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Lou C, Lan T, Xu S, Hu X, Li J, Xiang Z, Lin S, Fan X, Chen J, Xu X. Heterogeneity and plasticity of cholangiocytes in liver injury: a journey from pathophysiology to therapeutic utility. Gut 2025:gutjnl-2025-334763. [PMID: 40490318 DOI: 10.1136/gutjnl-2025-334763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 05/12/2025] [Indexed: 06/11/2025]
Abstract
Cholangiocytes are highly specialised cells participating in the pathobiology of various liver diseases and recognised to play a crucial role in response to liver injury. Cholangiocytes exhibit dramatic heterogeneity and plasticity, with distinct subtypes performing disparate functions during liver injury and regeneration. Acting as the liver progenitor cells, cholangiocytes can also convert to hepatocytes in the context of impaired hepatocyte proliferation. Harnessing the intrinsic regenerative ability of cholangiocytes is of great importance to alleviate liver injury and promote cholangiocyte-driven liver regeneration. Clinically, cholangiocytes and cholangiocyte organoids are expected to serve as favourable sources for cell therapy in cholangiopathies, which are known as a group of complex diseases involving the biliary system while lacking effective therapeutic options. A comprehensive understanding of the biological characteristics of cholangiocytes provides insights into developing cholangiocyte cell therapy for cholangiopathies. In this review, we discuss the critical role of cholangiocytes in liver injury and regeneration, reveal the underlying mechanism of cholangiocyte plasticity, and explore the prospects and challenges of using cholangiocytes as a source for cell therapy.
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Affiliation(s)
- Chengtao Lou
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Tianchen Lan
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Shengjun Xu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, China
| | - Xinhao Hu
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jiarui Li
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Ze Xiang
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Shengda Lin
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiaohui Fan
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jian Chen
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, China
| | - Xiao Xu
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Institute of Translational Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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2
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Liang G, Ma Y, Deng P, Li S, He C, He H, Liu H, Fan Y, Li Z. Role of cell-based therapies in digestive disorders: Obstacles and opportunities. Regen Ther 2025; 29:1-18. [PMID: 40124469 PMCID: PMC11925584 DOI: 10.1016/j.reth.2025.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 02/01/2025] [Accepted: 02/20/2025] [Indexed: 03/25/2025] Open
Abstract
Stem cell-based therapies have emerged as a promising frontier in the treatment of gastrointestinal disorders, offering potential solutions for challenges posed by conventional treatments. This review comprehensively examines recent advancements in cell-based therapeutic strategies, particularly focusing on stem cell applications, immunotherapy, and cellular therapies for digestive diseases. It highlights the successful differentiation of enteric neural progenitors from pluripotent stem cells and their application in animal models, such as Hirschsprung disease. Furthermore, the review evaluates clinical trials and experimental studies demonstrating the potential of stem cells in regenerating damaged tissues, modulating immune responses, and promoting healing in conditions like Crohn's disease and liver failure. By addressing challenges, such as scalability, immunogenicity, and ethical considerations, the review underscores the translational opportunities and obstacles in realizing the clinical potential of these therapies. Concluding with an emphasis on future directions, the study provides insights into optimizing therapeutic efficacy and fostering innovations in personalized medicine for digestive disorders.
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Affiliation(s)
- Guodong Liang
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
| | - Yuehan Ma
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
| | - Ping Deng
- Medical Department, Jilin Cancer Hospital, Changchun 130012, China
| | - Shufeng Li
- First Department of Gynecological Tumor, Jilin Cancer Hospital, Changchun 130012, China
| | - Chunyan He
- Department of Anaesthesia, Jilin Cancer Hospital, Changchun 130012, China
| | - Haihang He
- Department of Otorhinolaryngology, Oral Maxillofacial, Head and Neck, Jilin Cancer Hospital, Changchun 130012, China
| | - Hairui Liu
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
| | - Yunda Fan
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
| | - Ze Li
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
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Baquero C, Iniesta‐González M, Palao N, Fernández‐Infante C, Cueto‐Remacha M, Mancebo J, de la Cámara‐Fuentes S, Rodrigo‐Faus M, Valdecantos MP, Valverde AM, Sequera C, Manzano S, Cuesta ÁM, Gutierrez‐Uzquiza A, Bragado P, Guerrero C, Porras A. Platelet C3G protects from liver fibrosis, while enhancing tumor growth through regulation of the immune response. J Pathol 2025; 265:502-517. [PMID: 39989399 PMCID: PMC11880977 DOI: 10.1002/path.6403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 11/29/2024] [Accepted: 01/09/2025] [Indexed: 02/25/2025]
Abstract
Primary liver cancer usually occurs in the context of chronic liver disease (CLD), in association with fibrosis. Platelets have emerged as important regulators of CLD and liver cancer, although their precise function and mechanism of action need to be clarified. C3G (RapGEF1) regulates platelet activation, adhesion, and secretion. Here we evaluate the role of platelet C3G in chemically induced fibrosis and liver cancer associated with fibrosis using genetically modified mouse models. We found that while overexpression of full-length C3G in platelets decreased liver fibrosis induced by chronic treatment with CCl4, overexpressed C3G lacking the catalytic domain did not, although in both cases platelet recruitment to the liver was similar. In addition, C3G deletion in platelets (PF4-C3GKO mouse model) increased CCl4-induced liver damage and hepatic fibrosis, reducing liver platelets and macrophages. Moreover, early liver immune response to CCl4 was altered in PF4-C3GKO mice, with a remarkable lower activation of macrophages and increased monocyte-derived macrophages compared to WT mice. On the other hand, in response to DEN+CCl4, PF4-C3G WT mice exhibited more and larger liver tumors than PF4-C3GKO mice, accompanied by the presence of more platelets, despite having less fibrosis in previous steps. Liver immune cell populations were also differentially regulated in PF4-C3GKO mice, highlighting the higher number of macrophages, likely with a pro-inflammatory phenotype, present in the liver in response to chronic DEN+CCl4 treatment. Proteins upregulated or downregulated in platelet-rich plasma from PF4-C3GKO compared to WT mice might regulate the immune response and tumor development. In this regard, enrichment analyses using proteomic data showed changes in several proteins involved in platelet activation and immune response pathways. Additionally, the higher secretion of CD40L by PF4-C3GKO platelets could contribute to their antitumor effect. Therefore, platelet C3G presents antifibrotic and protumor effects in the liver, likely mediated by changes in the immune response. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Cristina Baquero
- Departamento de Bioquímica y Biología Molecular, Facultad de FarmaciaUniversidad Complutense de MadridMadridSpain
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC)MadridSpain
| | - Minerva Iniesta‐González
- Departamento de Bioquímica y Biología Molecular, Facultad de FarmaciaUniversidad Complutense de MadridMadridSpain
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC)MadridSpain
| | - Nerea Palao
- Departamento de Bioquímica y Biología Molecular, Facultad de FarmaciaUniversidad Complutense de MadridMadridSpain
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC)MadridSpain
| | - Cristina Fernández‐Infante
- Instituto de Biología Molecular y Celular del Cáncer (IMBCC)Universidad de Salamanca‐CSICSalamancaSpain
- Instituto de Investigación Biomédica de Salamanca (IBSAL)SalamancaSpain
| | - Mateo Cueto‐Remacha
- Departamento de Bioquímica y Biología Molecular, Facultad de FarmaciaUniversidad Complutense de MadridMadridSpain
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC)MadridSpain
| | - Jaime Mancebo
- Departamento de Bioquímica y Biología Molecular, Facultad de FarmaciaUniversidad Complutense de MadridMadridSpain
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC)MadridSpain
| | | | - María Rodrigo‐Faus
- Departamento de Bioquímica y Biología Molecular, Facultad de FarmaciaUniversidad Complutense de MadridMadridSpain
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC)MadridSpain
| | - M Pilar Valdecantos
- Instituto de Investigaciones Biomédicas (IIBM) Alberto Sols‐Morreale (CSIC‐UAM)MadridSpain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem)Instituto de Salud Carlos IIIMadridSpain
| | - Angela M Valverde
- Instituto de Investigaciones Biomédicas (IIBM) Alberto Sols‐Morreale (CSIC‐UAM)MadridSpain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem)Instituto de Salud Carlos IIIMadridSpain
| | - Celia Sequera
- Departamento de Bioquímica y Biología Molecular, Facultad de FarmaciaUniversidad Complutense de MadridMadridSpain
- Aix Marseille Univ, CNRS, InsermInstitut Paoli‐Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM)MarseilleFrance
| | - Sara Manzano
- Departamento de Bioquímica y Biología Molecular, Facultad de FarmaciaUniversidad Complutense de MadridMadridSpain
| | - Ángel M Cuesta
- Departamento de Bioquímica y Biología Molecular, Facultad de FarmaciaUniversidad Complutense de MadridMadridSpain
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC)MadridSpain
| | - Alvaro Gutierrez‐Uzquiza
- Departamento de Bioquímica y Biología Molecular, Facultad de FarmaciaUniversidad Complutense de MadridMadridSpain
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC)MadridSpain
| | - Paloma Bragado
- Departamento de Bioquímica y Biología Molecular, Facultad de FarmaciaUniversidad Complutense de MadridMadridSpain
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC)MadridSpain
| | - Carmen Guerrero
- Instituto de Biología Molecular y Celular del Cáncer (IMBCC)Universidad de Salamanca‐CSICSalamancaSpain
- Instituto de Investigación Biomédica de Salamanca (IBSAL)SalamancaSpain
- Departamento de MedicinaUniversidad de SalamancaSalamancaSpain
| | - Almudena Porras
- Departamento de Bioquímica y Biología Molecular, Facultad de FarmaciaUniversidad Complutense de MadridMadridSpain
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC)MadridSpain
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Kucuktepe U, Selcuk OT, Ellidag HY, Aydenizoz D, Selcuk NT, Eyigor H, Renda L, Osma U, Yilmaz MD. Serum hepcidin and paraoxonase levels in patients with severe, moderate, and mild obstructive sleep apnea hypopnea syndrome (OSAS): A comparison between OSAS patients and simple snoring patients. Cranio 2025; 43:33-39. [PMID: 35522038 DOI: 10.1080/08869634.2022.2070698] [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] [Indexed: 10/18/2022]
Abstract
OBJECTIVE To investigate the importance of hepcidin and paraoxonase in obstructive sleep apnea syndrome (OSAS). METHODS Eighty-eight patients with sleep disorders were included and divided into four groups: simple snoring (SS), mild, moderate, and severe OSAS. All patients underwent polysomnography. The hepcidin and paraoxonase levels were examined and compared between the groups. RESULTS There were significant differences between the four groups in terms of paraoxonase levels. In the SS group, the paraoxonase value was significantly higher than in the other three groups. In the analysis, Apnea Hypopnea Index (AHI) was negatively correlated with paraoxonase levels. CONCLUSION A significant difference was found between the OSAS groups with respect to paraoxonase enzyme, and a negative correlation with AHI was observed. Paraoxonase level could be used as a biomarker in OSAS. No significant data was found for hepcidin levels; therefore, hepcidin cannot be used as a biomarker in OSAS.
