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Mishra F, Yuan Y, Yang JJ, Li B, Chan P, Liu Z. Depletion of Activated Hepatic Stellate Cells and Capillarized Liver Sinusoidal Endothelial Cells Using a Rationally Designed Protein for Nonalcoholic Steatohepatitis and Alcoholic Hepatitis Treatment. Int J Mol Sci 2024; 25:7447. [PMID: 39000553 PMCID: PMC11242029 DOI: 10.3390/ijms25137447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 06/28/2024] [Accepted: 07/01/2024] [Indexed: 07/16/2024] Open
Abstract
Nonalcoholic steatohepatitis (NASH) and alcoholic hepatitis (AH) affect a large part of the general population worldwide. Dysregulation of lipid metabolism and alcohol toxicity drive disease progression by the activation of hepatic stellate cells and the capillarization of liver sinusoidal endothelial cells. Collagen deposition, along with sinusoidal remodeling, alters sinusoid structure, resulting in hepatic inflammation, portal hypertension, liver failure, and other complications. Efforts were made to develop treatments for NASH and AH. However, the success of such treatments is limited and unpredictable. We report a strategy for NASH and AH treatment involving the induction of integrin αvβ3-mediated cell apoptosis using a rationally designed protein (ProAgio). Integrin αvβ3 is highly expressed in activated hepatic stellate cells (αHSCs), the angiogenic endothelium, and capillarized liver sinusoidal endothelial cells (caLSECs). ProAgio induces the apoptosis of these disease-driving cells, therefore decreasing collagen fibril, reversing sinusoid remodeling, and reducing immune cell infiltration. The reversal of sinusoid remodeling reduces the expression of leukocyte adhesion molecules on LSECs, thus decreasing leukocyte infiltration/activation in the diseased liver. Our studies present a novel and effective approach for NASH and AH treatment.
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Affiliation(s)
- Falguni Mishra
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA
| | - Yi Yuan
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA
| | - Jenny J Yang
- Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
| | - Bin Li
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA
| | - Payton Chan
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA
| | - Zhiren Liu
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA
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Wang Y, Wang J, Zhang J, Wang Y, Wang Y, Kang H, Zhao W, Bai W, Miao N, Wang J. Stiffness sensing via Piezo1 enhances macrophage efferocytosis and promotes the resolution of liver fibrosis. SCIENCE ADVANCES 2024; 10:eadj3289. [PMID: 38838160 DOI: 10.1126/sciadv.adj3289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 05/01/2024] [Indexed: 06/07/2024]
Abstract
Tissue stiffening is a predominant feature of fibrotic disorders, but the response of macrophages to changes in tissue stiffness and cellular context in fibrotic diseases remains unclear. Here, we found that the mechanosensitive ion channel Piezo1 was up-regulated in hepatic fibrosis. Macrophages lacking Piezo1 showed sustained inflammation and impaired spontaneous resolution of early liver fibrosis. Further analysis revealed an impairment of clearance of apoptotic cells by macrophages in the fibrotic liver. Macrophages showed enhanced efferocytosis when cultured on rigid substrates but not soft ones, suggesting stiffness-dependent efferocytosis of macrophages required Piezo1 activation. Besides, Piezo1 was involved in the efficient acidification of the engulfed cargo in the phagolysosomes and affected the subsequent expression of anti-inflammation genes after efferocytosis. Pharmacological activation of Piezo1 increased the efferocytosis capacity of macrophages and accelerated the resolution of inflammation and fibrosis. Our study supports the antifibrotic role of Piezo1-mediated mechanical sensation in liver fibrosis, suggesting that targeting PIEZO1 to enhance macrophage efferocytosis could induce fibrosis regression.
