture of the coelacanth differs from that of the lungfish in portal triad formation. Okajimas Folia Anat Jpn 2019; 96:1-11. [PMID: 31462619 DOI: 10.2535/ofaj.96.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The liver architecture of vertebrates can be classified into two types, the portal triad type (having periportal bile ducts) and the non-portal triad type (having non-periportal bile ducts). The former is detectable in the tetrapod liver whereas the lungfish liver has the latter. It remains to be revealed which type of hepatic architecture the coelacanth, which together with the lungfish belongs to the Sarcopterygii, possesses. The present study was undertaken to determine the histological characteristics of the coelacanth liver, and to compare with those of other vertebrates. The coelacanth liver had periportal bile ducts and ductules as detected in mammalian livers. The hepatic artery was found around large portal veins. Hagfish, shark, bichir, sturgeon, bowfin and frog livers had periportal bile ducts and bile ductules, whereas most intrahepatic bile ducts of the lungfish were independent of the distribution of the portal veins as seen in the Otocephala and Euteleostei. The lungfish liver developed duct and ductule structures in the parenchyma. These data indicate that the coelacanth liver had a mammalian-type hepatic architecture with a portal triad, and that the ancestors of tetrapods may have had a portal triad-type liver architecture.
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Affiliation(s)
| | - Sho Tanaka
- Department of Marine Biology, School of Marine Science and Technology, Tokai University
| | - Hayato Kawakami
- Laboratory for Electron Microscopy, Kyorin University School of Medicine.,Department of Anatomy, Kyorin University School of Medicine
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35
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Abstract
Introduction: Liver disease is an increasing cause of worldwide mortality, and currently the only curative treatment for end-stage liver disease is whole organ allograft transplantation. Whilst this is an effective treatment, there is a shortage of suitable grafts and consequently some patients die whilst on the waiting list. Cell therapy provides an alternative treatment to increase liver function and potentially ameliorate fibrosis. Areas covered: In this review, we discuss the different cellular sources for therapy investigated to date in humans including mature hepatocytes, hematopoietic stem cells, mesenchymal stromal cells and hepatic progenitor cells. Cells investigated in animals include embryonic stem cells, induced pluripotent stem cells and directly reprogrammed cells. We then appraise the experience and evidence base underlying each cell type. Expert opinion: We discuss how this field may evolve in the years to come focusing on opportunities to enhance the intrinsic regenerative response with therapeutic targets and cell therapies. Growing expertise in tissue engineering will likely lead to increasingly complex bio-reactors and bio-artificial livers, which open a further avenue to restore liver function and delay or prevent the need for transplantation.
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Affiliation(s)
- Alexander Boyd
- a NIHR Birmingham Biomedical Research Centre , University Hospitals Birmingham NHS Foundation Trust and University of Birmingham , Birmingham , UK.,b Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy , University of Birmingham , Birmingham , UK.,c Liver Unit , University Hospitals Birmingham NHS Foundation Trust , Birmingham , UK
| | - Philip Newsome
- a NIHR Birmingham Biomedical Research Centre , University Hospitals Birmingham NHS Foundation Trust and University of Birmingham , Birmingham , UK.,b Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy , University of Birmingham , Birmingham , UK.,c Liver Unit , University Hospitals Birmingham NHS Foundation Trust , Birmingham , UK
| | - Wei-Yu Lu
- b Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy , University of Birmingham , Birmingham , UK
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36
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Sun M, Wong JY, Nugraha B, Ananthanarayanan A, Liu Z, Lee F, Gupta K, Fong EL, Huang X, Yu H. Cleavable cellulosic sponge for functional hepatic cell culture and retrieval. Biomaterials 2019; 201:16-32. [DOI: 10.1016/j.biomaterials.2019.01.046] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 01/18/2019] [Accepted: 01/20/2019] [Indexed: 12/27/2022]
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Abstract
It has been demonstrated that the liver remarkably alter its tissue structures during regeneration, and various types of liver stem or progenitor cells locating in specific areas in the liver tissue contribute to regeneration. Therefore, it is important to analyze the dynamic rearrangement of the liver tissue structures in 3D for better understanding the process and mechanism of liver regeneration. Here we describe a macroscopic analysis method to visualize the whole 3D structure of the vasculatures and the biliary tree, which are dynamically remodeled during regeneration, and a microscopic analysis method to visualize detailed structures at the cellular level, which can compensate what cannot be detected in the macroscopic analysis.