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Affiliation(s)
| | - Omer Tarik Selcuk
- ENT Department, Antalya Research and Teaching Hospital, Antalya, Turkey
| | - Hamit Yasar Ellidag
- Biochemistry Department, Antalya Research and Teaching Hospital, Antalya, Turkey
| | - Dogukan Aydenizoz
- ENT Department, Antalya Research and Teaching Hospital, Antalya, Turkey
| | | | - Hulya Eyigor
- ENT Department, Antalya Research and Teaching Hospital, Antalya, Turkey
| | - Levent Renda
- ENT Department, Antalya Research and Teaching Hospital, Antalya, Turkey
| | - Ustun Osma
- ENT Department, Antalya Research and Teaching Hospital, Antalya, Turkey
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Xu C, Fang X, Song Y, Xiang Z, Xu X, Wei X. Transcriptional Control: A Directional Sign at the Crossroads of Adult Hepatic Progenitor Cells' Fates. Int J Biol Sci 2024; 20:3544-3556. [PMID: 38993564 PMCID: PMC11234216 DOI: 10.7150/ijbs.93739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 05/31/2024] [Indexed: 07/13/2024] Open
Abstract
Hepatic progenitor cells (HPCs) have a bidirectional potential to differentiate into hepatocytes and bile duct epithelial cells and constitute a second barrier to liver regeneration in the adult liver. They are usually located in the Hering duct in the portal vein region where various cells, extracellular matrix, cytokines, and communication signals together constitute the niche of HPCs in homeostasis to maintain cellular plasticity. In various types of liver injury, different cellular signaling streams crosstalk with each other and point to the inducible transcription factor set, including FoxA1/2/3, YB-1, Foxl1, Sox9, HNF4α, HNF1α, and HNF1β. These transcription factors exert different functions by binding to specific target genes, and their products often interact with each other, with diverse cascades of regulation in different molecular events that are essential for homeostatic regulation, self-renewal, proliferation, and selective differentiation of HPCs. Furthermore, the tumor predisposition of adult HPCs is found to be significantly increased under transcriptional factor dysregulation in transcriptional analysis, and the altered initial commitment of the differentiation pathway of HPCs may be one of the sources of intrahepatic tumors. Related transcription factors such as HNF4α and HNF1 are expected to be future targets for tumor treatment.
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Affiliation(s)
- Chenhao Xu
- Zhejiang University School of Medicine, Hangzhou First People's Hospital, Hangzhou 310006, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Xixi Fang
- Hangzhou Normal University, Hangzhou 310006, China
| | - Yisu Song
- Zhejiang University School of Medicine, Hangzhou First People's Hospital, Hangzhou 310006, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Ze Xiang
- Zhejiang University School of Medicine, Hangzhou First People's Hospital, Hangzhou 310006, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Xuyong Wei
- Zhejiang University School of Medicine, Hangzhou First People's Hospital, Hangzhou 310006, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
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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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Faccioli LA, Dias ML, Martins-Santos R, Paredes BD, Takiya CM, dos Santos Goldenberg RC. Resident Liver Stem Cells. RESIDENT STEM CELLS AND REGENERATIVE THERAPY 2024:23-51. [DOI: 10.1016/b978-0-443-15289-4.00015-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Cuesta ÁM, Palao N, Bragado P, Gutierrez-Uzquiza A, Herrera B, Sánchez A, Porras A. New and Old Key Players in Liver Cancer. Int J Mol Sci 2023; 24:17152. [PMID: 38138981 PMCID: PMC10742790 DOI: 10.3390/ijms242417152] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 11/27/2023] [Accepted: 11/28/2023] [Indexed: 12/24/2023] Open
Abstract
Liver cancer represents a major health problem worldwide with growing incidence and high mortality, hepatocellular carcinoma (HCC) being the most frequent. Hepatocytes are likely the cellular origin of most HCCs through the accumulation of genetic alterations, although hepatic progenitor cells (HPCs) might also be candidates in specific cases, as discussed here. HCC usually develops in a context of chronic inflammation, fibrosis, and cirrhosis, although the role of fibrosis is controversial. The interplay between hepatocytes, immune cells and hepatic stellate cells is a key issue. This review summarizes critical aspects of the liver tumor microenvironment paying special attention to platelets as new key players, which exert both pro- and anti-tumor effects, determined by specific contexts and a tight regulation of platelet signaling. Additionally, the relevance of specific signaling pathways, mainly HGF/MET, EGFR and TGF-β is discussed. HGF and TGF-β are produced by different liver cells and platelets and regulate not only tumor cell fate but also HPCs, inflammation and fibrosis, these being key players in these processes. The role of C3G/RAPGEF1, required for the proper function of HGF/MET signaling in HCC and HPCs, is highlighted, due to its ability to promote HCC growth and, regulate HPC fate and platelet-mediated actions on liver cancer.
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Affiliation(s)
- Ángel M. Cuesta
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Nerea Palao
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Paloma Bragado
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Alvaro Gutierrez-Uzquiza
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Blanca Herrera
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD-ISCIII), 28040 Madrid, Spain
| | - Aránzazu Sánchez
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD-ISCIII), 28040 Madrid, Spain
| | - Almudena Porras
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
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9
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Zhang SL, Wang HL. Ancillary tests for hepatobiliary neoplasms: what we know and what we need to know. Hum Pathol 2023; 141:183-200. [PMID: 36775105 DOI: 10.1016/j.humpath.2023.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/29/2023] [Accepted: 02/04/2023] [Indexed: 02/12/2023]
Abstract
Ancillary tests are commonly used in the surgical pathology setting for diagnosing challenging neoplastic diseases of the liver and biliary tract, while histology and clinical correlation remain to be critically important. With continuous discoveries, more and more useful ancillary tests have become available, which can help distinguish between malignant and benign hepatocellular neoplasms, malignant and benign biliary tract entities, and intrahepatic and metastatic carcinomas. This review will focus on existing and emerging biomarkers (such as glutamine synthetase, organic anion transporting polypeptide 1B3, insulin-like growth factor-II mRNA binding protein-3, S100P, SMAD4, enhancer of zeste homolog 2, albumin, hepatocyte nuclear factor-1β, etc.) that can be used for the diagnosis, classification and prognostication of hepatobiliary neoplasms.
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Affiliation(s)
- Sarah L Zhang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine and Ronald Reagan Medical Center, University of California at Los Angeles, Los Angeles, CA, 90095, USA
| | - Hanlin L Wang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine and Ronald Reagan Medical Center, University of California at Los Angeles, Los Angeles, CA, 90095, USA.
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10
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Tan Y, Liu L, Lu Z. Ductular reaction is a prognostic factor in primary biliary cholangitis. JHEP Rep 2023; 5:100750. [PMID: 37456677 PMCID: PMC10339248 DOI: 10.1016/j.jhepr.2023.100750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 03/14/2023] [Indexed: 07/18/2023] Open
Affiliation(s)
- Youwen Tan
- Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu University, No. 300, Daijiamen, Runzhou Distinct, Zhenjiang 212003, China
| | - Liping Liu
- Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu University, No. 300, Daijiamen, Runzhou Distinct, Zhenjiang 212003, China
| | - Zhonghua Lu
- Department of Liver Disease, Wuxi No. 5 People's Hospital Affiliated to Jiangnan University, GuangRui Road 1215# Wuxi City, Wuxi 214000, Jiangsu Province, China
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Sjölin J, Jonsson M, Orback C, Oldfors A, Jeppsson A, Synnergren J, Rotter Sopasakis V, Vukusic K. Expression of Stem Cell Niche-Related Biomarkers at the Base of the Human Tricuspid Valve. Stem Cells Dev 2023; 32:140-151. [PMID: 36565027 PMCID: PMC9986114 DOI: 10.1089/scd.2022.0253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Stem cell niches have been thoroughly investigated in tissue with high regenerative capacity but not in tissues where cell turnover is slow, such as the human heart. The left AtrioVentricular junction (AVj), the base of the mitral valve, has previously been proposed as a niche region for cardiac progenitors in the adult human heart. In the present study, we explore the right side of the human heart, the base of the tricuspid valve, to investigate the potential of this region as a progenitor niche. Paired biopsies from explanted human hearts were collected from multi-organ donors (N = 12). The lateral side of the AVj, right atria (RA), and right ventricle (RV) were compared for the expression of stem cell niche-related biomarkers using RNA sequencing. Gene expression data indicated upregulation of genes related to embryonic development and extracellular matrix (ECM) composition in the proposed niche region, that is, the AVj. In addition, immunohistochemistry showed high expression of the fetal cardiac markers MDR1, SSEA4, and WT1 within the same region. Nuclear expression of HIF1α was detected suggesting hypoxia. Rare cells were found with the co-staining of the proliferation marker PCNA and Ki67 with cardiomyocyte nuclei marker PCM1 and cardiac Troponin T (cTnT), indicating proliferation of small cardiomyocytes. WT1+/cTnT+ and SSEA4+/cTnT+ cells were also found, suggesting cardiomyocyte-specific progenitors. The expression of the stem cell markers gradually decreased with distance from the tricuspid valve. No expression of these markers was observed in the RV tissue. In summary, the base of the tricuspid valve is an ECM-rich region containing cells with expression of several stem cell niche-associated markers. Co-expression of stem cell markers with cTnT indicates cardiomyocyte-specific progenitors. We previously reported similar data from the base of the mitral valve and thus propose that human adult cardiomyocyte progenitors reside around both atrioventricular valves.