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Affiliation(s)
- Yang Wang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jin Wang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jiahao Zhang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yina Wang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yuanyuan Wang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Haixia Kang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Wenying Zhao
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Wenjuan Bai
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Naijun Miao
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jing Wang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Center for Immune-related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Leaker BD, Sojoodi M, Tanabe KK, Popov YV, Tam J, Anderson RR. Increased susceptibility to ischemia causes exacerbated response to microinjuries in the cirrhotic liver. FASEB J 2024; 38:e23585. [PMID: 38661043 DOI: 10.1096/fj.202301438rr] [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: 07/14/2023] [Revised: 03/07/2024] [Accepted: 03/18/2024] [Indexed: 04/26/2024]
Abstract
Fractional laser ablation is a technique developed in dermatology to induce remodeling of skin scars by creating a dense pattern of microinjuries. Despite remarkable clinical results, this technique has yet to be tested for scars in other tissues. As a first step toward determining the suitability of this technique, we aimed to (1) characterize the response to microinjuries in the healthy and cirrhotic liver, and (2) determine the underlying cause for any differences in response. Healthy and cirrhotic rats were treated with a fractional laser then euthanized from 0 h up to 14 days after treatment. Differential expression was assessed using RNAseq with a difference-in-differences model. Spatial maps of tissue oxygenation were acquired with hyperspectral imaging and disruptions in blood supply were assessed with tomato lectin perfusion. Healthy rats showed little damage beyond the initial microinjury and healed completely by 7 days without scarring. In cirrhotic rats, hepatocytes surrounding microinjury sites died 4-6 h after ablation, resulting in enlarged and heterogeneous zones of cell death. Hepatocytes near blood vessels were spared, particularly near the highly vascularized septa. Gene sets related to ischemia and angiogenesis were enriched at 4 h. Laser-treated regions had reduced oxygen saturation and broadly disrupted perfusion of nodule microvasculature, which matched the zones of cell death. Our results demonstrate that the cirrhotic liver has an exacerbated response to microinjuries and increased susceptibility to ischemia from microvascular damage, likely related to the vascular derangements that occur during cirrhosis development. Modifications to the fractional laser tool, such as using a femtosecond laser or reducing the spot size, may be able to prevent large disruptions of perfusion and enable further development of a laser-induced microinjury treatment for cirrhosis.
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Affiliation(s)
- Ben D Leaker
- Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Mozhdeh Sojoodi
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA
| | - Kenneth K Tanabe
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA
| | - Yury V Popov
- Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Joshua Tam
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Dermatology, Harvard Medical School, Boston, Massachusetts, USA
| | - R Rox Anderson
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Dermatology, Harvard Medical School, Boston, Massachusetts, USA
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Schaub JR, Chen JY, Turner SM. Integrins in biliary injury and fibrosis. Curr Opin Gastroenterol 2024; 40:85-91. [PMID: 38190346 DOI: 10.1097/mog.0000000000000995] [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] [Indexed: 01/10/2024]
Abstract
PURPOSE OF REVIEW Current treatment options for cholangiopathies are severely limited and there is thus a critical need to identify and develop therapies. This review discusses the role of integrins in biliary injury and fibrosis and their potential as therapeutic targets. RECENT FINDINGS There are a diverse set of roles that integrins play in biliary injury and fibrosis. Some integrins activate TGF-β signaling or are involved in sensing of the extracellular matrix, making them attractive targets for biliary fibrosis. In recent work, autoantibodies to α v β 6 were identified in patients with PSC, supporting the relevance of this integrin in the disease. In addition, a role for α 2 β 1 in cyst formation was identified in a mouse model of polycystic liver disease. Leukocyte integrins (e.g. α E β 7 and α 4 β 7 ) contribute to lymphocyte trafficking, making them potential targets for biliary inflammation; however, this has not yet translated to the clinic. SUMMARY While all members of the same family of proteins, integrins have diverse roles in the pathogenesis of biliary disease. Targeting one or multiple of these integrins may slow or halt the progression of biliary injury and fibrosis by simultaneously impacting different pathologic cells and processes.