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38
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De novo formation of the biliary system by TGFβ-mediated hepatocyte transdifferentiation. Nature 2018; 557:247-251. [PMID: 29720662 PMCID: PMC6597492 DOI: 10.1038/s41586-018-0075-5] [Citation(s) in RCA: 211] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2016] [Accepted: 03/22/2018] [Indexed: 12/15/2022]
Abstract
Transdifferentiation is a complete and stable change in cell identity that serves as an alternative to stem-cell-mediated organ regeneration. In adult mammals, findings of transdifferentiation have been limited to the replenishment of cells lost from preexisting structures, in the presence of a fully developed scaffold and niche1. Here we show that transdifferentiation of hepatocytes in the mouse liver can build a structure that failed to form in development-the biliary system in a mouse model that mimics the hepatic phenotype of human Alagille syndrome (ALGS)2. In these mice, hepatocytes convert into mature cholangiocytes and form bile ducts that are effective in draining bile and persist after the cholestatic liver injury is reversed, consistent with transdifferentiation. These findings redefine hepatocyte plasticity, which appeared to be limited to metaplasia, that is, incomplete and transient biliary differentiation as an adaptation to cell injury, based on previous studies in mice with a fully developed biliary system3-6. In contrast to bile duct development7-9, we show that de novo bile duct formation by hepatocyte transdifferentiation is independent of NOTCH signalling. We identify TGFβ signalling as the driver of this compensatory mechanism and show that it is active in some patients with ALGS. Furthermore, we show that TGFβ signalling can be targeted to enhance the formation of the biliary system from hepatocytes, and that the transdifferentiation-inducing signals and remodelling capacity of the bile-duct-deficient liver can be harnessed with transplanted hepatocytes. Our results define the regenerative potential of mammalian transdifferentiation and reveal opportunities for the treatment of ALGS and other cholestatic liver diseases.
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Shiojiri N, Kametani H, Ota N, Akai Y, Fukuchi T, Abo T, Tanaka S, Sekiguchi J, Matsubara S, Kawakami H. Phylogenetic analyses of the hepatic architecture in vertebrates. J Anat 2017; 232:200-213. [PMID: 29205342 DOI: 10.1111/joa.12749] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2017] [Indexed: 12/18/2022] Open
Abstract
The mammalian liver has a structural and functional unit called the liver lobule, in the periphery of which the portal triad consisting of the portal vein, bile duct and hepatic artery is developed. This type of hepatic architecture is detectable in many other vertebrates, including amphibians and birds, whereas intrahepatic bile ducts run independently of portal vein distribution in actinopterygians such as the salmon and tilapia. It remains to be clarified how the hepatic architectures are phylogenetically developed among vertebrates. The present study morphologically and immunohistochemically analyzed the hepatic structures of various vertebrates, including as many classes and subclasses as possible, with reference to intrahepatic bile duct distribution. The livers of vertebrates belonging to the Agnatha, Chondrichthyes, Amphibia, Aves, Mammalia, and Actinopterygii before Elopomorpha, had the portal triad-type architecture. The Anguilliformes livers developed both periportal bile ducts and non-periportal bile ducts. The Otocephala and Euteleostei livers had independent configuration of bile ducts and portal veins. Pancreatic tissues penetrated the liver parenchyma along portal veins in the Euteleostei. The liver of the lungfish, which shares the same origin with amphibians, did not have the portal triad-type architecture. Teleostei and lungfish livers had ductular development in the liver parenchyma similar to oval cell proliferation in injured mammalian livers. Euteleostei livers had penetration of significant numbers of independent portal veins from their intestines, suggesting that each liver lobe might receive a different blood supply. The hepatic architectures of the portal triad-type changed to non-portal triad-type architecture along the evolution of the Actinopterygii. The hepatic architecture of the lungfish resembles that of the Actinopterygii after Elopomorpha in intrahepatic biliary configuration, which may be an example of convergent evolution.
