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Watanabe M, Salvadori A, Markovic M, Sudo R, Ovsianikov A. Advanced liver-on-chip model mimicking hepatic lobule with continuous microvascular network via high-definition laser patterning. Mater Today Bio 2025; 32:101643. [PMID: 40206147 PMCID: PMC11979415 DOI: 10.1016/j.mtbio.2025.101643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 11/09/2024] [Accepted: 03/06/2025] [Indexed: 04/11/2025] Open
Abstract
There is a great demand for development of advanced in vitro liver models to predict the efficacy and safety of drug candidates accurately in the preclinical drug development. Despite the great efforts to develop biomimetic models, it remains challenging to precisely mimic a functional unit of the liver (i.e., hepatic lobule) with a continuous microvascular network. Recent progress in laser patterning has allowed us to create arbitrary biomimetic structures with high resolution. Here, we propose an advanced liver-on-chip model mimicking the hepatic lobule with a continuous microvascular network, ranging from the microvessels to the central vein of the liver, utilizing femtosecond laser patterning. Firstly, we optimize the laser power to pattern microchannels mimicking the microvessel and central vein of the hepatic lobule by using a femtosecond laser within a collagen-based hydrogel containing hepatic cells. Secondly, we construct continuous microvessels with luminal structures by comparing different microchannel sizes in diameter. Finally, we assemble a millimeter-scale hepatic lobule-like structure with multiple layers of microvascular networks in the liver-on-chip. Furthermore, our liver-on-chip model exhibits major liver functions and drug-induced hepatotoxicity, as evidenced by albumin and urea productions and by a toxic response to acetaminophen, respectively. Our approach provides valuable strategies for the development of advanced physiological and pathological liver-on-chip models for pharmaceutical and toxicological studies.
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Affiliation(s)
- Masafumi Watanabe
- Research Group 3D Printing and Biofabrication, Institute of Materials Science and Technology, Technische Universität Wien (TU Wien), 1060 Vienna, Austria
- Austrian Cluster for Tissue Regeneration (https://www.tissue-regeneration.at), Austria
- Japan Society for the Promotion of Science (JSPS) Overseas Research Fellow, Japan
| | - Alice Salvadori
- Research Group 3D Printing and Biofabrication, Institute of Materials Science and Technology, Technische Universität Wien (TU Wien), 1060 Vienna, Austria
- Austrian Cluster for Tissue Regeneration (https://www.tissue-regeneration.at), Austria
| | - Marica Markovic
- Research Group 3D Printing and Biofabrication, Institute of Materials Science and Technology, Technische Universität Wien (TU Wien), 1060 Vienna, Austria
- Austrian Cluster for Tissue Regeneration (https://www.tissue-regeneration.at), Austria
| | - Ryo Sudo
- Department of System Design Engineering, Keio University, 223-8522 Yokohama, Japan
| | - Aleksandr Ovsianikov
- Research Group 3D Printing and Biofabrication, Institute of Materials Science and Technology, Technische Universität Wien (TU Wien), 1060 Vienna, Austria
- Austrian Cluster for Tissue Regeneration (https://www.tissue-regeneration.at), Austria
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De Rudder M, Manco R, Coubeau L, Fontaine A, Bertrand C, Leclercq IA, Dili A. Vascular damage and excessive proliferation compromise liver function after extended hepatectomy in mice. Hepatology 2025; 81:1468-1484. [PMID: 38661628 DOI: 10.1097/hep.0000000000000900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 03/27/2024] [Indexed: 04/26/2024]
Abstract
BACKGROUND AND AIMS Surgical resection remains the gold standard for liver tumor treatment, yet the emergence of postoperative liver failure, known as the small-for-size syndrome (SFSS), poses a significant challenge. The activation of hypoxia sensors in an SFSS liver remnant initiated early angiogenesis, improving the vascular architecture, safeguarding against liver failure, and reducing mortality. The study aimed to elucidate vascular remodeling mechanisms in SFSS and their impact on hepatocyte function and subsequent liver failure. APPROACH AND RESULTS Mice underwent extended partial hepatectomy to induce SFSS, with a subset exposed to hypoxia immediately after surgery. Hypoxia bolstered posthepatectomy survival rates. The early proliferation of liver sinusoidal cells, coupled with recruitment of putative endothelial progenitor cells, increased vascular density, improved lobular perfusion, and limited hemorrhagic events in the regenerating liver under hypoxia. Administration of granulocyte colony-stimulating factor in hepatectomized mice mimicked the effects of hypoxia on vascular remodeling and endothelial progenitor cell recruitment but failed to rescue survival. Compared to normoxia, hypoxia favored hepatocyte function over proliferation, promoting functional preservation in the regenerating remnant. Injection of Adeno-associated virus serotype 8-thyroxine-binding globulin-hepatocyte nuclear factor 4 alpha virus for hepatocyte-specific overexpression of hepatocyte nuclear factor 4 alpha, the master regulator of hepatocyte function, enforced functionality in proliferating hepatocytes but did not rescue survival. The combination of hepatocyte nuclear factor 4 alpha overexpression and granulocyte colony-stimulating factor treatment rescued survival after SFSS-setting hepatectomy. CONCLUSIONS In summary, SFSS arises from an imbalance and desynchronized interplay between functional regeneration and vascular restructuring. To improve survival following SFSS hepatectomy, it is essential to adopt a 2-pronged strategy aimed at preserving the function of proliferating parenchymal cells and simultaneously attenuating vascular damage.
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Affiliation(s)
- Maxime De Rudder
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Rita Manco
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Laurent Coubeau
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), Brussels, Belgium
- Department of Surgery, University Clinics of St Luc, UCLouvain, Brussels, Belgium
| | - Alix Fontaine
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Claude Bertrand
- Department of Surgery, University Hospital of UCLouvain-Namur, Site of Godinne, Yvoir, Belgium
| | - Isabelle A Leclercq
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Alexandra Dili
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), Brussels, Belgium
- Department of Surgery, University Hospital of UCLouvain-Namur, Site of Godinne, Yvoir, Belgium
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Ning M, Lu D, Liang D, Ren PG. Single-cell RNA sequencing advances in revealing the development and progression of MASH: the identifications and interactions of non-parenchymal cells. Front Mol Biosci 2025; 12:1513993. [PMID: 40201243 PMCID: PMC11976672 DOI: 10.3389/fmolb.2025.1513993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Accepted: 03/05/2025] [Indexed: 04/10/2025] Open
Abstract
Developing drugs for the treatment of Metabolic Associated Steatohepatitis (MASH) has always been a significant challenge. Researchers have been dedicated to exploring drugs and therapeutic strategies to alleviate disease progression, but treatments remain limited. This is partly due to the complexity of the pathophysiological processes, and inadequate knowledge of the cellular and molecular mechanisms in MASH. Especially, the liver non-parenchymal cells (NPCs) like Kupffer cells, hepatic stellate cells and sinusoidal endothelial cells which play critical roles in live function, immune responses, fibrosis and disease progression. Deciphering how these cells function in MASH, would help understand the pathophysiological processes and find potential drug targets. In recent years, new technologies have been developed for single-cell transcriptomic sequencing, making cell-specific transcriptome profiling a reality in healthy and diseased livers. In this review, we discussed how the use of single-cell transcriptomic sequencing provided us with an in-depth understanding of the heterogeneous, cellular interactions among non-parenchymal cells and tried to highlight recent discoveries in MASH by this technology. It is hoped that the summarized features and markers of various subclusters in this review could provide a technical reference for further experiments and a theoretical basis for clinical applications.