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Affiliation(s)
| | - Jennifer Y Chen
- Department of Medicine
- The Liver Center, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
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Fu Y, Zhou X, Wang L, Fan W, Gao S, Zhang D, Ling Z, Zhang Y, Ma L, Bai F, Chen J, Sun B, Liu P. Salvianolic acid B attenuates liver fibrosis by targeting Ecm1 and inhibiting hepatocyte ferroptosis. Redox Biol 2024; 69:103029. [PMID: 38184998 PMCID: PMC10808927 DOI: 10.1016/j.redox.2024.103029] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 12/28/2023] [Accepted: 01/02/2024] [Indexed: 01/09/2024] Open
Abstract
Hepatocyte ferroptosis promotes the pathogenesis and progression of liver fibrosis. Salvianolic acid B (Sal B) exerts antifibrotic effects. However, the pharmacological mechanism and target has not yet been fully elucidated. In this study, liver fibrosis was induced by CCl4 in wild-type mice and hepatocyte-specific extracellular matrix protein 1 (Ecm1)-deficient mice, which were separately treated with Sal B, ferrostatin-1, sorafenib or cilengitide. Erastin- or CCl4-induced hepatocyte ferroptosis models with or without Ecm1 gene knockdown were evaluated in vitro. Subsequently, the interaction between Ecm1 and xCT and the binding kinetics of Sal B and Ecm1 were determined. We found that Sal B significantly attenuated liver fibrosis in CCl4-induced mice. Ecm1 deletion in hepatocytes abolished the antifibrotic effect of Sal B. Mechanistically, Sal B protected against hepatocyte ferroptosis by upregulating Ecm1. Further research revealed that Ecm1 as a direct target for treating liver fibrosis with Sal B. Interestingly, Ecm1 interacted with xCT to regulate hepatocyte ferroptosis. Hepatocyte ferroptosis in vitro was significantly attenuated by Sal B treatment, which was abrogated after knockdown of Ecm1 in LO2 cells. Therefore, Sal B alleviates liver fibrosis in mice by targeting up-regulation of Ecm1 and inhibiting hepatocyte ferroptosis. The interaction between Ecm1 and xCT regulates hepatocyte ferroptosis.
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Affiliation(s)
- Yadong Fu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai 201203, China; State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xiaoxi Zhou
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai 201203, China
| | - Lin Wang
- Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Weiguo Fan
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Siqi Gao
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai 201203, China; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Danyan Zhang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Zhiyang Ling
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yaguang Zhang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Liyan Ma
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Fang Bai
- Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Shanghai Clinical Research and Trial Center, Shanghai, 201210, China
| | - Jiamei Chen
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai 201203, China.
| | - Bing Sun
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Ping Liu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai 201203, China; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Yi M, Yuan Y, Ma L, Li L, Qin W, Wu B, Zheng B, Liao X, Hu G, Liu B. Inhibition of TGFβ1 activation prevents radiation-induced lung fibrosis. Clin Transl Med 2024; 14:e1546. [PMID: 38239077 PMCID: PMC10797247 DOI: 10.1002/ctm2.1546] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 12/26/2023] [Accepted: 01/03/2024] [Indexed: 01/22/2024] Open
Abstract
BACKGROUND Radiotherapy is the main treatment modality for thoracic tumours, but it may induce pulmonary fibrosis. Currently, the pathogenesis of radiation-induced pulmonary fibrosis (RIPF) is unclear, and effective treatments are lacking. Transforming growth factor beta 1 (TGFβ1) plays a central role in RIPF. We found that activated TGFβ1 had better performance for radiation pneumonitis (RP) risk prediction by detecting activated and total TGFβ1 levels in patient serum. αv integrin plays key roles in TGFβ1 activation, but the role of αv integrin-mediated TGFβ1 activation in RIPF is unclear. Here, we investigated the role of αv integrin-mediated TGFβ1 activation in RIPF and the application of the integrin antagonist cilengitide to prevent RIPF. METHODS ItgavloxP/loxP ;Pdgfrb-Cre mice were generated by conditionally knocking out Itgav in myofibroblasts, and wild-type mice were treated with cilengitide or placebo. All mice received 16 Gy of radiation or underwent a sham radiation procedure. Lung fibrosis was measured by a modified Ashcroft score and microcomputed tomography (CT). An enzyme-linked immunosorbent assay (ELISA) was used to measure the serum TGFβ1 concentration, and total Smad2/3 and p-Smad2/3 levels were determined via Western blotting. RESULTS Conditional Itgav knockout significantly attenuated RIPF (p < .01). Hounsfield units (HUs) in the lungs were reduced in the knockout mice compared with the control mice (p < .001). Conditional Itgav knockout decreased active TGFβ1 secretion and inhibited fibroblast p-Smad2/3 expression. Exogenous active TGFβ1, but not latent TGFβ1, reversed these reductions. Furthermore, cilengitide treatment elicited similar results and prevented RIPF. CONCLUSIONS The present study revealed that conditional Itgav knockout and cilengitide treatment both significantly attenuated RIPF in mice by inhibiting αv integrin-mediated TGFβ1 activation. HIGHLIGHTS Activated TGFβ1 has a superior capacity in predicting radiation pneumonitis (RP) risk and plays a vital role in the development of radiation-induced pulmonary fibrosis (RIPF). Conditional knock out Itgav in myofibroblasts prevented mice from developing RIPF. Cilengitide alleviated the development of RIPF by inhibiting αv integrin-mediated TGFβ1 activation and may be used in targeted approaches for preventing RIPF.