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Affiliation(s)
- Jacob Sjölin
- Department of Laboratory Medicine, Institute of Biomedicine, and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Marianne Jonsson
- Department of Laboratory Medicine, Institute of Biomedicine, and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Charlotta Orback
- Department of Laboratory Medicine, Institute of Biomedicine, and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Anders Oldfors
- Department of Laboratory Medicine, Institute of Biomedicine, and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Pathology, and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Anders Jeppsson
- Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.,Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Jane Synnergren
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Biology and Bioinformatics, School of Bioscience, University of Skövde, Skövde, Sweden
| | - Victoria Rotter Sopasakis
- Department of Laboratory Medicine, Institute of Biomedicine, and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Kristina Vukusic
- Department of Laboratory Medicine, Institute of Biomedicine, and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden
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12
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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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13
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Tan Y, Wang J. Letter: ductular reaction is a risk factor for prognosis of chronic hepatitis B complicated with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2023; 57:446-447. [PMID: 36710539 DOI: 10.1111/apt.17383] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 12/29/2022] [Accepted: 12/29/2022] [Indexed: 01/31/2023]
Affiliation(s)
- Youwen Tan
- Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
| | - Jiaming Wang
- Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
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14
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Pathology of Combined Hepatocellular Carcinoma-Cholangiocarcinoma: An Update. Cancers (Basel) 2023; 15:cancers15020494. [PMID: 36672443 PMCID: PMC9856551 DOI: 10.3390/cancers15020494] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/08/2023] [Accepted: 01/11/2023] [Indexed: 01/15/2023] Open
Abstract
Combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer that is composed of both hepatocellular and cholangiocellular differentiated cells. It is slightly more common in men and among Asian and Pacific islanders. Overall, risk factors are similar to classic risk factors of hepatocellular carcinoma (HCC). The classification has significantly evolved over time. The last WHO classification (2019) mainly emphasized diagnosis on morphological basis with routine stainings, discarded previously recognized classifications with carcinomas with stem cell features, introduced intermediate cell carcinoma as a specific subtype and considered cholangiolocarcinoma as a subtype of cholangiocellular carcinoma. Immunohistochemical markers may be applied for further specification but have limited value for diagnosis. Recent discoveries in molecular pathway regulation may pioneer new therapeutic approaches for this poor prognostic and challenging diagnosis.
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15
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Fu Q, Ohnishi S, Suda G, Sakamoto N. Small-molecule inhibitor cocktail promotes the proliferation of pre-existing liver progenitor cells. Stem Cell Reports 2022; 17:1589-1603. [PMID: 35777357 PMCID: PMC9287679 DOI: 10.1016/j.stemcr.2022.05.023] [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: 03/03/2021] [Revised: 05/31/2022] [Accepted: 05/31/2022] [Indexed: 11/09/2022] Open
Abstract
A recent study showed that a cocktail of three small molecules, Y-27632, A83-01, and CHIR99021 (YAC), converts mature hepatocytes (MHs) into proliferative bipotent cells that can be induced into MHs and cholangiocytes in rats. However, when we reproduced these experiments, it was found that bipotent cells may be derived from resident liver progenitor cells (LPCs), whose proliferative activity was promoted by YAC. A simple and efficient sorting scheme was also developed in this study to harvest high-purity and high-yield LPCs. The inducible bipotency of purified LPCs was verified; in addition, they were found to spontaneously differentiate into hepatocytes and cholangiocytes due to changes in proliferative status even without induction. Moreover, during the differentiation process, some hepatocytes spontaneously reconverted to LPCs under certain conditions, such as the release of contact inhibition. These findings may improve our understanding of LPCs and provide a cell source for regenerative medicine.
A small-molecule cocktail promotes rat liver progenitor proliferation in vitro Highly purified progenitors can be simply obtained by their physical properties Purified progenitors preferentially proliferate and then spontaneously differentiate Progenitor differentiation is closely related to varied proliferation signals
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Affiliation(s)
- Qingjie Fu
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Shunsuke Ohnishi
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
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16
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Radial Glia and Neuronal-like Ependymal Cells Are Present within the Spinal Cord of the Trunk (Body) in the Leopard Gecko (Eublepharis macularius). J Dev Biol 2022; 10:jdb10020021. [PMID: 35735912 PMCID: PMC9224675 DOI: 10.3390/jdb10020021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/12/2022] [Accepted: 05/20/2022] [Indexed: 11/28/2022] Open
Abstract
As is the case for many lizards, leopard geckos (Eublepharis macularius) can self-detach a portion of their tail to escape predation, and then regenerate a replacement complete with a spinal cord. Previous research has shown that endogenous populations of neural stem/progenitor cells (NSPCs) reside within the spinal cord of the original tail. In response to tail loss, these NSPCs are activated and contribute to regeneration. Here, we investigate whether similar populations of NSPCs are found within the spinal cord of the trunk (body). Using a long-duration 5-bromo-2′-deoxyuridine pulse-chase experiment, we determined that a population of cells within the ependymal layer are label-retaining following a 20-week chase. Tail loss does not significantly alter rates of ependymal cell proliferation within the trunk spinal cord. Ependymal cells of the trunk spinal cord express SOX2 and represent at least two distinct cell populations: radial glial-like (glial fibrillary acidic protein- and Vimentin-expressing) cells; and neuronal-like (HuCD-expressing) cells. Taken together, these data demonstrate that NSPCs of the trunk spinal cord closely resemble those of the tail and support the use of the tail spinal cord as a less invasive proxy for body spinal cord injury investigations.
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17
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Shao C, Jing Y, Zhao S, Yang X, Hu Y, Meng Y, Huang Y, Ye F, Gao L, Liu W, Sheng D, Li R, Zhang X, Wei L. LPS/Bcl3/YAP1 signaling promotes Sox9 +HNF4α + hepatocyte-mediated liver regeneration after hepatectomy. Cell Death Dis 2022; 13:277. [PMID: 35351855 PMCID: PMC8964805 DOI: 10.1038/s41419-022-04715-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 03/02/2022] [Accepted: 03/09/2022] [Indexed: 11/09/2022]
Abstract
Recent reports have demonstrated that Sox9+HNF4α+ hepatocytes are involved in liver regeneration after chronic liver injury; however, little is known about the origin of Sox9+HNF4α+ hepatocytes and the regulatory mechanism. Employing a combination of chimeric lineage tracing, immunofluorescence, and immunohistochemistry, we demonstrate that Sox9+HNF4α+ hepatocytes, generated by transition from mature hepatocytes, play an important role in the initial phase after partial hepatectomy (PHx). Additionally, knocking down the expression of Sox9 suppresses hepatocyte proliferation and blocks the recovery of lost hepatic tissue. In vitro and in vivo assays demonstrated that Bcl3, activated by LPS, promotes hepatocyte conversion and liver regeneration. Mechanistically, Bcl3 forms a complex with and deubiquitinates YAP1 and further induces YAP1 to translocate into the nucleus, resulting in Sox9 upregulation and mature hepatocyte conversion. We demonstrate that Bcl3 promotes Sox9+HNF4α+ hepatocytes to participate in liver regeneration, and might therefore be a potential target for enhancing regeneration after liver injury.
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Affiliation(s)
- Changchun Shao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Yingying Jing
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
| | - Shanmin Zhao
- Laboratory Animal Center of Second Military Medical University, Shanghai, 200433, China
| | - Xue Yang
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Yiming Hu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou, 510000, China
| | - Yan Meng
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Yihua Huang
- Department of Pathology, the School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350108, China
| | - Fei Ye
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Lu Gao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Wenting Liu
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Dandan Sheng
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Rong Li
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Xiaoren Zhang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou, 510000, China.
| | - Lixin Wei
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China.
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18
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Early histopathologic changes in primary biliary cholangitis: does 'minimal change' primary biliary cholangitis exist? A pathologist's view. Eur J Gastroenterol Hepatol 2021; 33:e7-e12. [PMID: 32804848 DOI: 10.1097/meg.0000000000001876] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is an autoimmune, slowly progressive, cholestatic liver disease characterized by nonsuppurative destructive cholangitis, and interlobular bile duct destruction. Necroinflammatory activities of the hepatic parenchyma and limiting plates of milder form along with late liver fibrosis may develop. Serum liver tests include elevated serum alkaline phosphatase along with a positive antimitochondrial antibody (AMA) in nearly 95% of patients. Liver biopsies are an important confirmatory and staging tool and are additionally very helpful when AMA is negative. More specifically, the earliest changes in liver biopsy suspicious for PBC can be detected, namely loss of the canals of Hering (CoH), as proposed by various authors recently. CoH loss has been described as an early feature of PBC. We focus on early histologic features of PBC, investigating through the literature the possible role of 'minimal change' supporting the clinical diagnosis of PBC, even in the absence of characteristic granulomatous duct destructive lesions.
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19
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Gill RM, Theise ND. Rappaport, Glisson, Hering, and Mall-Champions of Liver Microanatomy: Microscopic and Ultramicroscopic Anatomy of the Liver Into the Modern Age. Clin Liver Dis (Hoboken) 2021; 18:76-92. [PMID: 34745585 PMCID: PMC8555463 DOI: 10.1002/cld.1145] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 05/27/2021] [Indexed: 02/04/2023] Open
Abstract
Content available: Author Interview and Audio Recording.