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Affiliation(s)
- Meng Ning
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen, China
- Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Donghui Lu
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Dong Liang
- Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Pei-Gen Ren
- Center for Cancer Immunology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- University of Chinese Academy of Sciences, Beijing, China
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Follert P, Große‐Segerath L, Lammert E. Blood flow-induced angiocrine signals promote organ growth and regeneration. Bioessays 2025; 47:e2400207. [PMID: 39529434 PMCID: PMC11755702 DOI: 10.1002/bies.202400207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 10/15/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024]
Abstract
Recently, we identified myeloid-derived growth factor (MYDGF) as a blood flow-induced angiocrine signal that promotes human and mouse hepatocyte proliferation and survival. Here, we review literature reporting changes in blood flow after partial organ resection in the liver, lung, and kidney, and we describe the angiocrine signals released by endothelial cells (ECs) upon blood flow alterations in these organs. While hepatocyte growth factor (HGF) and MYDGF are important angiocrine signals for liver regeneration, by now, angiocrine signals have also been reported to stimulate hyperplasia and/or hypertrophy during the regeneration of lungs and kidneys. In addition, angiocrine signals play a critical role in tumor growth. Understanding the mechano-elastic properties and flow-mediated alterations in the organ-specific microvasculature is crucial for therapeutic approaches to maintain organ health and initiate organ renewal.
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Affiliation(s)
- Paula Follert
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural SciencesInstitute of Metabolic PhysiologyDüsseldorfGermany
| | - Linda Große‐Segerath
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural SciencesInstitute of Metabolic PhysiologyDüsseldorfGermany
- German Diabetes Center (DDZ)Leibniz Center for Diabetes Research at Heinrich Heine University DüsseldorfDüsseldorfGermany
- German Center for Diabetes Research (DZD e.V.)NeuherbergGermany
| | - Eckhard Lammert
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural SciencesInstitute of Metabolic PhysiologyDüsseldorfGermany
- German Diabetes Center (DDZ)Leibniz Center for Diabetes Research at Heinrich Heine University DüsseldorfDüsseldorfGermany
- German Center for Diabetes Research (DZD e.V.)NeuherbergGermany
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Hoffmann J, Schüler J, Dietsch B, Kürschner-Zacharias SW, Sticht C, Trogisch FA, Schreitmüller M, Baljkas T, Schledzewski K, Reinhart M, Wohlfeil SA, Winkler M, Schmid CD, Heineke J, Géraud C, Goerdt S, Reiners-Koch PS, Olsavszky V. Steatohepatitis-induced vascular niche alterations promote melanoma metastasis. Cancer Metab 2025; 13:5. [PMID: 39875968 PMCID: PMC11776123 DOI: 10.1186/s40170-025-00374-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 01/13/2025] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND In malignant melanoma, liver metastases significantly reduce survival, even despite highly effective new therapies. Given the increase in metabolic liver diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), this study investigated the impact of liver sinusoidal endothelial cell (LSEC)-specific alterations in MASLD/MASH on hepatic melanoma metastasis. METHODS Mice were fed a choline-deficient L-amino acid-defined (CDAA) diet for ten weeks to induce MASH-associated liver fibrosis, or a CDAA diet or a high fat diet (HFD) for shorter periods of time to induce early steatosis-associated alterations. Liver metastasis formation was assessed using melanoma cell lines B16F10Luc2 and Wt31. LSEC-specific GATA4 knockout mice (Gata4LSEC-KO/BL) developing MASH-like liver fibrosis without steatosis via a pathogenic angiocrine switch were included to compare the impact of liver fibrosis versus hepatic steatosis on hepatic melanoma metastasis. Bulk RNA-Seq of isolated LSECs from CDAA-fed and control mice was performed. Levels of adhesion molecules (VCAM1, ICAM1, E-selectin) were monitored, and ICAM1 and VCAM1 antibody therapy was employed. RESULTS Feeding a CDAA diet, in contrast to a HFD, led to increased metastasis before the development of liver fibrosis. Gata4LSEC-KO/BL mice characterized by vascular changes ensuing perisinusoidal liver fibrosis without steatosis also exhibited increased metastasis. Early molecular alterations in the hepatic vascular niche, rather than fibrosis or steatosis, correlated with metastasis, as shown by LSEC dedifferentiation and upregulation of endothelial adhesion molecules. The metastatic process in CDAA-fed mice was also dependent on the respective melanoma cell lines used and on the route of their metastatic spread. ICAM1 inhibition, but not VCAM1 inhibition reduced melanoma cell retention. CONCLUSION We discovered that the hepatic vascular niche acts as a delicate sensor to even short-term nutritional alterations during the development of MASLD/MASH. The dynamic adaptations to the metabolic challenges of developing MASLD/MASH caused an early shift from the normal hepatic vascular niche to a pre-metastatic vascular niche that promoted hepatic melanoma metastasis in the context of cell-autonomous and acquired melanoma cell features. Altogether, our findings provide a potential avenue for angiotargeted therapies to prevent hepatic melanoma metastasis.
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Affiliation(s)
- Johannes Hoffmann
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, 68167, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Julia Schüler
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, 68167, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Bianca Dietsch
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, 68167, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Section of Clinical and Molecular Dermatology, Department of Dermatology, Venereology and Allergy, Medical Faculty Mannheim, University Medical Centerand, Heidelberg University , Mannheim, Germany
| | - Sina Wietje Kürschner-Zacharias
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, 68167, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Carsten Sticht
- Core Facility Platform Mannheim (CFPM), Medical Faculty Mannheim, NGS Core Facility, Heidelberg University, Mannheim, Germany
| | - Felix A Trogisch
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Core Facility Platform Mannheim (CFPM), Cardiac Imaging Center, Mannheim, Faculty of Medicine, Heidelberg University, Mannheim, 68167, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Mannheim, Germany
| | - Maren Schreitmüller
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, 68167, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Section of Clinical and Molecular Dermatology, Department of Dermatology, Venereology and Allergy, Medical Faculty Mannheim, University Medical Centerand, Heidelberg University , Mannheim, Germany
| | - Tinja Baljkas
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, 68167, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Kai Schledzewski
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, 68167, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Manuel Reinhart
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, 68167, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sebastian A Wohlfeil
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, 68167, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Section of Clinical and Molecular Dermatology, Department of Dermatology, Venereology and Allergy, Medical Faculty Mannheim, University Medical Centerand, Heidelberg University , Mannheim, Germany
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
| | - Manuel Winkler
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, 68167, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Christian David Schmid
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, 68167, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Joerg Heineke
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Core Facility Platform Mannheim (CFPM), Cardiac Imaging Center, Mannheim, Faculty of Medicine, Heidelberg University, Mannheim, 68167, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Mannheim, Germany
| | - Cyrill Géraud
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, 68167, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Section of Clinical and Molecular Dermatology, Department of Dermatology, Venereology and Allergy, Medical Faculty Mannheim, University Medical Centerand, Heidelberg University , Mannheim, Germany
| | - Sergij Goerdt
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, 68167, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Philipp-Sebastian Reiners-Koch
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, 68167, Germany.
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
| | - Victor Olsavszky
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, 68167, Germany.