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Affiliation(s)
- Minxiao Yi
- Department of OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Ye Yuan
- School of Computer Science and TechnologyHuazhong University of Science and TechnologyWuhanChina
| | - Li Ma
- Department of OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Long Li
- Department of OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Wan Qin
- Department of OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Bili Wu
- Department of OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Bolong Zheng
- School of Computer Science and TechnologyHuazhong University of Science and TechnologyWuhanChina
| | - Xin Liao
- Department of Integrative MedicineTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Guangyuan Hu
- Department of OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Bo Liu
- Department of OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
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Felli E, Selicean S, Guixé-Muntet S, Wang C, Bosch J, Berzigotti A, Gracia-Sancho J. Mechanobiology of portal hypertension. JHEP Rep 2023; 5:100869. [PMID: 37841641 PMCID: PMC10568428 DOI: 10.1016/j.jhepr.2023.100869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 06/28/2023] [Accepted: 07/03/2023] [Indexed: 10/17/2023] Open
Abstract
The interplay between mechanical stimuli and cellular mechanobiology orchestrates the physiology of tissues and organs in a dynamic balance characterized by constant remodelling and adaptative processes. Environmental mechanical properties can be interpreted as a complex set of information and instructions that cells read continuously, and to which they respond. In cirrhosis, chronic inflammation and injury drive liver cells dysfunction, leading to excessive extracellular matrix deposition, sinusoidal pseudocapillarization, vascular occlusion and parenchymal extinction. These pathological events result in marked remodelling of the liver microarchitecture, which is cause and result of abnormal environmental mechanical forces, triggering and sustaining the long-standing and progressive process of liver fibrosis. Multiple mechanical forces such as strain, shear stress, and hydrostatic pressure can converge at different stages of the disease until reaching a point of no return where the fibrosis is considered non-reversible. Thereafter, reciprocal communication between cells and their niches becomes the driving force for disease progression. Accumulating evidence supports the idea that, rather than being a passive consequence of fibrosis and portal hypertension (PH), mechanical force-mediated pathways could themselves represent strategic targets for novel therapeutic approaches. In this manuscript, we aim to provide a comprehensive review of the mechanobiology of PH, by furnishing an introduction on the most important mechanisms, integrating these concepts into a discussion on the pathogenesis of PH, and exploring potential therapeutic strategies.