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Affiliation(s)
- Nobuyoshi Shiojiri
- Department of Biology, Faculty of Science, Shizuoka University, Shizuoka, Japan
| | - Harunobu Kametani
- Department of Biology, Faculty of Science, Shizuoka University, Shizuoka, Japan
| | - Noriaki Ota
- Department of Biology, Faculty of Science, Shizuoka University, Shizuoka, Japan
| | - Yusuke Akai
- Department of Biology, Faculty of Science, Shizuoka University, Shizuoka, Japan
| | - Tomokazu Fukuchi
- Department of Biology, Faculty of Science, Shizuoka University, Shizuoka, Japan
| | - Tomoka Abo
- Department of Biology, Faculty of Science, Shizuoka University, Shizuoka, Japan
| | - Sho Tanaka
- Department of Marine Biology, School of Marine Science and Technology, Tokai University, Shizuoka, Japan
| | - Junri Sekiguchi
- Laboratory for Electron Microscopy, Kyorin University School of Medicine, Mitaka, Japan.,Department of Anatomy, Kyorin University School of Medicine, Mitaka, Japan
| | - Sachie Matsubara
- Laboratory for Electron Microscopy, Kyorin University School of Medicine, Mitaka, Japan.,Department of Anatomy, Kyorin University School of Medicine, Mitaka, Japan
| | - Hayato Kawakami
- Laboratory for Electron Microscopy, Kyorin University School of Medicine, Mitaka, Japan.,Department of Anatomy, Kyorin University School of Medicine, Mitaka, Japan
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Yamamoto M, Xin B, Watanabe K, Ooshio T, Fujii K, Chen X, Okada Y, Abe H, Taguchi Y, Miyokawa N, Furukawa H, Nishikawa Y. Oncogenic Determination of a Broad Spectrum of Phenotypes of Hepatocyte-Derived Mouse Liver Tumors. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:2711-2725. [PMID: 28964793 DOI: 10.1016/j.ajpath.2017.07.022] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 06/27/2017] [Accepted: 07/28/2017] [Indexed: 12/11/2022]
Abstract
Activation of the phosphoinositide 3-kinase-AKT, Yes-associated protein (YAP), and MYC pathways is involved in human liver cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). However, the nature of the interactions among these pathways has remained poorly understood. Herein, we demonstrate the coordination of these pathways during the formation of mouse liver tumors induced by hepatocyte-specific somatic integration of myristoylated AKT, mutant YAP, Myc, or their combinations. Although the introduction of YAP or Myc alone was inefficient in inducing tumors, these proteins accelerated tumorigenesis induced by AKT. The generated tumors demonstrated various histological features: low-grade HCC by AKT/Myc, CC by AKT/YAP, and high-grade HCC by AKT/Myc/YAP. CC induced by AKT/YAP was associated with activation of the Notch pathway. Interestingly, the combination of Myc and YAP generated tumors composed of hepatoblast/stem-like cells expressing mRNA for Afp, Dlk1, Nanog, and Sox2 and occasionally forming immature ducts. Finally, immunohistochemical analysis revealed that human HCC and CC were predominantly associated with phosphorylation of S6 and glycogen synthase kinase-3β, respectively, and >60% of CC cases were positive for both phosphorylated glycogen synthase kinase--3β and YAP. Our study suggests that hepatocyte-derived tumors demonstrate a wide spectrum of tumor phenotypes, including HCC, CC, and hepatoblastoma-like, through the combinatory effects of the oncogenic pathways and that the state of the phosphoinositide 3-kinase-AKT pathway is a key determinant of differentiation.