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
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Tanaka S, Elgaabari A, Seki M, Kuwakado S, Zushi K, Miyamoto J, Sawano S, Mizunoya W, Ehara K, Watanabe N, Ogawa Y, Imakyure H, Fujimaru R, Osaki R, Shitamitsu K, Mizoguchi K, Ushijima T, Maeno T, Nakashima T, Suzuki T, Nakamura M, Anderson JE, Tatsumi R. In vitro immuno-prevention of nitration/dysfunction of myogenic stem cell activator HGF, towards developing a strategy for age-related muscle atrophy. Aging Cell 2024; 23:e14337. [PMID: 39297318 PMCID: PMC11464115 DOI: 10.1111/acel.14337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 08/24/2024] [Accepted: 09/02/2024] [Indexed: 10/11/2024] Open
Abstract
In response to peroxynitrite (ONOO-) generation, myogenic stem satellite cell activator HGF (hepatocyte growth factor) undergoes nitration of tyrosine residues (Y198 and Y250) predominantly on fast IIa and IIx myofibers to lose its binding to the signaling receptor c-met, thereby disturbing muscle homeostasis during aging. Here we show that rat anti-HGF monoclonal antibody (mAb) 1H41C10, which was raised in-house against a synthetic peptide FTSNPEVRnitroY198EV, a site well-conserved in mammals, functions to confer resistance to nitration dysfunction on HGF. 1H41C10 was characterized by recognizing both nitrated and non-nitrated HGF with different affinities as revealed by Western blotting, indicating that the paratope of 1H41C10 may bind to the immediate vicinity of Y198. Subsequent experiments showed that 1H41C10-bound HGF resists peroxynitrite-induced nitration of Y198. A companion mAb-1H42F4 presented similar immuno-reactivity, but did not protect Y198 nitration, and thus served as the control. Importantly, 1H41C10-HGF also withstood Y250 nitration to retain c-met binding and satellite cell activation functions in culture. The Fab region of 1H41C10 exerts resistivity to Y250 nitration possibly due to its localization in the immediate vicinity to Y250, as supported by an additional set of experiments showing that the 1H41C10-Fab confers Y250-nitration resistance which the Fc segment does not. Findings highlight the in vitro preventive impact of 1H41C10 on HGF nitration-dysfunction that strongly impairs myogenic stem cell dynamics, potentially pioneering cogent strategies for counteracting or treating age-related muscle atrophy with fibrosis (including sarcopenia and frailty) and the therapeutic application of investigational HGF drugs.
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Affiliation(s)
- Sakiho Tanaka
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Alaa Elgaabari
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
- Department of Physiology, Faculty of Veterinary MedicineKafrelsheikh UniversityKafrelsheikhEgypt
| | - Miyumi Seki
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - So Kuwakado
- Department of Orthopaedic Surgery, Faculty of Medical SciencesKyushu UniversityFukuokaJapan
| | - Kahona Zushi
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Junri Miyamoto
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Shoko Sawano
- Department of Food and Life Science, School of Life and Environmental ScienceAzabu UniversitySagamiharaJapan
| | - Wataru Mizunoya
- Department of Animal Science and Biotechnology, School of Veterinary MedicineAzabu UniversitySagamiharaJapan
| | - Kenshiro Ehara
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Naruha Watanabe
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Yohei Ogawa
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Hikaru Imakyure
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Reina Fujimaru
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Rika Osaki
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Kazuki Shitamitsu
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Kaoru Mizoguchi
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Tomoki Ushijima
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Takahiro Maeno
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Takashi Nakashima
- Department of Bioscience and Biotechnology, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Takahiro Suzuki
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Mako Nakamura
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Judy E. Anderson
- Department of Biological Sciences, Faculty of ScienceUniversity of ManitobaWinnipegManitobaCanada
| | - Ryuichi Tatsumi
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
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Okumura A, Aoshima K, Tanimizu N. Generation of in vivo-like multicellular liver organoids by mimicking developmental processes: A review. Regen Ther 2024; 26:219-234. [PMID: 38903867 PMCID: PMC11186971 DOI: 10.1016/j.reth.2024.05.020] [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: 05/01/2024] [Revised: 05/24/2024] [Accepted: 05/30/2024] [Indexed: 06/22/2024] Open
Abstract
Liver is involved in metabolic reactions, ammonia detoxification, and immunity. Multicellular liver tissue cultures are more desirable for drug screening, disease modeling, and researching transplantation therapy, than hepatocytes monocultures. Hepatocytes monocultures are not stable for long. Further, hepatocyte-like cells induced from pluripotent stem cells and in vivo hepatocytes are functionally dissimilar. Organoid technology circumvents these issues by generating functional ex vivo liver tissue from intrinsic liver progenitor cells and extrinsic stem cells, including pluripotent stem cells. To function as in vivo liver tissue, the liver organoid cells must be arranged precisely in the 3-dimensional space, closely mimicking in vivo liver tissue. Moreover, for long term functioning, liver organoids must be appropriately vascularized and in contact with neighboring epithelial tissues (e.g., bile canaliculi and intrahepatic bile duct, or intrahepatic and extrahepatic bile ducts). Recent discoveries in liver developmental biology allows one to successfully induce liver component cells and generate organoids. Thus, here, in this review, we summarize the current state of knowledge on liver development with a focus on its application in generating different liver organoids. We also cover the future prospects in creating (functionally and structurally) in vivo-like liver organoids using the current knowledge on liver development.
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Affiliation(s)
- Ayumu Okumura
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan
| | - Kenji Aoshima
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan
| | - Naoki Tanimizu
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan
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8
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Zuo B, Yang F, Huang L, Han J, Li T, Ma Z, Cao L, Li Y, Bai X, Jiang M, He Y, Xia L. Endothelial Slc35a1 Deficiency Causes Loss of LSEC Identity and Exacerbates Neonatal Lipid Deposition in the Liver in Mice. Cell Mol Gastroenterol Hepatol 2024; 17:1039-1061. [PMID: 38467191 PMCID: PMC11061248 DOI: 10.1016/j.jcmgh.2024.03.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 03/05/2024] [Accepted: 03/06/2024] [Indexed: 03/13/2024]
Abstract
BACKGROUND & AIMS The functional maturation of the liver largely occurs after birth. In the early stages of life, the liver of a newborn encounters enormous high-fat metabolic stress caused by the consumption of breast milk. It is unclear how the maturing liver adapts to high lipid metabolism. Liver sinusoidal endothelial cells (LSECs) play a fundamental role in establishing liver vasculature and are decorated with many glycoproteins on their surface. The Slc35a1 gene encodes a cytidine-5'-monophosphate (CMP)-sialic acid transporter responsible for transporting CMP-sialic acids between the cytoplasm and the Golgi apparatus for protein sialylation. This study aimed to determine whether endothelial sialylation plays a role in hepatic vasculogenesis and functional maturation. METHODS Endothelial-specific Slc35a1 knockout mice were generated. Liver tissues were collected for histologic analysis, lipidomic profiling, RNA sequencing, confocal immunofluorescence, and immunoblot analyses. RESULTS Endothelial Slc35a1-deficient mice exhibited excessive neonatal hepatic lipid deposition, severe liver damage, and high mortality. Endothelial deletion of Slc35a1 led to sinusoidal capillarization and disrupted hepatic zonation. Mechanistically, vascular endothelial growth factor receptor 2 (VEGFR2) in LSECs was desialylated and VEGFR2 signaling was enhanced in Slc35a1-deficient mice. Inhibition of VEGFR2 signaling by SU5416 alleviated lipid deposition and restored hepatic vasculature in Slc35a1-deficient mice. CONCLUSIONS Our findings suggest that sialylation of LSECs is critical for maintaining hepatic vascular development and lipid homeostasis. Targeting VEGFR2 signaling may be a new strategy to prevent liver disorders associated with abnormal vasculature and lipid deposition.
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Affiliation(s)
- Bin Zuo
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China; Engineering Center of Hematological Disease of Ministry of Education, Cyrus Tang Hematology Center, Soochow University, Suzhou, China
| | - Fei Yang
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lulu Huang
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jingjing Han
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Tianyi Li
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhenni Ma
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lijuan Cao
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yun Li
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xia Bai
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China; Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Miao Jiang
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yang He
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China; Engineering Center of Hematological Disease of Ministry of Education, Cyrus Tang Hematology Center, Soochow University, Suzhou, China; Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
| | - Lijun Xia
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China; Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.