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Affiliation(s)
- Eric Felli
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Sonia Selicean
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Sergi Guixé-Muntet
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Spain
| | - Cong Wang
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Jaume Bosch
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Spain
| | - Annalisa Berzigotti
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Jordi Gracia-Sancho
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Spain
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Eriksson O, Velikyan I. Radiotracers for Imaging of Fibrosis: Advances during the Last Two Decades and Future Directions. Pharmaceuticals (Basel) 2023; 16:1540. [PMID: 38004406 PMCID: PMC10674214 DOI: 10.3390/ph16111540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 10/13/2023] [Accepted: 10/25/2023] [Indexed: 11/26/2023] Open
Abstract
Fibrosis accompanies various pathologies, and there is thus an unmet medical need for non-invasive, sensitive, and quantitative methods for the assessment of fibrotic processes. Currently, needle biopsy with subsequent histological analysis is routinely used for the diagnosis along with morphological imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound (US). However, none of these imaging techniques are sufficiently sensitive and accurate to detect minor changes in fibrosis. More importantly, they do not provide information on fibrotic activity on the molecular level, which is critical for fundamental understanding of the underlying biology and disease course. Molecular imaging technology using positron emission tomography (PET) offers the possibility of imaging not only physiological real-time activity, but also high-sensitivity and accurate quantification. This diagnostic tool is well established in oncology and has exhibited exponential development during the last two decades. However, PET diagnostics has only recently been widely applied in the area of fibrosis. This review presents the progress of development of radiopharmaceuticals for non-invasive detection of fibrotic processes, including the fibrotic scar itself, the deposition of new fibrotic components (fibrogenesis), or the degradation of existing fibrosis (fibrolysis).
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Affiliation(s)
- Olof Eriksson
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, Sweden;
- Antaros Tracer AB, Dragarbrunnsgatan 46, 2 tr, 753 20 Uppsala, Sweden
| | - Irina Velikyan
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, Sweden;
- Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, 752 85 Uppsala, Sweden
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Gil M, Khouri L, Raurell I, Rafael D, Andrade F, Abasolo I, Schwartz S, Martínez-Gómez M, Salcedo MT, Pericàs JM, Hide D, Wei M, Metanis N, Genescà J, Martell M. Optimization of Statin-Loaded Delivery Nanoparticles for Treating Chronic Liver Diseases by Targeting Liver Sinusoidal Endothelial Cells. Pharmaceutics 2023; 15:2463. [PMID: 37896223 PMCID: PMC11340786 DOI: 10.3390/pharmaceutics15102463] [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: 09/14/2023] [Revised: 10/08/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
In this study, we developed functionalized polymeric micelles (FPMs) loaded with simvastatin (FPM-Sim) as a drug delivery system to target liver sinusoidal endothelial cells (LSECs) for preserving liver function in chronic liver disease (CLD). Polymeric micelles (PMs) were functionalized by coupling peptide ligands of LSEC membrane receptors CD32b, CD36 and ITGB3. Functionalization was confirmed via spectroscopy and electron microscopy. In vitro and in vivo FPM-Sim internalization was assessed by means of flow cytometry in LSECs, hepatocytes, Kupffer and hepatic stellate cells from healthy rats. Maximum tolerated dose assays were performed in healthy mice and efficacy studies of FPM-Sim were carried out in bile duct ligation (BDL) and thioacetamide (TAA) induction rat models of cirrhosis. Functionalization with the three peptide ligands resulted in stable formulations with a greater degree of in vivo internalization in LSECs than non-functionalized PMs. Administration of FPM-Sim in BDL rats reduced toxicity relative to free simvastatin, albeit with a moderate portal-pressure-lowering effect. In a less severe model of TAA-induced cirrhosis, treatment with FPM-CD32b-Sim nanoparticles for two weeks significantly decreased portal pressure, which was associated with a reduction in liver fibrosis, lower collagen expression as well as the stimulation of nitric oxide synthesis. In conclusion, CD32b-FPM stands out as a good nanotransporter for drug delivery, targeting LSECs, key inducers of liver injury.