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Affiliation(s)
- Ryan M. Gill
- Department of PathologyUniversity of California, San FranciscoSan FranciscoCA
| | - Neil D. Theise
- Department of PathologyNew York University School of MedicineNew YorkNY
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20
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Shao C, Yang X, Jing Y, Hou X, Huang Y, Zong C, Gao L, Liu W, Jiang J, Ye F, Shi J, Zhao Q, Li R, Zhang X, Wei L. The stemness of hepatocytes is maintained by high levels of lipopolysaccharide via YAP1 activation. Stem Cell Res Ther 2021; 12:342. [PMID: 34112239 PMCID: PMC8193885 DOI: 10.1186/s13287-021-02421-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 05/26/2021] [Indexed: 12/14/2022] Open
Abstract
Background The liver possesses a powerful regeneration ability, which is correlated with the stemness of hepatocytes in the portal vein (PV). However, the mechanism underlying the maintenance of hepatocyte stemness has not been elucidated. Here, we hypothesized that high levels of lipopolysaccharide from the portal vein might maintain the stemness of hepatocytes in the PV area. Methods First, we examined the location of hepatic stem cells and the concentration of lipopolysaccharide (LPS) in the portal vein and inferior vena cava. Then, we assessed the effect of LPS on stemness maintenance in mice by using antibiotics to eliminate LPS and knocking out the LPS receptor, TLR4. In vitro, the effect of LPS on the stemness of hepatocytes was investigated by colony and sphere formation assays and assessment of pluripotent and stem cell marker expression. Furthermore, we studied the mechanism by which LPS regulates the stemness of hepatocytes. Finally, we ligated the portal vein branch to further verify the effect of LPS. Results We found that a high level of LPS from the portal vein was correlated with the location of hepatic stem cells in the PV area, and elimination of LPS by antibiotics inhibited the expression of the stemness marker. LPS promoted colony and sphere formation and induced the upregulation of pluripotent and stem cell markers in AML12 cells. Furthermore, in the reprogramming medium, LPS facilitated the dedifferentiation of mature hepatocytes into hepatic progenitor-like cells, which exhibited a bipotent differentiation capacity in vivo and in vitro. Mechanistically, LPS bound TLR4 to regulate stemness of hepatocytes via the activation of YAP1 signaling, and blockade of YAP1 abolished the LPS-induced cell stemness and upregulation of pluripotent markers. Conclusions Our study implies a correlation between LPS/TLR4/YAP1 signaling and cell stemness, and LPS was shown to be involved in stemness maintenance of hepatocytes in the PV area. LPS might be used to induce the dedifferentiation of mature hepatocytes into progenitor-like cells for repair of liver injury. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02421-7.
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Affiliation(s)
- Changchun Shao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Xue Yang
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Yingying Jing
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
| | - Xiaojuan Hou
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Yihua Huang
- Department of Pathology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350108, China
| | - Chen Zong
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Lu Gao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Wenting Liu
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Jinghua Jiang
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Fei Ye
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Junxia Shi
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Qiudong Zhao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Rong Li
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Xiaoren Zhang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou, 510000, China.
| | - Lixin Wei
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China.
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21
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Macrophages and Stem Cells-Two to Tango for Tissue Repair? Biomolecules 2021; 11:biom11050697. [PMID: 34066618 PMCID: PMC8148606 DOI: 10.3390/biom11050697] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 04/26/2021] [Accepted: 05/04/2021] [Indexed: 12/25/2022] Open
Abstract
Macrophages (MCs) are present in all tissues, not only supporting homeostasis, but also playing an important role in organogenesis, post-injury regeneration, and diseases. They are a heterogeneous cell population due to their origin, tissue specificity, and polarization in response to aggression factors, depending on environmental cues. Thus, as pro-inflammatory M1 phagocytic MCs, they contribute to tissue damage and even fibrosis, but the anti-inflammatory M2 phenotype participates in repairing processes and wound healing through a molecular interplay with most cells in adult stem cell niches. In this review, we emphasize MC phenotypic heterogeneity in health and disease, highlighting their systemic and systematic contribution to tissue homeostasis and repair. Unraveling the intervention of both resident and migrated MCs on the behavior of stem cells and the regulation of the stem cell niche is crucial for opening new perspectives for novel therapeutic strategies in different diseases.
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22
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Beaufrère A, Calderaro J, Paradis V. Combined hepatocellular-cholangiocarcinoma: An update. J Hepatol 2021; 74:1212-1224. [PMID: 33545267 DOI: 10.1016/j.jhep.2021.01.035] [Citation(s) in RCA: 128] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 01/08/2021] [Accepted: 01/18/2021] [Indexed: 12/13/2022]
Abstract
Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a tumour that exhibits both hepatocytic and biliary differentiation. Classical risk factors for hepatocellular carcinoma (HCC) seem to also predispose patients to the development of cHCC-CCA. The pathological definition of cHCC-CCA has significantly evolved over time. The last 2019 WHO classification highlighted that the diagnosis of cHCC-CCA should be primarily based on morphology using routine stainings, with additional immunostaining used to refine the identification of subtypes. Among them, "intermediate cell carcinoma" is recognised as a specific subtype, while "cholangiolocellular carcinoma" is now considered a subtype of iCCA. Increasing molecular evidence supports the clonal nature of cHCC-CCA and parallels its biphenotypic histological appearance, with genetic alterations that are classically observed in HCC and/or iCCA. That said, the morphological diagnosis of cHCC-CCA is still challenging for radiologists and pathologists, especially on biopsy specimens. Identification of cHCC-CCA's cell of origin remains an area of active research. Its prognosis is generally worse than that of HCC, and similar to that of iCCA. Resection with lymph node dissection is unfortunately the only curative option for patients with cHCC-CCA. Thus, there remains an urgent need to develop specific therapeutic strategies for this unique clinical entity.
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Affiliation(s)
- Aurélie Beaufrère
- Université de Paris, INSERM U1149, Hôpital Beaujon, Clichy, France; Pathology Department, Hôpital Beaujon, AP-HP, Clichy, France
| | | | - Valérie Paradis
- Université de Paris, INSERM U1149, Hôpital Beaujon, Clichy, France; Pathology Department, Hôpital Beaujon, AP-HP, Clichy, France.
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Distribution of Label-Retaining Cells and their Properties in the Newborn Vocal Fold Mucosa. J Voice 2021:S0892-1997(21)00099-0. [PMID: 33865655 DOI: 10.1016/j.jvoice.2021.03.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 02/26/2021] [Accepted: 03/01/2021] [Indexed: 01/05/2023]
Abstract
OBJECTIVES There is growing evidence that the cells in the maculae flavae (MFe) are candidates for tissue stem cells of the vocal fold mucosa and the MFe are a stem cell niche. Distribution of label-retaining cells and their properties in the postnatal vocal fold mucosa were investigated. METHODS Oral administration of bromodeoxyuridine (BrdU) was given to pregnant Sprague-Dawley rats and the label-retaining cells in the postnatal vocal fold mucosa were observed by immunohistochemistry. Immunoreactivity to antibodies directed to Ki-67 was studied to investigate the cell cycle. RESULTS At day 1 after birth, BrdU positive cells were identified in the MFe (60.1 ± 1.7%), epithelium (58.7 ± 10.6%) and lamina propria (52.4 ± 7.8%) of the vocal fold mucosa. At day 56 after birth, the number of BrdU positive cells in the epithelium (4.8 ± 2.2%) and lamina propria (32.3 ± 16.5%) were significantly lower compared to day 1 after birth (P < 0.05). However, the number of BrdU positive cells remaining in the MFe was still high (56.2 ± 2.5%). The label-retaining cells were distributed throughout the MFe. Few Ki-67 positive cells were identified in the MFe indicating they were resting cells. CONCLUSIONS The results of this study are consistent with the hypothesis that the cells in the postnatal MFe are candidates for tissue stem cells. At birth, these cells are already present in the MFe of the newborn vocal fold and they are likely ready to start the growth and development of the vocal fold mucosa.
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Prabhakar B, Lee S, Bochanis A, He W, Manautou JE, Rasmussen TP. lnc-RHL, a novel long non-coding RNA required for the differentiation of hepatocytes from human bipotent progenitor cells. Cell Prolif 2021; 54:e12978. [PMID: 33393114 PMCID: PMC7848967 DOI: 10.1111/cpr.12978] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 12/17/2020] [Accepted: 12/18/2020] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES The final stage of liver development is the production of hepatocytes and cholangiocytes (biliary epithelial cells) from bipotent hepatic progenitor cells. We used HepaRG cells, which are bipotent and able to differentiate into both hepatocytes and cholangiocytes, as a model to study the action of a novel lncRNA (lnc-RHL) and its role in the regulation of bipotency leading to hepatocytes and cholangiocytes. MATERIALS AND METHODS Differentiation of HepaRG cells was assessed by marker expression and morphology which revealed their ability to differentiate into hepatocytes and cholangiocytes (modelling the behaviour of hepatoblasts in vivo). Using a qRT-PCR and RACE, we cloned a novel lncRNA (lnc-RHL; regulator of hepatic lineages) that is upregulated upon HepaRG differentiation. Using inducible knockdown of lnc-RHL concurrently with differentiation, we show that lnc-RHL is required for proper HepaRG cell differentiation resulting in diminution of the hepatocyte lineage. RESULTS Here, we report the discovery of lnc-RHL, a spliced and polyadenylated 670 base lncRNA expressed from the 11q23.3 apolipoprotein gene cluster. lnc-RHL expression is confined to hepatic lineages and is upregulated when bipotent HepaRG cells are caused to differentiate. HepaRG cells made deficient for lnc-RHL have reduced ability to differentiate into hepatocytes, but retain their ability to differentiate into cholangiocytes. CONCLUSIONS Deficiency for lnc-RHL in HepaRG cells converts them from bipotent progenitor cells to unipotent progenitor cells with impaired ability to yield hepatocytes. We conclude that lnc-RHL is a key regulator of bipotency in HepaRG cells.
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Affiliation(s)
| | - Soowan Lee
- Department of Pharmaceutical SciencesStorrsCTUSA
| | | | - Wu He
- Flow Cytometry Core FacilityCenter for Open Research Resources and EquipmentStorrsCTUSA
| | | | - Theodore P. Rasmussen
- Department of Pharmaceutical SciencesStorrsCTUSA
- Institute for Systems GenomicsStorrs/FarmingtonCTUSA
- University of Connecticut Stem Cell InstituteStorrs/FarmingtonCTUSA
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25
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Stem Cells an Overview. Stem Cells 2021. [DOI: 10.1007/978-981-16-1638-9_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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26
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Chowdhury S, Ghosh S. Sources, Isolation and culture of stem cells? Stem Cells 2021. [DOI: 10.1007/978-981-16-1638-9_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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27
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Xu T, Lu Z, Xiao Z, Liu F, Chen Y, Wang Z, Zhu S, Song Y. Myofibroblast induces hepatocyte-to-ductal metaplasia via laminin-ɑvβ6 integrin in liver fibrosis. Cell Death Dis 2020; 11:199. [PMID: 32251270 PMCID: PMC7090046 DOI: 10.1038/s41419-020-2372-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 02/19/2020] [Accepted: 02/19/2020] [Indexed: 12/20/2022]
Abstract
Hepatocytes undergo the metaplasia into ductal biliary epithelial cells (BECs) in response to chronic injury, and subsequently contribute to liver regeneration. The mechanism underlying hepatocyte-to-ductal metaplasia has not been explored until now. In mouse models of liver fibrosis, a florid BEC response was observed in fibrotic liver, and the depletion of myofibroblasts attenuated BEC expansion remarkably. Then, in hepatocyte fate-tracing mouse model, we demonstrated the conversion of mature hepatocytes into ductal BECs in fibrotic liver, and the depletion of myofibroblasts diminished the hepatocyte-to-ductal metaplasia. Finally, the mechanism underlying the metaplasia was investigated. Myofibroblasts secreted laminin-rich extracellular matrix, and then laminin induced hepatocyte-to-ductal metaplasia through ɑvβ6 integrin. Therefore, our results demonstrated myofibroblasts induce the conversion of mature hepatocytes into ductal BECs through laminin-ɑvβ6 integrin, which reveals that the strategy improve regeneration in fibrotic liver through the modification of specific microenvironment.