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9
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Große-Segerath L, Follert P, Behnke K, Ettich J, Buschmann T, Kirschner P, Hartwig S, Lehr S, Korf-Klingebiel M, Eberhard D, Lehwald-Tywuschik N, Al-Hasani H, Knoefel WT, Heinrich S, Levkau B, Wollert KC, Scheller J, Lammert E. Identification of myeloid-derived growth factor as a mechanically-induced, growth-promoting angiocrine signal for human hepatocytes. Nat Commun 2024; 15:1076. [PMID: 38316785 PMCID: PMC10844291 DOI: 10.1038/s41467-024-44760-y] [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: 05/24/2022] [Accepted: 01/02/2024] [Indexed: 02/07/2024] Open
Abstract
Recently, we have shown that after partial hepatectomy (PHx), an increased hepatic blood flow initiates liver growth in mice by vasodilation and mechanically-triggered release of angiocrine signals. Here, we use mass spectrometry to identify a mechanically-induced angiocrine signal in human hepatic endothelial cells, that is, myeloid-derived growth factor (MYDGF). We show that it induces proliferation and promotes survival of primary human hepatocytes derived from different donors in two-dimensional cell culture, via activation of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3). MYDGF also enhances proliferation of human hepatocytes in three-dimensional organoids. In vivo, genetic deletion of MYDGF decreases hepatocyte proliferation in the regenerating mouse liver after PHx; conversely, adeno-associated viral delivery of MYDGF increases hepatocyte proliferation and MAPK signaling after PHx. We conclude that MYDGF represents a mechanically-induced angiocrine signal and that it triggers growth of, and provides protection to, primary mouse and human hepatocytes.
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Affiliation(s)
- Linda Große-Segerath
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, 40225, Düsseldorf, Germany
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, 40225, Düsseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, 85764, Neuherberg, Germany
| | - Paula Follert
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, 40225, Düsseldorf, Germany
| | - Kristina Behnke
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany
| | - Julia Ettich
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany
| | - Tobias Buschmann
- Institute for Molecular Medicine III, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany
| | - Philip Kirschner
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, 40225, Düsseldorf, Germany
| | - Sonja Hartwig
- German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, 85764, Neuherberg, Germany
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Medical Faculty, 40225, Düsseldorf, Germany
| | - Stefan Lehr
- German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, 85764, Neuherberg, Germany
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Medical Faculty, 40225, Düsseldorf, Germany
| | - Mortimer Korf-Klingebiel
- Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School, 30625, Hannover, Germany
| | - Daniel Eberhard
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, 40225, Düsseldorf, Germany
| | - Nadja Lehwald-Tywuschik
- Department of General, Visceral, Thorax and Pediatric Surgery, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany
| | - Hadi Al-Hasani
- German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, 85764, Neuherberg, Germany
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Medical Faculty, 40225, Düsseldorf, Germany
| | - Wolfram Trudo Knoefel
- Department of General, Visceral, Thorax and Pediatric Surgery, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany
| | - Stefan Heinrich
- Department of General, Visceral and Transplantation Surgery, University Hospital Center Mainz, 55131, Mainz, Germany
| | - Bodo Levkau
- Institute for Molecular Medicine III, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany
| | - Kai C Wollert
- Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School, 30625, Hannover, Germany
| | - Jürgen Scheller
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany
| | - Eckhard Lammert
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, 40225, Düsseldorf, Germany.
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, 40225, Düsseldorf, Germany.
- German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, 85764, Neuherberg, Germany.
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10
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Elgaabari A, Imatomi N, Kido H, Nakashima T, Okuda S, Manabe Y, Sawano S, Mizunoya W, Kaneko R, Tanaka S, Maeno T, Matsuyoshi Y, Seki M, Kuwakado S, Zushi K, Daneshvar N, Nakamura M, Suzuki T, Sunagawa K, Anderson JE, Allen RE, Tatsumi R. Age-related nitration/dysfunction of myogenic stem cell activator HGF. Aging Cell 2024; 23:e14041. [PMID: 37985931 PMCID: PMC10861216 DOI: 10.1111/acel.14041] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 10/27/2023] [Accepted: 10/28/2023] [Indexed: 11/22/2023] Open
Abstract
Mechanical perturbation triggers activation of resident myogenic stem cells to enter the cell cycle through a cascade of events including hepatocyte growth factor (HGF) release from its extracellular tethering and the subsequent presentation to signaling-receptor c-met. Here, we show that with aging, extracellular HGF undergoes tyrosine-residue (Y) nitration and loses c-met binding, thereby disturbing muscle homeostasis. Biochemical studies demonstrated that nitration/dysfunction is specific to HGF among other major growth factors and is characterized by its locations at Y198 and Y250 in c-met-binding domains. Direct-immunofluorescence microscopy of lower hind limb muscles from three age groups of rat, provided direct in vivo evidence for age-related increases in nitration of ECM-bound HGF, preferentially stained for anti-nitrated Y198 and Y250-HGF mAbs (raised in-house) in fast IIa and IIx myofibers. Overall, findings highlight inhibitory impacts of HGF nitration on myogenic stem cell dynamics, pioneering a cogent discussion for better understanding age-related muscle atrophy and impaired regeneration with fibrosis (including sarcopenia and frailty).
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Affiliation(s)
- Alaa Elgaabari
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
- Department of Physiology, Faculty of Veterinary MedicineKafrelsheikh UniversityKafrelsheikhEgypt
| | - Nana Imatomi
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Hirochika Kido
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Takashi Nakashima
- Department of Bioscience and Biotechnology, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Shoko Okuda
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Yoshitaka Manabe
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Shoko Sawano
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
- Present address:
Department of Food and Life Science, School of Life and Environmental ScienceAzabu UniversitySagamiharaJapan
| | - Wataru Mizunoya
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
- Present address:
Department of Animal Science and Biotechnology, School of Veterinary MedicineAzabu UniversitySagamiharaJapan
| | - Ryuki Kaneko
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Sakiho Tanaka
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Takahiro Maeno
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Yuji Matsuyoshi
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Miyumi Seki
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - So Kuwakado
- Department of Orthopaedic Surgery, Faculty of Medical SciencesKyushu UniversityFukuokaJapan
| | - Kahona Zushi
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Nasibeh Daneshvar
- Department of Biological Sciences, Faculty of ScienceUniversity of ManitobaWinnipegManitobaCanada
| | - Mako Nakamura
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Takahiro Suzuki
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Kenji Sunagawa
- Department of Cardiovascular Medicine, Graduate School of MedicineKyushu UniversityFukuokaJapan
| | - Judy E. Anderson
- Department of Biological Sciences, Faculty of ScienceUniversity of ManitobaWinnipegManitobaCanada
| | - Ronald E. Allen
- The School of Animal and Comparative Biomedical SciencesUniversity of ArizonaTucsonArizonaUSA
| | - Ryuichi Tatsumi
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
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11
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Li ZW, Ruan B, Yang PJ, Liu JJ, Song P, Duan JL, Wang L. Oit3, a promising hallmark gene for targeting liver sinusoidal endothelial cells. Signal Transduct Target Ther 2023; 8:344. [PMID: 37696816 PMCID: PMC10495338 DOI: 10.1038/s41392-023-01621-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 08/22/2023] [Accepted: 08/22/2023] [Indexed: 09/13/2023] Open
Abstract
Liver sinusoidal endothelial cells (LSECs) play a pivotal role in maintaining liver homeostasis and influencing the pathological processes of various liver diseases. However, neither LSEC-specific hallmark genes nor a LSEC promoter-driven Cre mouse line has been introduced before, which largely restricts the study of liver diseases with vascular disorders. To explore LSEC-specific hallmark genes, we compared the top 50 marker genes between liver endothelial cells (ECs) and liver capillary ECs and identified 18 overlapping genes. After excluding globally expressed genes and those with low expression percentages, we narrowed our focus to two final candidates: Oit3 and Dnase1l3. Through single-cell RNA sequencing (scRNA-seq) and analysis of the NCBI database, we confirmed the extrahepatic expression of Dnase1l3. The paired-cell sequencing data further demonstrated that Oit3 was predominantly expressed in the midlobular liver ECs. Subsequently, we constructed inducible Oit3-CreERT2 transgenic mice, which were further crossed with ROSA26-tdTomato mice. Microscopy validated that the established Oit3-CreERT2-tdTomato mice exhibited significant fluorescence in the liver rather than in other organs. The staining analysis confirmed the colocalization of tdTomato and EC markers. Ex-vivo experiments further confirmed that isolated tdTomato+ cells exhibited well-differentiated fenestrae and highly expressed EC markers, confirming their identity as LSECs. Overall, Oit3 is a promising hallmark gene for tracing LSECs. The establishment of Oit3-CreERT2-tdTomato mice provides a valuable model for studying the complexities of LSECs in liver diseases.