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Affiliation(s)
- Mar Gil
- Liver Disease Group, Liver Unit, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, Universitat Autonòma de Barcelona (UAB), 08035 Barcelona, Spain; (M.G.); (J.G.)
| | - Lareen Khouri
- Institut of Chemistry, Casali Center for Applied Chemistry, The Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
| | - Imma Raurell
- Liver Disease Group, Liver Unit, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, Universitat Autonòma de Barcelona (UAB), 08035 Barcelona, Spain; (M.G.); (J.G.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto De Salud Carlos III, 08035 Barcelona, Spain
| | - Diana Rafael
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Bioingenería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto De Salud Carlos III, 08035 Barcelona, Spain
| | - Fernanda Andrade
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Bioingenería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto De Salud Carlos III, 08035 Barcelona, Spain
- Departament de Farmàcia i Tecnologia Farmacèutica i Fisicoquímica, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona (UB), 08007 Barcelona, Spain
| | - Ibane Abasolo
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Bioingenería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto De Salud Carlos III, 08035 Barcelona, Spain
- Clinical Biochemistry Service, Vall d’Hebron University Hospital, Vall d’Hebron Barcelona Hospital Campus, 08035e Barcelona, Spain
| | - Simo Schwartz
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Bioingenería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto De Salud Carlos III, 08035 Barcelona, Spain
- Clinical Biochemistry Service, Vall d’Hebron University Hospital, Vall d’Hebron Barcelona Hospital Campus, 08035e Barcelona, Spain
| | - María Martínez-Gómez
- Liver Disease Group, Liver Unit, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, Universitat Autonòma de Barcelona (UAB), 08035 Barcelona, Spain; (M.G.); (J.G.)
| | - María Teresa Salcedo
- Pathology Department, Vall d’Hebron University Hospital, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| | - Juan Manuel Pericàs
- Liver Disease Group, Liver Unit, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, Universitat Autonòma de Barcelona (UAB), 08035 Barcelona, Spain; (M.G.); (J.G.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto De Salud Carlos III, 08035 Barcelona, Spain
| | - Diana Hide
- Liver Disease Group, Liver Unit, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, Universitat Autonòma de Barcelona (UAB), 08035 Barcelona, Spain; (M.G.); (J.G.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto De Salud Carlos III, 08035 Barcelona, Spain
| | - Mingxing Wei
- Cellvax, SAS Villejuif Bio Park, 93230 Villejuif, France;
| | - Norman Metanis
- Institut of Chemistry, Casali Center for Applied Chemistry, The Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
| | - Joan Genescà
- Liver Disease Group, Liver Unit, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, Universitat Autonòma de Barcelona (UAB), 08035 Barcelona, Spain; (M.G.); (J.G.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto De Salud Carlos III, 08035 Barcelona, Spain
| | - María Martell
- Liver Disease Group, Liver Unit, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, Universitat Autonòma de Barcelona (UAB), 08035 Barcelona, Spain; (M.G.); (J.G.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto De Salud Carlos III, 08035 Barcelona, Spain
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10
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Ezzo M, Hinz B. Novel approaches to target fibroblast mechanotransduction in fibroproliferative diseases. Pharmacol Ther 2023; 250:108528. [PMID: 37708995 DOI: 10.1016/j.pharmthera.2023.108528] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/09/2023] [Accepted: 09/07/2023] [Indexed: 09/16/2023]
Abstract
The ability of cells to sense and respond to changes in mechanical environment is vital in conditions of organ injury when the architecture of normal tissues is disturbed or lost. Among the various cellular players that respond to injury, fibroblasts take center stage in re-establishing tissue integrity by secreting and organizing extracellular matrix into stabilizing scar tissue. Activation, activity, survival, and death of scar-forming fibroblasts are tightly controlled by mechanical environment and proper mechanotransduction ensures that fibroblast activities cease after completion of the tissue repair process. Conversely, dysregulated mechanotransduction often results in fibroblast over-activation or persistence beyond the state of normal repair. The resulting pathological accumulation of extracellular matrix is called fibrosis, a condition that has been associated with over 40% of all deaths in the industrialized countries. Consequently, elements in fibroblast mechanotransduction are scrutinized for their suitability as anti-fibrotic therapeutic targets. We review the current knowledge on mechanically relevant factors in the fibroblast extracellular environment, cell-matrix and cell-cell adhesion structures, stretch-activated membrane channels, stress-regulated cytoskeletal structures, and co-transcription factors. We critically discuss the targetability of these elements in therapeutic approaches and their progress in pre-clinical and/or clinical trials to treat organ fibrosis.