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Affiliation(s)
- Masahiro Yamamoto
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Bing Xin
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Kenji Watanabe
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan; Division of Gastroenterological and General Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Takako Ooshio
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Kiyonaga Fujii
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Xi Chen
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Yoko Okada
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Hiroaki Abe
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Yoshimitsu Taguchi
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Naoyuki Miyokawa
- Department of Surgical Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Hiroyuki Furukawa
- Division of Gastroenterological and General Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Yuji Nishikawa
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.
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41
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A label-retaining but unipotent cell population resides in biliary compartment of mammalian liver. Sci Rep 2017; 7:40322. [PMID: 28084309 PMCID: PMC5234023 DOI: 10.1038/srep40322] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 12/05/2016] [Indexed: 12/17/2022] Open
Abstract
Cells with slow proliferation kinetics that retain the nuclear label over long time periods-the label-retaining cells (LRCs)-represent multipotent stem cells in a number of adult tissues. Since the identity of liver LRCs (LLRCs) had remained elusive we utilized a genetic approach to reveal LLRCs in normal non-injured livers and characterized their regenerative properties in vivo and in culture. We found that LLRCs were located in biliary vessels and participated in the regeneration of biliary but not hepatocyte injury. In culture experiments the sorted LLRCs displayed an enhanced self-renewal capacity but a unipotent biliary differentiation potential. Transcriptome analysis revealed a unique set of tumorigenesis- and nervous system-related genes upregulated in LLRCs when compared to non-LRC cholangiocytes. We conclude that the LLRCs established during the normal morphogenesis of the liver do not represent a multipotent primitive somatic stem cell population but act as unipotent biliary progenitor cells.
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42
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Progressive induction of hepatocyte progenitor cells in chronically injured liver. Sci Rep 2017; 7:39990. [PMID: 28051157 PMCID: PMC5209740 DOI: 10.1038/srep39990] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 11/30/2016] [Indexed: 12/19/2022] Open
Abstract
Differentiated epithelial cells show substantial lineage plasticity upon severe tissue injuries. In chronically injured mouse livers, part of hepatocytes become Sry-HMG box containing 9 (Sox9) (+) epithelial cell adhesion molecule (−) hepatocyte nuclear factor 4 α (+) biphenotypic hepatocytes. However, it is not clear whether all Sox9+ hepatocytes uniformly possess cellular properties as hepatocyte progenitors. Here, we examined the microarray data comparing Sox9+ hepatocytes with mature hepatocytes and identified CD24 as a novel marker for biphenotypic hepatocytes. Immunohistochemical analyses showed that part of Sox9+ hepatocytes near expanded ductular structures expressed CD24 in the liver injured by 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC) diet and by bile duct ligation. Indeed, Sox9+ hepatocytes could be separated into CD24− and CD24+ cells by fluorescence activated cell sorting. The ratio of CD24+ cells against CD24− ones in Sox9+ hepatocytes gradually increased while DDC-injury progressed and colony-forming capability mostly attributed to CD24+ cells. Although hepatocyte markers were remarkably downregulated in of Sox9+ CD24+ hepatocytes, they re-differentiated into mature hepatocytes in vitro and in vivo. Our current results demonstrate that the emergence of biphenotypic hepatocytes is a sequential event including the transition from CD24− and CD24+ status, which may be a crucial step for hepatocytes to acquire progenitor properties.