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Affiliation(s)
- Ting Xu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Zhiwen Lu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Zhuanglong Xiao
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Fang Liu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Yuhua Chen
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Zhijun Wang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Shenghua Zhu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Yuhu Song
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
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28
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Theise ND, Crawford JM, Nakanuma Y, Quaglia A. Canal of Hering loss is an initiating step for primary biliary cholangitis (PBC): A hypothesis. Med Hypotheses 2020; 140:109680. [PMID: 32240960 DOI: 10.1016/j.mehy.2020.109680] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 03/09/2020] [Accepted: 03/15/2020] [Indexed: 12/20/2022]
Abstract
The origin and initiating features of PBC remain obscure despite decades of study. However, recent papers have demonstrated loss of canals of Hering (CoH) to be the earliest histologic change in liver biopsy specimens from patients with primary biliary cholangitis (PBC). We posit that CoH loss prior to significant inflammation or evidence of bile duct injury might be a very early, perhaps even an initiating lesion of PBC. As a potential target of inflammatory or toxic injury, CoH loss may initiate rather than follow the cascade of events leading to duct injury and loss and their sequelae. Toxins may be exogenous in origin, such as environmental toxins or drug exposures, or endogenous, resulting from genetic or epigenetic alterations in canalicular bile transporters upstream from the CoH. In turn, this hypothesis suggests that loss of CoH would lead to altered bile flow and composition injurious to downstream bile ducts, because bile composition has not been modulated by normal CoH physiologic functions or because, in the absence of CoH, canalicular fluid flow into the biliary tree is disrupted interfering with soluble trophic factors important for bile duct integrity. Regardless of the pathogenic mechanism causing CoH loss, only following such loss would the characteristic diagnostic findings of PBC become evident: damage to downstream interlobular and sub-lobular bile ducts. To the extent that the causal mechanisms for CoH loss can be identified, clinical identification (as through early identification of CoH loss) and intervention (depending on the inciting cause) may offer promise for treatment of this enigmatic disease.
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Affiliation(s)
- Neil D Theise
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.
| | - James M Crawford
- Department of Pathology and Laboratory Medicine, Donald and Barbara School of Medicine at Hofstra/Northwell, New York, NY, USA
| | - Yasuni Nakanuma
- Department of Pathology, Fukui Saiseikai Hospital, Fukui 918-8503, Japan
| | - Alberto Quaglia
- Department of Cellular Pathology, Royal Free Hospital, London, UK
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29
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Sciarra A, Park YN, Sempoux C. Updates in the diagnosis of combined hepatocellular-cholangiocarcinoma. Hum Pathol 2020; 96:48-55. [DOI: 10.1016/j.humpath.2019.11.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 11/04/2019] [Indexed: 12/13/2022]
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30
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Zanchi A, Reidy J, Feldman HJ, Qualter J, Gouw AS, Osbeck J, Kofman A, Balabaud C, Bioulac-Sage P, Tiniakos DG, Theise ND. Innervation of the proximal human biliary tree. Virchows Arch 2020; 477:385-392. [DOI: 10.1007/s00428-020-02761-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 01/06/2020] [Accepted: 01/21/2020] [Indexed: 01/03/2023]
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31
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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: 111] [Impact Index Per Article: 22.2] [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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32
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Abstract
Recent advances in culturing of intestinal stem cells and pluripotent stem cells have led to the development of intestinal organoids. These are self-organizing 3D structures, which recapitulate the characteristics and physiological features of in vivo intestinal epithelium. Intestinal organoids have allowed the development of novel in vitro models to study various gastrointestinal diseases expanding our understanding of the pathophysiology of diseases and leading to the development of innovative therapies. This article aims to summarize the current usage of intestinal organoids as a model of gastrointestinal diseases and the potential applications of intestinal organoids in infants and children. Intestinal organoids allow the study of intestinal epithelium responses to stress factors. Mimicking intestinal injury such as necrotizing enterocolitis, intestinal organoids increases the expression of pro-inflammatory cytokine genes and shows disruption of tight junctions after they are injured by lipopolysaccharide and hypoxia. In cystic fibrosis, intestinal organoids derived from rectal biopsies have provided benefits in genetic studies and development of novel therapeutic gene modulation. Transplantation of intestinal organoids via enema has been shown to rescue damaged colonic epithelium in mice. In addition, tissue-engineered small intestine derived from intestinal organoids have been successfully established providing a potential novel treatment and a new hope for children with short bowel syndrome.
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33
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Qian L, Zhang H, Gu Y, Li D, He S, Wang H, Cheng Y, Yang W, Yu H, Zhao X, Cai W, Meng L, Jin M, Wang Y, Zhang Y. Reduced production of laminin by hepatic stellate cells contributes to impairment in oval cell response to liver injury in aged mice. Aging (Albany NY) 2019; 10:3713-3735. [PMID: 30513510 PMCID: PMC6326669 DOI: 10.18632/aging.101665] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 11/15/2018] [Indexed: 12/13/2022]
Abstract
Aged liver is usually impaired in response to hepatic injury. Tissue-specific stem cells participate in the repair of tissue injury. However, how oval cells (OCs) respond to injury and how the process is regulated by tissue microenvironment in aged mice have not been fully understood. In this study, taking advantage of well-established murine OC activation model, we demonstrated that OCs were less activated upon injury in aged mice and the impairment was mainly attributed to dysfunction in their niche. Through analyzing global gene expression, we found that the genes differentially expressed in damaged young and aged mouse liver tissues were predominantly those required for the formation and remodeling of extracellular matrix. As one of the most important extracellular matrix components in the OC niche, laminin was shown to promote the proliferation of OCs. Not surprisingly, laminin was downregulated with aging. Consistent with the downregulation of genes encoding DNA-dependent protein kinase (DNA-PK) proteins in aged hepatic stellate cells (HSCs), inhibition of DNA-PK also led to reduced expression of laminin in HSCs. Moreover, impairment in OC activation caused by less supporting from DNA-damaged HSCs could be rescued by laminin. This study reveals a new cellular mechanism underlying impaired OCs functionality during aging.
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Affiliation(s)
- Liu Qian
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China.,Department of General Surgery, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Hui Zhang
- Department of General Surgery, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Yuting Gu
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Dechun Li
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China
| | - Songbing He
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China
| | - Hui Wang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China.,Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yiji Cheng
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Wanlin Yang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China
| | - Hongshuang Yu
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Xiaonan Zhao
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Wei Cai
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Lijun Meng
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China
| | - Min Jin
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yanan Wang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China
| | - Yanyun Zhang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China.,Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
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34
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Meta-Analysis of Human and Mouse Biliary Epithelial Cell Gene Profiles. Cells 2019; 8:cells8101117. [PMID: 31547151 PMCID: PMC6829476 DOI: 10.3390/cells8101117] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 09/03/2019] [Accepted: 09/18/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Chronic liver diseases are frequently accompanied with activation of biliary epithelial cells (BECs) that can differentiate into hepatocytes and cholangiocytes, providing an endogenous back-up system. Functional studies on BECs often rely on isolations of an BEC cell population from healthy and/or injured livers. However, a consensus on the characterization of these cells has not yet been reached. The aim of this study was to compare the publicly available transcriptome profiles of human and mouse BECs and to establish gene signatures that can identify quiescent and activated human and mouse BECs. METHODS We used publicly available transcriptome data sets of human and mouse BECs, compared their profiles and analyzed co-expressed genes and pathways. By merging both human and mouse BEC-enriched genes, we obtained a quiescent and activation gene signature and tested them on BEC-like cells and different liver diseases using gene set enrichment analysis. In addition, we identified several genes from both gene signatures to identify BECs in a scRNA sequencing data set. RESULTS Comparison of mouse BEC transcriptome data sets showed that the isolation method and array platform strongly influences their general profile, still most populations are highly enriched in most genes currently associated with BECs. Pathway analysis on human and mouse BECs revealed the KRAS signaling as a new potential pathway in BEC activation. We established a quiescent and activated BEC gene signature that can be used to identify BEC-like cells and detect BEC enrichment in alcoholic hepatitis, non-alcoholic steatohepatitis (NASH) and peribiliary sclerotic livers. Finally, we identified a gene set that can distinguish BECs from other liver cells in mouse and human scRNAseq data. CONCLUSIONS Through a meta-analysis of human and mouse BEC gene profiles we identified new potential pathways in BEC activation and created unique gene signatures for quiescent and activated BECs. These signatures and pathways will help in the further characterization of this progenitor cell type in mouse and human liver development and disease.
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35
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Bizzaro D, Russo FP, Burra P. New Perspectives in Liver Transplantation: From Regeneration to Bioengineering. Bioengineering (Basel) 2019; 6:81. [PMID: 31514475 PMCID: PMC6783848 DOI: 10.3390/bioengineering6030081] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 09/09/2019] [Accepted: 09/10/2019] [Indexed: 12/18/2022] Open
Abstract
Advanced liver diseases have very high morbidity and mortality due to associated complications, and liver transplantation represents the only current therapeutic option. However, due to worldwide donor shortages, new alternative approaches are mandatory for such patients. Regenerative medicine could be the more appropriate answer to this need. Advances in knowledge of physiology of liver regeneration, stem cells, and 3D scaffolds for tissue engineering have accelerated the race towards efficient therapies for liver failure. In this review, we propose an update on liver regeneration, cell-based regenerative medicine and bioengineering alternatives to liver transplantation.