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Affiliation(s)
- Zhi-Wen Li
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, 710032, Xi'an, China
| | - Bai Ruan
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, 710032, Xi'an, China
- Center of Clinical Aerospace Medicine & Department of Aviation Medicine, Fourth Military Medical University, 710032, Xi'an, China
| | - Pei-Jun Yang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, 710032, Xi'an, China
| | - Jing-Jing Liu
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, 710032, Xi'an, China
| | - Ping Song
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, 710032, Xi'an, China
| | - Juan-Li Duan
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, 710032, Xi'an, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, 710032, Xi'an, China.
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12
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McConnell MJ, Kostallari E, Ibrahim SH, Iwakiri Y. The evolving role of liver sinusoidal endothelial cells in liver health and disease. Hepatology 2023; 78:649-669. [PMID: 36626620 PMCID: PMC10315420 DOI: 10.1097/hep.0000000000000207] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/25/2022] [Indexed: 01/12/2023]
Abstract
LSECs are a unique population of endothelial cells within the liver and are recognized as key regulators of liver homeostasis. LSECs also play a key role in liver disease, as dysregulation of their quiescent phenotype promotes pathological processes within the liver including inflammation, microvascular thrombosis, fibrosis, and portal hypertension. Recent technical advances in single-cell analysis have characterized distinct subpopulations of the LSECs themselves with a high resolution and defined their gene expression profile and phenotype, broadening our understanding of their mechanistic role in liver biology. This article will review 4 broad advances in our understanding of LSEC biology in general: (1) LSEC heterogeneity, (2) LSEC aging and senescence, (3) LSEC role in liver regeneration, and (4) LSEC role in liver inflammation and will then review the role of LSECs in various liver pathologies including fibrosis, DILI, alcohol-associated liver disease, NASH, viral hepatitis, liver transplant rejection, and ischemia reperfusion injury. The review will conclude with a discussion of gaps in knowledge and areas for future research.
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Affiliation(s)
- Matthew J. McConnell
- Section of Digestive Disease, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
| | | | - Samar H. Ibrahim
- Division of Gastroenterology, Mayo Clinic, Rochester, MN
- Division of Pediatric Gastroenterology, Mayo Clinic, Rochester, MN
| | - Yasuko Iwakiri
- Section of Digestive Disease, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
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13
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Cooper SA, Kostallari E, Shah VH. Angiocrine Signaling in Sinusoidal Health and Disease. Semin Liver Dis 2023; 43:245-257. [PMID: 37442155 PMCID: PMC10798369 DOI: 10.1055/a-2128-5907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/15/2023]
Abstract
Liver sinusoidal endothelial cells (LSECs) are key players in maintaining hepatic homeostasis. They also play crucial roles during liver injury by communicating with liver cell types as well as immune cells and promoting portal hypertension, fibrosis, and inflammation. Cutting-edge technology, such as single cell and spatial transcriptomics, have revealed the existence of distinct LSEC subpopulations with a clear zonation in the liver. The signals released by LSECs are commonly called "angiocrine signaling." In this review, we summarize the role of angiocrine signaling in health and disease, including zonation in healthy liver, regeneration, fibrosis, portal hypertension, nonalcoholic fatty liver disease, alcohol-associated liver disease, aging, drug-induced liver injury, and ischemia/reperfusion, as well as potential therapeutic advances. In conclusion, sinusoidal endotheliopathy is recognized in liver disease and promising preclinical studies are paving the path toward LSEC-specific pharmacotherapies.
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Affiliation(s)
- Shawna A. Cooper
- Biochemistry and Molecular Biology Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota
| | - Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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14
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Bishop D, Schwarz Q, Wiszniak S. Endothelial-derived angiocrine factors as instructors of embryonic development. Front Cell Dev Biol 2023; 11:1172114. [PMID: 37457293 PMCID: PMC10339107 DOI: 10.3389/fcell.2023.1172114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 06/19/2023] [Indexed: 07/18/2023] Open
Abstract
Blood vessels are well-known to play roles in organ development and repair, primarily owing to their fundamental function in delivering oxygen and nutrients to tissues to promote their growth and homeostasis. Endothelial cells however are not merely passive conduits for carrying blood. There is now evidence that endothelial cells of the vasculature actively regulate tissue-specific development, morphogenesis and organ function, as well as playing roles in disease and cancer. Angiocrine factors are growth factors, cytokines, signaling molecules or other regulators produced directly from endothelial cells to instruct a diverse range of signaling outcomes in the cellular microenvironment, and are critical mediators of the vascular control of organ function. The roles of angiocrine signaling are only beginning to be uncovered in diverse fields such as homeostasis, regeneration, organogenesis, stem-cell maintenance, cell differentiation and tumour growth. While in some cases the specific angiocrine factor involved in these processes has been identified, in many cases the molecular identity of the angiocrine factor(s) remain to be discovered, even though the importance of angiocrine signaling has been implicated. In this review, we will specifically focus on roles for endothelial-derived angiocrine signaling in instructing tissue morphogenesis and organogenesis during embryonic and perinatal development.
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15
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Hu XH, Chen L, Wu H, Tang YB, Zheng QM, Wei XY, Wei Q, Huang Q, Chen J, Xu X. Cell therapy in end-stage liver disease: replace and remodel. Stem Cell Res Ther 2023; 14:141. [PMID: 37231461 DOI: 10.1186/s13287-023-03370-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 04/26/2023] [Indexed: 05/27/2023] Open
Abstract
Liver disease is prevalent worldwide. When it reaches the end stage, mortality rises to 50% or more. Although liver transplantation has emerged as the most efficient treatment for end-stage liver disease, its application has been limited by the scarcity of donor livers. The lack of acceptable donor organs implies that patients are at high risk while waiting for suitable livers. In this scenario, cell therapy has emerged as a promising treatment approach. Most of the time, transplanted cells can replace host hepatocytes and remodel the hepatic microenvironment. For instance, hepatocytes derived from donor livers or stem cells colonize and proliferate in the liver, can replace host hepatocytes, and restore liver function. Other cellular therapy candidates, such as macrophages and mesenchymal stem cells, can remodel the hepatic microenvironment, thereby repairing the damaged liver. In recent years, cell therapy has transitioned from animal research to early human studies. In this review, we will discuss cell therapy in end-stage liver disease treatment, especially focusing on various cell types utilized for cell transplantation, and elucidate the processes involved. Furthermore, we will also summarize the practical obstacles of cell therapy and offer potential solutions.