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Suzuki Y, Katagiri H, Wang T, Kakisaka K, Kume K, Nishizuka SS, Takikawa Y. Ductular reactions in the liver regeneration process with local inflammation after physical partial hepatectomy. J Transl Med 2016; 96:1211-1222. [PMID: 27617400 DOI: 10.1038/labinvest.2016.97] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Revised: 07/27/2016] [Accepted: 08/09/2016] [Indexed: 01/06/2023] Open
Abstract
Partial hepatectomy models in mice have been widely used for liver regeneration studies. A typical procedure removes ~2/3 of the liver by lobular ligation without tissue dissection. However, hepatectomy in humans involves physical damage (ie, physical partial hepatectomy, PPHx). Therefore, the liver regeneration process after PPHx should involve reactions to acute local injury followed by systematic remodeling. To clarify the liver regeneration process after PPHx, we used a murine liver injury model that mimics the actual human surgical procedure. A 20-30% PPHx was performed by transection of the left lobe of the liver using an ultrasonically activated scalpel in mice. Gene expression and morphological characteristics were analyzed during the liver regeneration process. Liver weight continuously increased by hypertrophic reaction of hepatocytes, whereas Ki67 staining showed hepatocyte proliferation. At the transected border, emergence of ductular reactions, a representative process of hepatic tissue remodeling that contain liver stem/progenitor cells, were observed. Gene expression of the transected border and non-damaged lobes revealed that inflammatory cytokine- and extracellular matrix-associated genes were significantly upregulated at the transected border. Our PPHx model triggered local extracellular matrix remodeling that resulted in ductular reactions. These processes occurred during the tissue repair process in local inflammatory responses as well as compensatory hepatocyte hypertrophy of the entire liver. These findings may provide insight for elucidating the mechanism of tissue repair and regeneration of the liver after PPHx.
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Affiliation(s)
- Yuji Suzuki
- Molecular Therapeutics Laboratory, Department of Surgery, School of Medicine, Iwate Medical University, Morioka, Japan.,Division of Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Hirokatsu Katagiri
- Molecular Therapeutics Laboratory, Department of Surgery, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Ting Wang
- Division of Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Keisuke Kakisaka
- Division of Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Kohei Kume
- Molecular Therapeutics Laboratory, Department of Surgery, School of Medicine, Iwate Medical University, Morioka, Japan.,Institute of Biomedical Sciences, Iwate Medical University, Yahaba, Japan
| | - Satoshi S Nishizuka
- Molecular Therapeutics Laboratory, Department of Surgery, School of Medicine, Iwate Medical University, Morioka, Japan.,Institute of Biomedical Sciences, Iwate Medical University, Yahaba, Japan
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
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Kaji K, Factor VM, Andersen JB, Durkin ME, Tomokuni A, Marquardt JU, Matter MS, Hoang T, Conner EA, Thorgeirsson SS. DNMT1 is a required genomic regulator for murine liver histogenesis and regeneration. Hepatology 2016; 64:582-98. [PMID: 26999257 PMCID: PMC5841553 DOI: 10.1002/hep.28563] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 02/18/2016] [Accepted: 03/15/2016] [Indexed: 12/11/2022]
Abstract
UNLABELLED DNA methyltransferase 1 (DNMT1) is an essential regulator maintaining both epigenetic reprogramming during DNA replication and genome stability. We investigated the role of DNMT1 in the regulation of postnatal liver histogenesis under homeostasis and stress conditions. We generated Dnmt1 conditional knockout mice (Dnmt1(Δalb) ) by crossing Dnmt1(fl/fl) with albumin-cyclization recombination transgenic mice. Serum, liver tissues, and primary hepatocytes were collected from 1-week-old to 20-week old mice. The Dnmt1(Δalb) phenotype was assessed by histology, confocal and electron microscopy, biochemistry, as well as transcriptome and methylation profiling. Regenerative growth was induced by partial hepatectomy and exposure to carbon tetrachloride. The impact of Dnmt1 knockdown was also analyzed in hepatic progenitor cell lines; proliferation, apoptosis, DNA damage, and sphere formation were assessed. Dnmt1 loss in postnatal hepatocytes caused global hypomethylation, enhanced DNA damage response, and initiated a senescence state causing a progressive inability to maintain tissue homeostasis and proliferate in response to injury. The liver regenerated through activation and repopulation from progenitors due to lineage-dependent differences in albumin-cyclization recombination expression, providing a basis for selection of less mature and therefore less damaged hepatic progenitor cell progeny. Consistently, efficient knockdown of Dnmt1 in cultured hepatic progenitor cells caused severe DNA damage, cell cycle arrest, senescence, and cell death. Mx1-cyclization recombination-driven deletion of Dnmt1 in adult quiescent hepatocytes did not affect liver homeostasis. CONCLUSION These results establish the indispensable role of DNMT1-mediated epigenetic regulation in postnatal liver growth and regeneration; Dnmt1(Δalb) mice provide a unique experimental model to study the role of senescence and the contribution of progenitor cells to physiological and regenerative liver growth. (Hepatology 2016;64:582-598).