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Affiliation(s)
- Debora Bizzaro
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology/Multivisceral Transplant Section, University/Hospital Padua, 35128 Padua, Italy.
| | - Francesco Paolo Russo
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology/Multivisceral Transplant Section, University/Hospital Padua, 35128 Padua, Italy.
| | - Patrizia Burra
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology/Multivisceral Transplant Section, University/Hospital Padua, 35128 Padua, Italy.
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36
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Clerbaux LA, Manco R, Van Hul N, Bouzin C, Sciarra A, Sempoux C, Theise ND, Leclercq IA. Invasive Ductular Reaction Operates Hepatobiliary Junctions upon Hepatocellular Injury in Rodents and Humans. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:1569-1581. [PMID: 31108103 DOI: 10.1016/j.ajpath.2019.04.011] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 03/18/2019] [Accepted: 04/23/2019] [Indexed: 02/08/2023]
Abstract
Ductular reaction (DR) is observed in virtually all liver diseases in both humans and rodents. Depending on the injury, DR is confined within the periportal area or invades the parenchyma. On severe hepatocellular injury, invasive DR has been proposed to arise for supplying the liver with new hepatocytes. However, experimental data evidenced that DR contribution to hepatocyte repopulation is at the most modest, unless replicative capacity of hepatocytes is abrogated. Herein, we proposed that invasive DR could contribute to operating hepatobiliary junctions on hepatocellular injury. The choline-deficient ethionine-supplemented mouse model of hepatocellular injury and human liver samples were used to evaluate the hepatobiliary junctional role of the invasive form of DR. Choline-deficient ethionine-supplemented-induced DR expanded as biliary epithelium into the lobule and established new junctions with the canaliculi. By contrast, no new ductular-canalicular junctions were observed in mouse models of biliary obstructive injury exhibiting noninvasive DR. Similarly, in humans, an increased number of hepatobiliary junctions were observed in hepatocellular diseases (viral, drug induced, or metabolic) in which DR invaded the lobule but not in biliary diseases (obstruction or cholangitis) in which DR was contained within the portal mesenchyme. In conclusion, our data in rodents and humans support that invasive DR plays a hepatobiliary junctional role to maintain structural continuity between hepatocytes and ducts in disorders affecting hepatocytes.
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Affiliation(s)
- Laure-Alix Clerbaux
- Laboratory of Gastroenterology, Université Catholique de Louvain, Brussels, Belgium
| | - Rita Manco
- Laboratory of Gastroenterology, Université Catholique de Louvain, Brussels, Belgium
| | - Noémi Van Hul
- Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
| | - Caroline Bouzin
- Imaging Platform, Institute of clinical and Experimental Research, Université Catholique de Louvain, Brussels, Belgium
| | - Amedeo Sciarra
- Service of Clinical Pathology, Lausanne University Hospital, Institute of Pathology, Lausanne, Switzerland
| | - Christine Sempoux
- Service of Clinical Pathology, Lausanne University Hospital, Institute of Pathology, Lausanne, Switzerland
| | - Neil D Theise
- Department of Pathology, New York University School of Medicine, New York, New York
| | - Isabelle A Leclercq
- Laboratory of Gastroenterology, Université Catholique de Louvain, Brussels, Belgium.
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Sánchez-Romero N, Sainz-Arnal P, Pla-Palacín I, Dachary PR, Almeida H, Pastor C, Soto DR, Rodriguez MC, Arbizu EO, Martinez LB, Serrano-Aulló T, Baptista PM. The role of extracellular matrix on liver stem cell fate: A dynamic relationship in health and disease. Differentiation 2019; 106:49-56. [PMID: 30878881 DOI: 10.1016/j.diff.2019.03.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 03/01/2019] [Accepted: 03/06/2019] [Indexed: 02/07/2023]
Abstract
The liver stem cell niche is a specialized and dynamic microenvironment with biomechanical and biochemical characteristics that regulate stem cell behavior. This is feasible due to the coordination of a complex network of secreted factors, small molecules, neural, blood inputs and extracellular matrix (ECM) components involved in the regulation of stem cell fate (self-renewal, survival, and differentiation into more mature phenotypes like hepatocytes and cholangiocytes). In this review, we describe and summarize all the major components that play essential roles in the liver stem cell niche, in particular, growth factor signaling and the biomechanical properties of the ECM.
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Affiliation(s)
| | - Pilar Sainz-Arnal
- Health Research Institute of Aragón (IIS Aragón), Zaragoza, Spain; Aragon's Health Science Research Institute (IACS), Zaragoza, Spain
| | - Iris Pla-Palacín
- Health Research Institute of Aragón (IIS Aragón), Zaragoza, Spain
| | | | - Helen Almeida
- Health Research Institute of Aragón (IIS Aragón), Zaragoza, Spain
| | - Cristina Pastor
- Aragon's Health Science Research Institute (IACS), Zaragoza, Spain
| | - Daniela Rubio Soto
- Health Research Institute of Aragón (IIS Aragón), Zaragoza, Spain; Health Research Institute of Jiménez Díaz Foundation (IIS FJD), Madrid, Spain; Biomedical and Aerospace Engineering Department, University Carlos III of Madrid, Spain
| | | | | | | | | | - Pedro M Baptista
- Health Research Institute of Aragón (IIS Aragón), Zaragoza, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Health Research Institute of Jiménez Díaz Foundation (IIS FJD), Madrid, Spain; Biomedical and Aerospace Engineering Department, University Carlos III of Madrid, Spain.
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38
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Tsuchiya A, Lu WY. Liver stem cells: Plasticity of the liver epithelium. World J Gastroenterol 2019; 25:1037-1049. [PMID: 30862993 PMCID: PMC6406190 DOI: 10.3748/wjg.v25.i9.1037] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 01/21/2019] [Accepted: 01/26/2019] [Indexed: 02/06/2023] Open
Abstract
The liver has a high regenerative capacity after acute liver injury, but this is often impaired during chronic liver injury. The existence of a dedicated liver stem cell population that acts as a source of regeneration during chronic liver injury has been controversial. Recent advances in transgenic models and cellular reprogramming have provided new insights into the plasticity of the liver epithelium and directions for the development of future therapies. This article will highlight recent findings about the cellular source of regeneration during liver injury and the advances in promoting liver regeneration.
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Affiliation(s)
- Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate school of medical and dental sciences, Niigata University, Chuo-ku, Niigata 951-8510, Japan
| | - Wei-Yu Lu
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, the University of Birmingham, Birmingham B15 2TT, United Kingdom
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39
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Sato K, Kurita T, Chitose SI, Sato K, Umeno H, Yano H. Distribution of label-retaining cells and their properties in the vocal fold mucosa. Laryngoscope Investig Otolaryngol 2018; 4:76-82. [PMID: 30828622 PMCID: PMC6383309 DOI: 10.1002/lio2.219] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Revised: 07/06/2018] [Accepted: 09/22/2018] [Indexed: 11/12/2022] Open
Abstract
Objective The latest research suggests cells in the maculae flavae (MFe) are putative stem cells of the vocal fold mucosa and the MFe are a candidate for a stem cell niche. Distribution and properties of label-retaining cells (LRCs) in the vocal fold mucosa were investigated. Study Design Histologic analysis of the rat vocal folds. Methods Oral administration of bromodeoxyuridine (BrdU) was given to rats and the LRCs in the vocal fold mucosa were observed by immunohistochemistry. Immunoreactivity to antibodies directed to BrdU, Ki67, cytokeratin, vimentin, glial fibrillary acidic protein, desmin, Sox17, CD34, CD45, Type I collagen, and CD44 was studied. Extracellular matrices around LRCs were observed by Alcian blue staining and hyaluronidase digestion study. Results LRCs were present in the MFe and were resting cells (G0-phase). They expressed epithelium, muscle, neural, and mesenchymal cell-associated intermediate filament proteins, and an endodermal marker, indicating cells in the MFe are undifferentiated and express proteins of all three germ layers. They expressed hematopoietic markers (CD34, CD45) and Type I collagen, which are the major markers of bone marrow derived circulating fibrocytes. The hyaluronan concentration in the MFe was high and the cells in the MFe expressed the surface hyaluronan receptor CD44, indicating that the MFe were a hyaluronan-rich matrix. Conclusion LRCs reside in the MFe and MFe had a hyaluronan-rich matrix. The results of this study are consistent with the hypothesis that the cells in the MFe are putative stem cells and the MFe are a candidate for a stem cell niche. Level of Evidence N/A.
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Affiliation(s)
- Kiminobu Sato
- Department of Otolaryngology-Head and Neck Surgery Kurume University School of Medicine Kurume Japan
| | - Takashi Kurita
- Department of Otolaryngology-Head and Neck Surgery Kurume University School of Medicine Kurume Japan
| | - Shun-Ichi Chitose
- Department of Otolaryngology-Head and Neck Surgery Kurume University School of Medicine Kurume Japan
| | - Kiminori Sato
- Department of Otolaryngology-Head and Neck Surgery Kurume University School of Medicine Kurume Japan.,Department of Pathology Kurume University School of Medicine Kurume Japan
| | - Hirohito Umeno
- Department of Otolaryngology-Head and Neck Surgery Kurume University School of Medicine Kurume Japan
| | - Hirohisa Yano
- Department of Pathology Kurume University School of Medicine Kurume Japan
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40
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Alison MR. The many ways to mend your liver: A critical appraisal. Int J Exp Pathol 2018; 99:106-112. [PMID: 29882223 DOI: 10.1111/iep.12272] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 05/07/2018] [Indexed: 12/12/2022] Open
Abstract
In the latter half of the 20th century, our understanding of mammalian liver regeneration was shaped by the manner of compensatory hyperplasia occurring after a partial rat liver resection. This response involves almost all hepatocytes and thus is unlikely to be the outcome of the multiple cycling of a small stem cell population. It was most intense in the outer third of lobule, the location closest to the afferent arterial blood supply. With the advent of heritable genetic labelling techniques, usually applied to mice, hitherto unrecognized hepatocytes with clonogenic potential have been discovered, contributing to homoeostatic renewal and/or regenerative responses after tissue loss. This review combines observations from cell lineage tracing studies with other data to summarize the Four proposed anatomical locations for hepatocyte stem cells: the periportal zone, the pericentral zone, a randomized distribution and finally within the intrahepatic biliary tree. As in other endodermal-derived tissues, it appears that there are both homoeostatic stem cells and regenerative stem cells, while some normally homoeostatic stem cells can become more active to boost regeneration.