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Affiliation(s)
- Xin-Hao Hu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Lan Chen
- Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Hao Wu
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
| | - Yang-Bo Tang
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
| | - Qiu-Min Zheng
- Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Xu-Yong Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Qiang Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Qi Huang
- Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Jian Chen
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
| | - Xiao Xu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
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16
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Li ZW, Wang L. The role of liver sinusoidal endothelial cells in liver remodeling after injury. Hepatobiliary Pancreat Dis Int 2023; 22:22-27. [PMID: 36182636 DOI: 10.1016/j.hbpd.2022.09.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 09/15/2022] [Indexed: 02/07/2023]
Abstract
Liver transplantation is the optimal treatment for patients with end-stage liver disease, metabolic liver diseases, and hepatic malignancies that are not amenable to resection. Hepatic ischemia-reperfusion injury (IRI) is the main problem in liver transplantation and liver resection, leading to parenchymal cell injury and organ dysfunction. The damage of liver sinusoidal endothelial cells (LSECs) is a critical event in IRI. LSECs work as an important regulating factor of liver regeneration after partial hepatectomy. This review primarily describes the mechanisms of LSECs injury in IRI and explores the roles of LSECs in liver regeneration, and briefly introduces the protective strategies targeting LSECs damaged in IRI.
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Affiliation(s)
- Zhi-Wen Li
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
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17
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Jauch AS, Wohlfeil SA, Weller C, Dietsch B, Häfele V, Stojanovic A, Kittel M, Nolte H, Cerwenka A, Neumaier M, Schledzewski K, Sticht C, Reiners-Koch PS, Goerdt S, Géraud C. Lyve-1 deficiency enhances the hepatic immune microenvironment entailing altered susceptibility to melanoma liver metastasis. Cancer Cell Int 2022; 22:398. [PMID: 36496412 PMCID: PMC9741792 DOI: 10.1186/s12935-022-02800-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/21/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Hyaluronan receptor LYVE-1 is expressed by liver sinusoidal endothelial cells (LSEC), lymphatic endothelial cells and specialized macrophages. Besides binding to hyaluronan, LYVE-1 can mediate adhesion of leukocytes and cancer cells to endothelial cells. Here, we assessed the impact of LYVE-1 on physiological liver functions and metastasis. METHODS Mice with deficiency of Lyve-1 (Lyve-1-KO) were analyzed using histology, immunofluorescence, microarray analysis, plasma proteomics and flow cytometry. Liver metastasis was studied by intrasplenic/intravenous injection of melanoma (B16F10 luc2, WT31) or colorectal carcinoma (MC38). RESULTS Hepatic architecture, liver size, endothelial differentiation and angiocrine functions were unaltered in Lyve-1-KO. Hyaluronan plasma levels were significantly increased in Lyve-1-KO. Besides, plasma proteomics revealed increased carbonic anhydrase-2 and decreased FXIIIA. Furthermore, gene expression analysis of LSEC indicated regulation of immunological pathways. Therefore, liver metastasis of highly and weakly immunogenic tumors, i.e. melanoma and colorectal carcinoma (CRC), was analyzed. Hepatic metastasis of B16F10 luc2 and WT31 melanoma cells, but not MC38 CRC cells, was significantly reduced in Lyve-1-KO mice. In vivo retention assays with B16F10 luc2 cells were unaltered between Lyve-1-KO and control mice. However, in tumor-free Lyve-1-KO livers numbers of hepatic CD4+, CD8+ and regulatory T cells were increased. In addition, iron deposition was found in F4/80+ liver macrophages known to exert pro-inflammatory effects. CONCLUSION Lyve-1 deficiency controlled hepatic metastasis in a tumor cell-specific manner leading to reduced growth of hepatic metastases of melanoma, but not CRC. Anti-tumorigenic effects are likely due to enhancement of the premetastatic hepatic immune microenvironment influencing early liver metastasis formation.
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Affiliation(s)
- Anna Sophia Jauch
- grid.7700.00000 0001 2190 4373Section of Clinical and Molecular Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sebastian A. Wohlfeil
- grid.7700.00000 0001 2190 4373Department of Dermatology, Venereology, and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, 68135 Mannheim, Germany ,grid.7497.d0000 0004 0492 0584Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Céline Weller
- grid.7700.00000 0001 2190 4373Section of Clinical and Molecular Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Bianca Dietsch
- grid.7700.00000 0001 2190 4373Section of Clinical and Molecular Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Verena Häfele
- grid.7700.00000 0001 2190 4373Section of Clinical and Molecular Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Ana Stojanovic
- grid.7700.00000 0001 2190 4373Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany ,grid.7700.00000 0001 2190 4373European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Maximilian Kittel
- grid.7700.00000 0001 2190 4373Institute for Clinical Chemistry, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Hendrik Nolte
- grid.419502.b0000 0004 0373 6590Max-Planck-Institute for Biology of Ageing, Cologne, Germany
| | - Adelheid Cerwenka
- grid.7700.00000 0001 2190 4373Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany ,grid.7700.00000 0001 2190 4373European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Michael Neumaier
- grid.7700.00000 0001 2190 4373Institute for Clinical Chemistry, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Kai Schledzewski
- grid.7700.00000 0001 2190 4373Department of Dermatology, Venereology, and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, 68135 Mannheim, Germany
| | - Carsten Sticht
- grid.7700.00000 0001 2190 4373NGS Core Facility, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Philipp-Sebastian Reiners-Koch
- grid.7700.00000 0001 2190 4373Department of Dermatology, Venereology, and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, 68135 Mannheim, Germany ,grid.7700.00000 0001 2190 4373European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sergij Goerdt
- grid.7700.00000 0001 2190 4373Department of Dermatology, Venereology, and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, 68135 Mannheim, Germany ,grid.7700.00000 0001 2190 4373European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Cyrill Géraud
- grid.7700.00000 0001 2190 4373Section of Clinical and Molecular Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany ,grid.7700.00000 0001 2190 4373Department of Dermatology, Venereology, and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, 68135 Mannheim, Germany ,grid.7700.00000 0001 2190 4373European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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18
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Hadjittofi C, Feretis M, Martin J, Harper S, Huguet E. Liver regeneration biology: Implications for liver tumour therapies. World J Clin Oncol 2021; 12:1101-1156. [PMID: 35070734 PMCID: PMC8716989 DOI: 10.5306/wjco.v12.i12.1101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.
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Affiliation(s)
- Christopher Hadjittofi
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Michael Feretis
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Jack Martin
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Simon Harper
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Huguet
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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19
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Koch PS, Sandorski K, Heil J, Schmid CD, Kürschner SW, Hoffmann J, Winkler M, Staniczek T, de la Torre C, Sticht C, Schledzewski K, Taketo MM, Trogisch FA, Heineke J, Géraud C, Goerdt S, Olsavszky V. Imbalanced Activation of Wnt-/β-Catenin-Signaling in Liver Endothelium Alters Normal Sinusoidal Differentiation. Front Physiol 2021; 12:722394. [PMID: 34658910 PMCID: PMC8511684 DOI: 10.3389/fphys.2021.722394] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 08/19/2021] [Indexed: 01/20/2023] Open
Abstract
Endothelial wingless-related integration site (Wnt)-/β-catenin signaling is a key regulator of the tightly sealed blood–brain barrier. In the hepatic vascular niche angiokine-mediated Wnt signaling was recently identified as an important regulator of hepatocyte function, including the determination of final adult liver size, liver regeneration, and metabolic liver zonation. Within the hepatic vasculature, the liver sinusoidal endothelial cells (LSECs) are morphologically unique and functionally specialized microvascular endothelial cells (ECs). Pathological changes of LSECs are involved in chronic liver diseases, hepatocarcinogenesis, and liver metastasis. To comprehensively analyze the effects of endothelial Wnt-/β-catenin signaling in the liver, we used endothelial subtype-specific Clec4g-iCre mice to generate hepatic ECs with overexpression of Ctnnb1. In the resultant Clec4g-iCretg/wt;Ctnnb1(Ex3)fl/wt (Ctnnb1OE−EC) mice, activation of endothelial Wnt-/β-catenin signaling resulted in sinusoidal transdifferentiation with disturbed endothelial zonation, that is, loss of midzonal LSEC marker lymphatic vessel endothelial hyaluronic acid receptor 1 (Lyve1) and enrichment of continuous EC genes, such as cluster of differentiation (CD)34 and Apln. Notably, gene set enrichment analysis revealed overrepresentation of brain endothelial transcripts. Activation of endothelial Wnt-/β-catenin signaling did not induce liver fibrosis or alter metabolic liver zonation, but Ctnnb1OE−EC mice exhibited significantly increased plasma triglyceride concentrations, while liver lipid content was slightly reduced. Ctnnb1 overexpression in arterial ECs of the heart has been reported previously to cause cardiomyopathy. As Clec4g-iCre is active in a subset of cardiac ECs, it was not unexpected that Ctnnb1OE−EC mice showed reduced overall survival and cardiac dysfunction. Altogether, balanced endothelial Wnt-/β-catenin signaling in the liver is required for normal LSEC differentiation and for maintenance of normal plasma triglyceride levels.