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Affiliation(s)
- Kosuke Kaji
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, 20892, USA
| | - Valentina M. Factor
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, 20892, USA
| | - Jesper B. Andersen
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, 20892, USA,Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen 2200, Denmark
| | - Marian E. Durkin
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, 20892, USA
| | - Akira Tomokuni
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, 20892, USA
| | - Jens U. Marquardt
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, 20892, USA,Department of Medicine I, Johannes Gutenberg University of Mainz, 55131 Mainz, Germany
| | - Matthias S. Matter
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, 20892, USA
| | - Tanya Hoang
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, 20892, USA
| | - Elizabeth A. Conner
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, 20892, USA
| | - Snorri S. Thorgeirsson
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, 20892, USA
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45
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Kamimoto K, Kaneko K, Kok CYY, Okada H, Miyajima A, Itoh T. Heterogeneity and stochastic growth regulation of biliary epithelial cells dictate dynamic epithelial tissue remodeling. eLife 2016; 5. [PMID: 27431614 PMCID: PMC4951195 DOI: 10.7554/elife.15034] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 06/13/2016] [Indexed: 12/12/2022] Open
Abstract
Dynamic remodeling of the intrahepatic biliary epithelial tissue plays key roles in liver regeneration, yet the cellular basis for this process remains unclear. We took an unbiased approach based on in vivo clonal labeling and tracking of biliary epithelial cells in the three-dimensional landscape, in combination with mathematical simulation, to understand their mode of proliferation in a mouse liver injury model where the nascent biliary structure formed in a tissue-intrinsic manner. An apparent heterogeneity among biliary epithelial cells was observed: whereas most of the responders that entered the cell cycle upon injury exhibited a limited and tapering growth potential, a select population continued to proliferate, making a major contribution in sustaining the biliary expansion. Our study has highlighted a unique mode of epithelial tissue dynamics, which depends not on a hierarchical system driven by fixated stem cells, but rather, on a stochastically maintained progenitor population with persistent proliferative activity. DOI:http://dx.doi.org/10.7554/eLife.15034.001 Cell proliferation – the process by which cells multiply – plays an important role in many biological processes, including tissue growth, maintenance and remodeling. In these processes, the way cells proliferate is reportedly related to their roles in the tissue and the structures that they form. The biliary tree, a piping system that exists to drain the bile produced in the liver, forms a complex, tree-like, tubular structure. The biliary tree is essential for healthy livers to work well, and has been known to grow and change its structure quite dynamically during an injury or while the liver regenerates. However, it was not clear how biliary tree cells behave as the biliary tree grows and remodels itself. Does each cell behave in the same way? And how does cell growth relate to changes in the structure of the biliary tree? Kamimoto et al. have now developed new methods to observe detailed three-dimensional tissue structures and to trace the behavior of single cells. Using these techniques to study a mouse model whose liver was injured by toxic chemicals revealed the behavior of biliary cells as they responded to the injury. None of the biliary cells proliferated uniformly, and there were some peculiar cells that proliferated quite vigorously compared to the others. Kamimoto et al. then made a mathematical model that could explain cell behavior and tissue remodeling at different scales. This showed that the activity of those peculiar, rapidly proliferating cells was maintained by chance as the biliary tree expanded. These findings help us understand how the biliary tissue grows and the liver regenerates. They may also provide us with a clue to understanding the nature of the behavior of living things, which is sometimes seemingly ordered and robust, and sometimes unpredictable and mysterious. It remains to be seen whether the new model can be applied to other types of tissues or in other species. Further work is also needed to investigate which genes and proteins are involved in controlling the behavior of cells in the growing biliary tissue. DOI:http://dx.doi.org/10.7554/eLife.15034.002