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Affiliation(s)
- Malcolm R Alison
- Centre for Tumour Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, London, UK
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41
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Lin F, Shi J, Wang HL, Ma XJ, Monroe R, Luo Y, Chen Z, Liu H. Detection of Albumin Expression by RNA In Situ Hybridization Is a Sensitive and Specific Method for Identification of Hepatocellular Carcinomas and Intrahepatic Cholangiocarcinomas. Am J Clin Pathol 2018; 150:58-64. [PMID: 29746696 DOI: 10.1093/ajcp/aqy030] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES Inconsistent data on detection of albumin expression by ribonucleic acid (RNA) in situ hybridization have been reported. We investigated the utility of RNAscope (Advanced Cell Diagnostics, Hayward, CA) in detection of albumin in hepatocellular carcinomas (HCCs), intrahepatic cholangiocarcinomas (ICCs), and carcinomas from various organs using manual and automated staining. METHODS RNAscope for albumin detection was performed on 482 cases on tissue microarray sections and on 22 cases of ICC, including 14 surgical resection and eight core biopsy specimens. RESULTS Thirty-six of 37 (97%) HCCs had detectable mRNA, whereas all non-HCC and non-ICC cases, except one lung adenocarcinoma, were negative for albumin. Fourteen of 22 ICCs (64%) were positive for albumin. CONCLUSIONS RNAscope for albumin is highly sensitive and specific for identifying HCCs and is highly specific and moderately sensitive for detection of ICCs; however, rare carcinomas (non-HCC, non-ICC, and those with no hepatoid histomorphology) can also have aberrant expression of albumin.
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Affiliation(s)
- Fan Lin
- Geisinger Medical Center, Danville, PA
| | | | - Hanlin L Wang
- Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles
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Kramer AS, Latham B, Diepeveen LA, Mou L, Laurent GJ, Elsegood C, Ochoa-Callejero L, Yeoh GC. InForm software: a semi-automated research tool to identify presumptive human hepatic progenitor cells, and other histological features of pathological significance. Sci Rep 2018; 8:3418. [PMID: 29467378 PMCID: PMC5821869 DOI: 10.1038/s41598-018-21757-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 01/30/2018] [Indexed: 12/19/2022] Open
Abstract
Hepatic progenitor cells (HPCs) play an important regenerative role in acute and chronic liver pathologies. Liver disease research often necessitates the grading of disease severity, and pathologists’ reports are the current gold-standard for assessment. However, it is often impractical to recruit pathologists in large cohort studies. In this study we utilise PerkinElmer’s “InForm” software package to semi-automate the scoring of patient liver biopsies, and compare outputs to a pathologist’s assessment. We examined a cohort of eleven acute hepatitis samples and three non-alcoholic fatty liver disease (NAFLD) samples, stained with HPC markers (GCTM-5 and Pan Cytokeratin), an inflammatory marker (CD45), Sirius Red to detect collagen and haematoxylin/eosin for general histology. InForm was configured to identify presumptive HPCs, CD45+ve inflammatory cells, areas of necrosis, fat and collagen deposition (p < 0.0001). Hepatitis samples were then evaluated both by a pathologist using the Ishak-Knodell scoring system, and by InForm through customised algorithms. Necroinflammation as evaluated by a pathologist, correlated with InForm outputs (r2 = 0.8192, p < 0.05). This study demonstrates that the InForm software package provides a useful tool for liver disease research, allowing rapid, and objective quantification of the presumptive HPCs and identifies histological features that assist with assessing liver disease severity, and potentially can facilitate diagnosis.
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Affiliation(s)
- Anne S Kramer
- Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia, Crawley, WA, Australia.,School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia.,Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia
| | - Bruce Latham
- PathWest Laboratory Medicine WA, Fiona Stanley Hospital, Murdoch, WA, Australia
| | - Luke A Diepeveen
- Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia, Crawley, WA, Australia
| | - Lingjun Mou
- WA Liver & Kidney Surgical Transplant Service, Sir Charles Gairdner Hospital, Nedlands, Australia
| | - Geoffrey J Laurent
- Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia
| | - Caryn Elsegood
- School of Pharmacy and Biomedical Science, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia
| | - Laura Ochoa-Callejero
- Angiogenesis group, Oncology Area, Centre for Biomedical Research of La Rioja, Logroño, Spain
| | - George C Yeoh
- Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia, Crawley, WA, Australia. .,School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia. .,Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia.
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Tomita H, Kanayama T, Niwa A, Noguchi K, Tanaka T, Hara A. The Stem Cells in Liver Cancers and the Controversies. STEM CELLS AND CANCER IN HEPATOLOGY 2018:273-287. [DOI: 10.1016/b978-0-12-812301-0.00013-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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44
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Liu J, Hu X, Chen J, Li X, Wang L, Wang B, Peng W, Yang C, Li Z, Chen Y, Wang YJ, Li C, Li X, Yan F, Wang Y, Shang C, Wang X, Chen T, Huang P. Pericentral hepatocytes produce insulin-like growth factor-2 to promote liver regeneration during selected injuries in mice. Hepatology 2017; 66:2002-2015. [PMID: 28653763 DOI: 10.1002/hep.29340] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 06/12/2017] [Accepted: 06/22/2017] [Indexed: 12/14/2022]
Abstract
UNLABELLED Liver regeneration (LR) happens after various types of injuries. Unlike the well-studied LR caused by partial hepatectomy (PHx), there is accumulating evidence suggesting that LR during other injuries may result from unknown mechanisms. In this study, we found that insulin-like growth factor 2 (IGF-2) was drastically induced following the liver injuries caused by tyrosinemia or long-term treatments of CCl4 . However, this was not observed during the early phase of acute liver injuries after PHx or single treatment of CCl4 . Remarkably, most IGF-2-expressing hepatocytes were located at the histological area around the central vein of the liver lobule after the liver injuries caused either in fumarylacetoacetate hydrolase-deficient mice or in CCl4 chronically treated mice. Hepatocyte proliferation in vivo was significantly promoted by induced IGF-2 overexpression, which could be inhibited by adeno-associated virus-delivered IGF-2 short hairpin RNAs or linsitinib, an inhibitor of IGF-2 signaling. Proliferating hepatocytes in vivo responded to IGF-2 through both insulin receptor and IGF-1 receptor. IGF-2 also significantly promoted DNA synthesis of primary hepatocytes in vitro. More interestingly, the significantly induced IGF-2 was also found to colocalize with glutamine synthetase in the region enriched with proliferating hepatocytes for the liver samples from patients with liver fibrosis. CONCLUSION IGF-2 is produced by pericentral hepatocytes to promote hepatocyte proliferation and repair tissue damage in the setting of chronic liver injury, which is distinct from the signaling that occurs post-PHx. (Hepatology 2017;66:2002-2015).
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Affiliation(s)
- Junlai Liu
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.,Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Xiao Hu
- Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Jie Chen
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xinqi Li
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.,Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Lu Wang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Binbin Wang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.,Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Wenbo Peng
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.,Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Cuiwei Yang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.,Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Zhijie Li
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.,Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Yan Chen
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yue J Wang
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA
| | - Chuanjiang Li
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiajun Li
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Fang Yan
- Stem Cell and Tissue Engineering Lab, Beijing Institute of Transfusion Medicine, Beijing, China
| | - Yunfang Wang
- Stem Cell and Tissue Engineering Lab, Beijing Institute of Transfusion Medicine, Beijing, China
| | - Changzhen Shang
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xin Wang
- The Key Laboratory of National Education Ministry for Mammalian Reproductive Biology and Biotechnology, Inner Mongolia University, Huhhot, P.R. China.,Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, MN.,Hepatoscience Incorporation, Sunnyvale, CA
| | - Tao Chen
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Pengyu Huang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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Bragazzi MC, Ridola L, Safarikia S, Matteo SD, Costantini D, Nevi L, Cardinale V. New insights into cholangiocarcinoma: multiple stems and related cell lineages of origin. Ann Gastroenterol 2017; 31:42-55. [PMID: 29333066 PMCID: PMC5759612 DOI: 10.20524/aog.2017.0209] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 09/14/2017] [Indexed: 12/12/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies that may develop at any level of the biliary tree. CCA is currently classified into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) on the basis of its anatomical location. Notably, although these three CCA subtypes have common features, they also have important inter- and intra-tumor differences that can affect their pathogenesis and outcome. A unique feature of CCA is that it manifests in the hepatic parenchyma or large intrahepatic and extrahepatic bile ducts, furnished by two distinct stem cell niches: the canals of Hering and the peribiliary glands, respectively. The complexity of CCA pathogenesis highlights the need for a multidisciplinary, translational, and systemic approach to this malignancy. This review focuses on advances in the knowledge of CCA histomorphology, risk factors, molecular pathogenesis, and subsets of CCA.
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Affiliation(s)
- Maria Consiglia Bragazzi
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Lorenzo Ridola
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Samira Safarikia
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Sabina Di Matteo
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Daniele Costantini
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Lorenzo Nevi
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
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Abe M, Yoshida T, Akiba J, Ikezono Y, Wada F, Masuda A, Sakaue T, Tanaka T, Iwamoto H, Nakamura T, Sata M, Koga H, Yoshimura A, Torimura T. STAT3 deficiency prevents hepatocarcinogenesis and promotes biliary proliferation in thioacetamide-induced liver injury. World J Gastroenterol 2017; 23:6833-6844. [PMID: 29085226 PMCID: PMC5645616 DOI: 10.3748/wjg.v23.i37.6833] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 08/24/2017] [Accepted: 09/05/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury.
METHODS We investigated thioacetamide (TAA)-induced liver injury, compensatory hepatocyte proliferation, and hepatocellular carcinoma (HCC) development in hepatic STAT3-deficient mice. In addition, we evaluated TAA-induced biliary ductular proliferation and analyzed the activation of sex determining region Y-box9 (SOX9) and Yes-associated protein (YAP), which regulate the transdifferentiation of hepatocytes to cholangiocytes.