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Affiliation(s)
- Philipp-Sebastian Koch
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Kajetan Sandorski
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Joschka Heil
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Christian D Schmid
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sina W Kürschner
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Johannes Hoffmann
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Manuel Winkler
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Theresa Staniczek
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Carolina de la Torre
- Next Generation Sequencing Core Facility, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Carsten Sticht
- Next Generation Sequencing Core Facility, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Kai Schledzewski
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Makoto Mark Taketo
- Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Felix A Trogisch
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Department of Cardiovascular Physiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Joerg Heineke
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Department of Cardiovascular Physiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Cyrill Géraud
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Section of Clinical and Molecular Dermatology, Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sergij Goerdt
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Victor Olsavszky
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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20
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Große-Segerath L, Lammert E. Role of vasodilation in liver regeneration and health. Biol Chem 2021; 402:1009-1019. [PMID: 33908220 DOI: 10.1515/hsz-2021-0155] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 04/12/2021] [Indexed: 12/14/2022]
Abstract
Recently, we have shown that an enhanced blood flow through the liver triggers hepatocyte proliferation and thereby liver growth. In this review, we first explain the literature on hepatic blood flow and its changes after partial hepatectomy (PHx), before we present the different steps of liver regeneration that take place right after the initial hemodynamic changes induced by PHx. Those parts of the molecular mechanisms governing liver regeneration, which are directly associated with the hepatic vascular system, are subsequently reviewed. These include β1 integrin-dependent mechanotransduction in liver sinusoidal endothelial cells (LSECs), triggering mechanically-induced activation of the vascular endothelial growth factor receptor-3 (VEGFR3) and matrix metalloproteinase-9 (MMP9) as well as release of growth-promoting angiocrine signals. Finally, we speculate how advanced age and obesity negatively affect the hepatic vasculature and thus liver regeneration and health, and we conclude our review with some recent technical progress in the clinic that employs liver perfusion. In sum, the mechano-elastic properties and alterations of the hepatic vasculature are key to better understand and influence liver health, regeneration, and disease.
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Affiliation(s)
- Linda Große-Segerath
- Institute of Metabolic Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, D-40225 Düsseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, D-85764 Neuherberg, Germany
| | - Eckhard Lammert
- Institute of Metabolic Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, D-40225 Düsseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, D-85764 Neuherberg, Germany
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21
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ADAM10 and ADAM17 regulate EGFR, c-Met and TNF RI signalling in liver regeneration and fibrosis. Sci Rep 2021; 11:11414. [PMID: 34075077 PMCID: PMC8169909 DOI: 10.1038/s41598-021-90716-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 05/04/2021] [Indexed: 12/26/2022] Open
Abstract
ADAM10 and ADAM17 are proteases that affect multiple signalling pathways by releasing molecules from the cell surface. As their substrate specificities partially overlaps, we investigated their concurrent role in liver regeneration and fibrosis, using three liver-specific deficient mouse lines: ADAM10- and ADAM17-deficient lines, and a line deficient for both proteases. In the model of partial hepatectomy, double deficient mice exhibited decreased AKT phosphorylation, decreased release of EGFR activating factors and lower shedding of HGF receptor c-Met. Thus, simultaneous ablation of ADAM10 and ADAM17 resulted in inhibited EGFR signalling, while HGF/c-Met signalling pathway was enhanced. In contrast, antagonistic effects of ADAM10 and ADAM17 were observed in the model of chronic CCl4 intoxication. While ADAM10-deficient mice develop more severe fibrosis manifested by high ALT, AST, ALP and higher collagen deposition, combined deficiency of ADAM10 and ADAM17 surprisingly results in comparable degree of liver damage as in control littermates. Therefore, ADAM17 deficiency is not protective in fibrosis development per se, but can ameliorate the damaging effect of ADAM10 deficiency on liver fibrosis development. Furthermore, we show that while ablation of ADAM17 resulted in decreased shedding of TNF RI, ADAM10 deficiency leads to increased levels of soluble TNF RI in serum. In conclusion, hepatocyte-derived ADAM10 and ADAM17 are important regulators of growth receptor signalling and TNF RI release, and pathological roles of these proteases are dependent on the cellular context.
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22
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Angiodiversity and organotypic functions of sinusoidal endothelial cells. Angiogenesis 2021; 24:289-310. [PMID: 33745018 PMCID: PMC7982081 DOI: 10.1007/s10456-021-09780-y] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 03/04/2021] [Indexed: 02/08/2023]
Abstract
‘Angiodiversity’ refers to the structural and functional heterogeneity of endothelial cells (EC) along the segments of the vascular tree and especially within the microvascular beds of different organs. Organotypically differentiated EC ranging from continuous, barrier-forming endothelium to discontinuous, fenestrated endothelium perform organ-specific functions such as the maintenance of the tightly sealed blood–brain barrier or the clearance of macromolecular waste products from the peripheral blood by liver EC-expressed scavenger receptors. The microvascular bed of the liver, composed of discontinuous, fenestrated liver sinusoidal endothelial cells (LSEC), is a prime example of organ-specific angiodiversity. Anatomy and development of LSEC have been extensively studied by electron microscopy as well as linage-tracing experiments. Recent advances in cell isolation and bulk transcriptomics or single-cell RNA sequencing techniques allowed the identification of distinct LSEC molecular programs and have led to the identification of LSEC subpopulations. LSEC execute homeostatic functions such as fine tuning the vascular tone, clearing noxious substances from the circulation, and modulating immunoregulatory mechanisms. In recent years, the identification and functional analysis of LSEC-derived angiocrine signals, which control liver homeostasis and disease pathogenesis in an instructive manner, marks a major change of paradigm in the understanding of liver function in health and disease. This review summarizes recent advances in the understanding of liver vascular angiodiversity and the functional consequences resulting thereof.
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23
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Szeky B, Mayer B, Gyongy M, Hajdara A, Barsi S, Karpati S, Nemeth K. Tri-Lineage Differentiation of NTERA2 Clone D1 Cells towards Neural, Hepatic and Osteogenic Lineages in Vitro. Folia Biol (Praha) 2021; 67:174-182. [PMID: 35439850 DOI: 10.14712/fb2021067050174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Over the past decades, the in vitro use of pluripotent cell lines gained a crucial role in toxicology, preclinical drug testing and developmental biology. NTERA2 clone D1 cells were identified as pluripotent cells with high potential for neural differentiation. Although they are commonly used cellular sources in neuropharmacology and neurodevelopmental studies, their endodermal and mesodermal differentiation potential awaits further characterization. Here, we devised improved protocols for hepatogenic and osteogenic differentiation of NTERA2 clone D1 cells. Our in vitro differentiation assays showed significant up-regulation of multiple hepatogenic markers. We also observed robust mineralization and osteogenic marker expression of NTERA2 clone D1 cells upon in vitro osteogenic induction. These results suggest that NTERA2 clone D1 cells may be utilized as an in vitro model system to study various aspects of liver biology and osteogenesis. In addition, tri-lineage differentiation of NTERA2 clone D1 cells may serve as a simple experimental control system when validating pluripotency of other cell types.