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Affiliation(s)
- Kenji Kamimoto
- Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan
| | - Kota Kaneko
- Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan
| | - Cindy Yuet-Yin Kok
- Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan
| | - Hajime Okada
- Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan
| | - Atsushi Miyajima
- Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan
| | - Tohru Itoh
- Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan
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Fukuda T, Fukuchi T, Yagi S, Shiojiri N. Immunohistochemical analyses of cell cycle progression and gene expression of biliary epithelial cells during liver regeneration after partial hepatectomy of the mouse. Exp Anim 2015; 65:135-46. [PMID: 26633692 PMCID: PMC4873482 DOI: 10.1538/expanim.15-0082] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The liver has a remarkable regeneration capacity, and, after surgical removal of its
mass, the remaining tissue undergoes rapid regeneration through compensatory growth of its
constituent cells. Although hepatocytes synchronously proliferate under the control of
various signaling molecules from neighboring cells, there have been few detailed analyses
on how biliary cells regenerate for their cell population after liver resection. The
present study was undertaken to clarify how biliary cells regenerate after partial
hepatectomy of mice through extensive analyses of their cell cycle progression and gene
expression using immunohistochemical and RT-PCR techniques. When expression of PCNA, Ki67
antigen, topoisomerase IIα and phosphorylated histone H3, which are cell cycle markers,
was immunohistochemically examined during liver regeneration, hepatocytes had a peak of
the S phase and M phase at 48–72 h after resection. By contrast, biliary epithelial cells
had much lower proliferative activity than that of hepatocytes, and their peak of the S
phase was delayed. Mitotic figures were rarely detectable in biliary cells. RT-PCR
analyses of gene expression of biliary markers such as Spp1
(osteopontin), Epcam and Hnf1b demonstrated that they
were upregulated during liver regeneration. Periportal hepatocytes expressed some of
biliary markers, including Spp1 mRNA and protein. Some periportal
hepatocytes had downregulated expression of HNF4α and HNF1α. Gene expression of Notch
signaling molecules responsible for cell fate decision of hepatoblasts to biliary cells
during development was upregulated during liver regeneration. Notch signaling may be
involved in biliary regeneration.
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Affiliation(s)
- Tatsuya Fukuda
- Department of Biology, Faculty of Science, Shizuoka University, Oya 836, Suruga-ku, Shizuoka city, Shizuoka 422-8529, Japan
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Kok CYY, Miyajima A, Itoh T. Adaptive remodeling of the biliary tree: the essence of liver progenitor cell expansion. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2015; 22:546-50. [PMID: 25900773 DOI: 10.1002/jhbp.250] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Accepted: 03/12/2015] [Indexed: 12/23/2022]
Abstract
The liver progenitor cell population has long been thought to exist within the liver. However, there are no standardized criteria for defining the liver progenitor cells, and there has been intense debate about the origin of these cells in the adult liver. The characteristics of such cells vary depending on the disease model used and also on the method of analysis. Visualization of three-dimensional biliary structures has revealed that the emergence of liver progenitor cells essentially reflects the adaptive remodeling of the hepatic biliary network in response to liver injury. We propose that the progenitor cell exists as a subpopulation in the biliary tree and show that the appearance of liver progenitor cells in injured parenchyma is reflective of extensive remodeling of the biliary structure.
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Affiliation(s)
- Cindy Yuet-Yin Kok
- Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan
| | - Atsushi Miyajima
- Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan
| | - Tohru Itoh
- Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
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