RESULTS Both compensatory hepatocyte proliferation and HCC formation were significantly decreased in hepatic STAT3-deficient mice as compared with control mice. STAT3 deficiency resulted in augmentation of hepatic necrosis and fibrosis. On the other hand, biliary ductular proliferation increased in hepatic STAT3-deficient livers as compared with control livers. SOX9 and YAP were upregulated in hepatic STAT3-deficient hepatocytes.
CONCLUSION STAT3 may regulate hepatocyte proliferation as well as transdifferentiation into cholangiocytes and serve as a therapeutic target for HCC inhibition and biliary regeneration.
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Affiliation(s)
- Mitsuhiko Abe
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Takafumi Yoshida
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
- Kurume Clinical Pharmacology Clinic, Kurume 830-0011, Japan
| | - Jun Akiba
- Department of Diagnostic Pathology, Kurume University Hospital, Kurume 830-0011, Japan
| | - Yu Ikezono
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Fumitaka Wada
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Atsutaka Masuda
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Takahiko Sakaue
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Toshimitsu Tanaka
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Toru Nakamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Michio Sata
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
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Cao W, Chen K, Bolkestein M, Yin Y, Verstegen MMA, Bijvelds MJC, Wang W, Tuysuz N, Ten Berge D, Sprengers D, Metselaar HJ, van der Laan LJW, Kwekkeboom J, Smits R, Peppelenbosch MP, Pan Q. Dynamics of Proliferative and Quiescent Stem Cells in Liver Homeostasis and Injury. Gastroenterology 2017; 153:1133-1147. [PMID: 28716722 DOI: 10.1053/j.gastro.2017.07.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 07/05/2017] [Accepted: 07/06/2017] [Indexed: 01/10/2023]
Abstract
BACKGROUND & AIMS Adult liver stem cells are usually maintained in a quiescent/slow-cycling state. However, a proliferative population, marked by leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), was recently identified as an important liver stem cell population. We aimed to investigate the dynamics and functions of proliferative and quiescent stem cells in healthy and injured livers. METHODS We studied LGR5-positive stem cells using diphtheria toxin receptor and green fluorescent protein (GFP) knock-in mice. In these mice, LGR5-positive cells specifically coexpress diphtheria toxin receptor and the GFP reporter. Lineage-tracing experiments were performed in mice in which LGR5-positive stem cells and their daughter cells expressed a yellow fluorescent protein/mTmG reporter. Slow-cycling stem cells were investigated using GFP-based, Tet-on controlled transgenic mice. We studied the dynamics of both stem cell populations during liver homeostasis and injury induced by carbon tetrachloride. Stem cells were isolated from mouse liver and organoid formation assays were performed. We analyzed hepatocyte and cholangiocyte lineage differentiation in cultured organoids. RESULTS We did not detect LGR5-expressing stem cells in livers of mice at any stage of a lifespan, but only following liver injury induced by carbon tetrachloride. In the liver stem cell niche, where the proliferating LGR5+ cells are located, we identified a quiescent/slow-cycling cell population, called label-retaining cells (LRCs). These cells were present in the homeostatic liver, capable of retaining the GFP label over 1 year, and expressed a panel of progenitor/stem cell markers. Isolated single LRCs were capable of forming organoids that could be carried in culture, expanded for months, and differentiated into hepatocyte and cholangiocyte lineages in vitro, demonstrating their bona fide stem cell properties. More interestingly, LRCs responded to liver injury and gave rise to LGR5-expressing stem cells, as well as other potential progenitor/stem cell populations, including SOX9- and CD44-positive cells. CONCLUSIONS Proliferative LGR5 cells are an intermediate stem cell population in the liver that emerge only during tissue injury. In contrast, LRCs are quiescent stem cells that are present in homeostatic liver, respond to tissue injury, and can give rise to LGR5 stem cells, as well as SOX9- and CD44-positive cells.
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Affiliation(s)
- Wanlu Cao
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Kan Chen
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands; College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China
| | - Michiel Bolkestein
- Department of Cell Biology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands; Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Yuebang Yin
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Monique M A Verstegen
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Marcel J C Bijvelds
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Wenshi Wang
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Nesrin Tuysuz
- Department of Cell Biology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Derk Ten Berge
- Department of Cell Biology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Dave Sprengers
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Herold J Metselaar
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Luc J W van der Laan
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Jaap Kwekkeboom
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Ron Smits
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
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Emerging advancements in liver regeneration and organogenesis as tools for liver replacement. Curr Opin Organ Transplant 2017; 21:581-587. [PMID: 27755169 DOI: 10.1097/mot.0000000000000365] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Although the liver possesses a unique, innate ability to regenerate through mass compensation, transplantation remains the only therapy when damage outpaces regeneration, or liver metabolic capacity is irreversibly impacted. Recent insight from developmental biology has greatly influenced the advancement of alternative options to transplantation in these settings. RECENT FINDINGS Factors known to direct liver cell specification, expansion, and differentiation have been used to generate hepatocyte-like cells from stem and somatic cells for developing cell therapies. Additionally, interactions between hepatic epithelial and nonepithelial cells key to establishing hepatic architecture have been used in tissue engineering approaches to advance self-organizing hepatic organoids and bioartificial liver devices. Simultaneously, recent clinically applicable advances in human hepatocyte transplantation and promotion of innate hepatic regeneration have been limited. SUMMARY Although mature hepatocytes have the potential to bridge to, or replace whole organ transplantation, limits in the ability to obtain healthy cells, stabilize in-vitro expansion, cryopreserve, and alleviate rejection, still exist. Alternative sources for generating hepatocytes hold promise for cell therapy and tissue engineering. These may allow generation of autologous or universal donor cells that eliminate the need for immunosuppression; however, limits exist regarding hepatocyte maturity and efficacy at liver repopulation, as well as applicability to human chronic liver disease.
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Bria A, Marda J, Zhou J, Sun X, Cao Q, Petersen BE, Pi L. Hepatic progenitor cell activation in liver repair. LIVER RESEARCH (BEIJING, CHINA) 2017; 1:81-87. [PMID: 29276644 PMCID: PMC5739327 DOI: 10.1016/j.livres.2017.08.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The liver possesses an extraordinary ability to regenerate after injury. Hepatocyte-driven liver regeneration is the default pathway in response to mild-to-moderate acute liver damage. When replication of mature hepatocytes is blocked, facultative hepatic progenitor cells (HPCs), also referred to as oval cells (OCs) in rodents, are activated. HPC/OCs have the ability to proliferate clonogenically and differentiate into several lineages including hepatocytes and bile ductal epithelia. This is a conserved liver injury response that has been studied in many species ranging from mammals (rat, mouse, and human) to fish. In addition, improper HPC/OC activation is closely associated with fibrotic responses, characterized by myofibroblast activation and extracellular matrix production, in many chronic liver diseases. Matrix remodeling and metalloprotease activities play an important role in the regulation of HPC/OC proliferation and fibrosis progression. Thus, understanding molecular mechanisms underlying HPC/OC activation has therapeutic implications for rational design of anti-fibrotic therapies.
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Affiliation(s)
- Adam Bria
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Jorgessen Marda
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Junmei Zhou
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Xiaowei Sun
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Qi Cao
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Bryon E. Petersen
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Liya Pi
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
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Chen J, Chen L, Zern MA, Theise ND, Diehl AM, Liu P, Duan Y. The diversity and plasticity of adult hepatic progenitor cells and their niche. Liver Int 2017; 37:1260-1271. [PMID: 28135758 PMCID: PMC5534384 DOI: 10.1111/liv.13377] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Accepted: 01/23/2017] [Indexed: 12/12/2022]
Abstract
The liver is a unique organ for homoeostasis with regenerative capacities. Hepatocytes possess a remarkable capacity to proliferate upon injury; however, in more severe scenarios liver regeneration is believed to arise from at least one, if not several facultative hepatic progenitor cell compartments. Newly identified pericentral stem/progenitor cells residing around the central vein is responsible for maintaining hepatocyte homoeostasis in the uninjured liver. In addition, hepatic progenitor cells have been reported to contribute to liver fibrosis and cancers. What drives liver homoeostasis, regeneration and diseases is determined by the physiological and pathological conditions, and especially the hepatic progenitor cell niches which influence the fate of hepatic progenitor cells. The hepatic progenitor cell niches are special microenvironments consisting of different cell types, releasing growth factors and cytokines and receiving signals, as well as the extracellular matrix (ECM) scaffold. The hepatic progenitor cell niches maintain and regulate stem cells to ensure organ homoeostasis and regeneration. In recent studies, more evidence has been shown that hepatic cells such as hepatocytes, cholangiocytes or myofibroblasts can be induced to be oval cell-like state through transitions under some circumstance, those transitional cell types as potential liver-resident progenitor cells play important roles in liver pathophysiology. In this review, we describe and update recent advances in the diversity and plasticity of hepatic progenitor cell and their niches and discuss evidence supporting their roles in liver homoeostasis, regeneration, fibrosis and cancers.
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Affiliation(s)
- Jiamei Chen
- Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Key Laboratory of Liver and Kidney Diseases of Ministry of Education of China, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai key laboratory of Traditional Chinese Medicine, Shanghai 201203, China
- E-institutes of Shanghai Municipal Education Commission, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Internal Medicine, University of California Davis Medical Center, Sacramento, California, USA
- Institute for Regenerative Cures, University of California Davis Medical Center, Sacramento, California, USA
| | - Long Chen
- Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Key Laboratory of Liver and Kidney Diseases of Ministry of Education of China, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai key laboratory of Traditional Chinese Medicine, Shanghai 201203, China
| | - Mark A Zern
- Department of Internal Medicine, University of California Davis Medical Center, Sacramento, California, USA
- Institute for Regenerative Cures, University of California Davis Medical Center, Sacramento, California, USA
| | - Neil D. Theise
- Departments of Pathology and Medicine, Beth Israel Medical Center of Albert Einstein College of Medicine, New York, New York, USA
| | - Ann Mae Diehl
- Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina, USA
| | - Ping Liu
- Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Key Laboratory of Liver and Kidney Diseases of Ministry of Education of China, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai key laboratory of Traditional Chinese Medicine, Shanghai 201203, China
- E-institutes of Shanghai Municipal Education Commission, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuyou Duan
- Department of Internal Medicine, University of California Davis Medical Center, Sacramento, California, USA
- Institute for Regenerative Cures, University of California Davis Medical Center, Sacramento, California, USA
- Department of Dermatology, University of California Davis Medical Center, Sacramento, California, USA
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