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Affiliation(s)
- B Szeky
- Roska Tamás Doctoral School of Science and Technology, Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary
- Stem Cell Research Laboratory, Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - B Mayer
- Stem Cell Research Laboratory, Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - M Gyongy
- Roska Tamás Doctoral School of Science and Technology, Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary
| | - A Hajdara
- Roska Tamás Doctoral School of Science and Technology, Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary
- Stem Cell Research Laboratory, Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - S Barsi
- Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - S Karpati
- Stem Cell Research Laboratory, Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - K Nemeth
- Stem Cell Research Laboratory, Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
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24
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Mak KM, Shin DW. Hepatic sinusoids versus central veins: Structures, markers, angiocrines, and roles in liver regeneration and homeostasis. Anat Rec (Hoboken) 2020; 304:1661-1691. [PMID: 33135318 DOI: 10.1002/ar.24560] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 10/14/2020] [Accepted: 10/22/2020] [Indexed: 01/20/2023]
Abstract
The blood circulates through the hepatic sinusoids delivering nutrients and oxygen to the liver parenchyma and drains into the hepatic central vein, yet the structures and phenotypes of these vessels are distinctively different. Sinusoidal endothelial cells are uniquely fenestrated, lack basal lamina and possess organelles involved in endocytosis, pinocytosis, degradation, synthesis and secretion. Hepatic central veins are nonfenestrated but are also active in synthesis and secretion. Endothelial cells of sinusoids and central veins secrete angiocrines that play respective roles in hepatic regeneration and metabolic homeostasis. The list of markers for identifying sinusoidal endothelial cells is long and their terminologies are complex. Further, their uses vary in different investigations and, in some instances, could be confusing. Central vein markers are fewer but more distinctive. Here we analyze and categorize the molecular pathways/modules associated with the sinusoid-mediated liver regeneration in response to partial hepatectomy and chemical-induced acute or chronic injury. Similarly, we highlight the findings that central vein-derived angiocrines interact with Wnt/β-catenin in perivenous hepatocytes to direct gene expression and maintain pericentral metabolic zonation. The proposal that perivenous hepatocytes behave as stem/progenitor cells to provoke hepatic homeostatic cell renewal is reevaluated and newer concepts of broad zonal distribution of hepatocyte proliferation in liver homeostasis and regeneration are updated. Thus, this review integrates the structures, biology and physiology of liver sinusoids and central veins in mediating hepatic regeneration and metabolic homeostasis.
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Affiliation(s)
- Ki M Mak
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Da Wi Shin
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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25
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Wencel A, Ciezkowska M, Wisniewska M, Zakrzewska KE, Pijanowska DG, Pluta KD. Effects of genetically modified human skin fibroblasts, stably overexpressing hepatocyte growth factor, on hepatic functions of cocultured C3A cells. Biotechnol Bioeng 2020; 118:72-81. [PMID: 32880912 DOI: 10.1002/bit.27551] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 08/04/2020] [Accepted: 09/01/2020] [Indexed: 01/18/2023]
Abstract
Diseases leading to terminal hepatic failure are among the most common causes of death worldwide. Transplant of the whole organ is the only effective method to cure liver failure. Unfortunately, this treatment option is not available universally due to the serious shortage of donors. Thus, alternative methods have been developed that are aimed at prolonging the life of patients, including hepatic cells transplantation and bridging therapy based on hybrid bioartificial liver devices. Parenchymal liver cells are highly differentiated and perform many complex functions, such as detoxification and protein synthesis. Unfortunately, isolated hepatocytes display a rapid decline in viability and liver-specific functions. A number of methods have been developed to maintain hepatocytes in their highly differentiated state in vitro, amongst them the most promising being 3D growth scaffolds and decellularized tissues or coculture with other cell types required for the heterotypic cell-cell interactions. Here we present a novel approach to the hepatic cells culture based on the feeder layer cells genetically modified using lentiviral vector to stably produce additional amounts of hepatocyte growth factor and show the positive influence of these coculture conditions on the preservation of the hepatic functions of the liver parenchymal cells' model-C3A cells.
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Affiliation(s)
- Agnieszka Wencel
- Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Warsaw, Poland
| | - Malgorzata Ciezkowska
- Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Warsaw, Poland
| | - Monika Wisniewska
- Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Warsaw, Poland
| | - Karolina E Zakrzewska
- Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Warsaw, Poland.,Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland
| | - Dorota G Pijanowska
- Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Warsaw, Poland
| | - Krzysztof D Pluta
- Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Warsaw, Poland
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Yu J, Chen GG, Lai PBS. Targeting hepatocyte growth factor/c-mesenchymal-epithelial transition factor axis in hepatocellular carcinoma: Rationale and therapeutic strategies. Med Res Rev 2020; 41:507-524. [PMID: 33026703 DOI: 10.1002/med.21738] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 08/27/2020] [Accepted: 09/27/2020] [Indexed: 12/27/2022]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. The outcome of current standard treatments, as well as targeted therapies in advanced stages, are still unsatisfactory. Attention has been drawn to novel strategies for better treatment efficacy. Hepatocyte growth factor/c-mesenchymal-epithelial transition factor (HGF/c-Met) axis has been known as an essential element in the regulation of liver diseases and as an oncogenic factor in HCC. In this review, we collected the evidence of HGF/c-Met as a tumor progression and prognostic marker, discussed the anti-c-Met therapy in vitro, summarized the outcome of c-Met inhibitors in clinical trials, and identified potential impetus for future anti-c-Met treatments. We also analyzed the inconsistency of HGF/c-Met from various publications and offered reasonable explanations based on the current understanding in this area. In conclusion, HGF/c-Met plays a crucial role in the progression and growth of HCC, and the strategies to inhibit this pathway may facilitate the development of new and effective treatments for HCC patients.
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Affiliation(s)
- Jianqing Yu
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - George G Chen
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Paul B S Lai
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
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27
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Zhu S, Bennett S, Kuek V, Xiang C, Xu H, Rosen V, Xu J. Endothelial cells produce angiocrine factors to regulate bone and cartilage via versatile mechanisms. Am J Cancer Res 2020; 10:5957-5965. [PMID: 32483430 PMCID: PMC7255007 DOI: 10.7150/thno.45422] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 04/14/2020] [Indexed: 02/06/2023] Open
Abstract
Blood vessels are conduits distributed throughout the body, supporting tissue growth and homeostasis by the transport of cells, oxygen and nutrients. Endothelial cells (ECs) form the linings of the blood vessels, and together with pericytes, are essential for organ development and tissue homeostasis through producing paracrine signalling molecules, called angiocrine factors. In the skeletal system, ECs - derived angiocrine factors, combined with bone cells-released angiogenic factors, orchestrate intercellular crosstalk of the bone microenvironment, and the coupling of angiogenesis-to-osteogenesis. Whilst the involvement of angiogenic factors and the blood vessels of the skeleton is relatively well established, the impact of ECs -derived angiocrine factors on bone and cartilage homeostasis is gradually emerging. In this review, we survey ECs - derived angiocrine factors, which are released by endothelial cells of the local microenvironment and by distal organs, and act specifically as regulators of skeletal growth and homeostasis. These may potentially include angiocrine factors with osteogenic property, such as Hedgehog, Notch, WNT, bone morphogenetic protein (BMP), fibroblast growth factor (FGF), insulin-like growth factor (IGF), and platelet-derived growth factor (PDGF). Understanding the versatile mechanisms by which ECs-derived angiocrine factors orchestrate bone and cartilage homeostasis, and pathogenesis, is an important step towards the development of therapeutic potential for skeletal diseases.
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