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Affiliation(s)
- Maya Ezzo
- Keenan Research Institute for Biomedical Science of the St. Michael's Hospital, and Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada
| | - Boris Hinz
- Keenan Research Institute for Biomedical Science of the St. Michael's Hospital, and Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
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11
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Luangmonkong T, Parichatikanond W, Olinga P. Targeting collagen homeostasis for the treatment of liver fibrosis: Opportunities and challenges. Biochem Pharmacol 2023; 215:115740. [PMID: 37567319 DOI: 10.1016/j.bcp.2023.115740] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 07/24/2023] [Accepted: 08/08/2023] [Indexed: 08/13/2023]
Abstract
Liver fibrosis is an excessive production, aberrant deposition, and deficit degradation of extracellular matrix (ECM). Patients with unresolved fibrosis ultimately undergo end-stage liver diseases. To date, the effective and safe strategy to cease fibrosis progression remains an unmet clinical need. Since collagens are the most abundant ECM protein which play an essential role in fibrogenesis, the suitable regulation of collagen homeostasis could be an effective strategy for the treatment of liver fibrosis. Therefore, this review provides a brief overview on the dysregulation of ECM homeostasis, focusing on collagens, in the pathogenesis of liver fibrosis. Most importantly, promising therapeutic mechanisms related to biosynthesis, deposition and extracellular interactions, and degradation of collagens, together with preclinical and clinical antifibrotic evidence of drugs affecting each target are orderly criticized. In addition, challenges for targeting collagen homeostasis in the treatment of liver fibrosis are discussed.
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Affiliation(s)
- Theerut Luangmonkong
- Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Thailand; Centre of Biopharmaceutical Science for Healthy Ageing (BSHA), Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
| | - Warisara Parichatikanond
- Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Thailand; Centre of Biopharmaceutical Science for Healthy Ageing (BSHA), Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Peter Olinga
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, The Netherlands
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12
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Hiroyama S, Matsunaga K, Ito M, Iimori H, Morita I, Nakamura J, Shimosegawa E, Abe K. Evaluation of an Integrin α vβ 3 Radiotracer, [ 18F]F-FPP-RGD 2, for Monitoring Pharmacological Effects of Integrin α v siRNA in the NASH Liver. Nucl Med Mol Imaging 2023; 57:172-179. [PMID: 37483876 PMCID: PMC10359219 DOI: 10.1007/s13139-023-00791-9] [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: 11/03/2022] [Revised: 01/19/2023] [Accepted: 02/07/2023] [Indexed: 03/09/2023] Open
Abstract
Purpose Integrin αv is a key regulator in the pathophysiology of hepatic fibrosis. In this study, we evaluated the potential utility of an integrin αvβ3 positron emission tomography (PET) radiotracer, 18F-labeled cyclic arginine-glycine-aspartic acid penta-peptide ([18F]F-FPP-RGD2), for detecting hepatic integrin αv and function in nonalcoholic steatohepatitis (NASH) model rats using integrin αv siRNA. Methods NASH model rats were produced by feeding a choline-deficient, low-methionine, high-fat diet for 8 weeks. PET/computerized tomography imaging and quantification of integrin αv protein, serum aspartate aminotransferase, and alanine aminotransferase were performed 1 week after single intravenous injection of integrin αv siRNA. Results Integrin αv siRNA (0.1 and 0.5 mg/kg) dose-dependently decreased hepatic integrin αv protein concentrations in control and NASH model rats. The hepatic mean standard uptake value of [18F]F-FPP-RGD2 was decreased dose-dependently by integrin αv siRNA. The mean standard uptake value was positively correlated with integrin αv protein levels in control and NASH model rats. Serum aspartate aminotransferase and alanine aminotransferase concentrations were also decreased by siRNA injection and correlated with liver integrin αv protein expression levels in NASH model rats. Conclusion This study suggests that [18F]F-FPP-RGD2 PET imaging is a promising radiotracer for monitoring hepatic integrin αv protein levels and hepatic function in NASH pathology.
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Affiliation(s)
- Shuichi Hiroyama
- Biomarker R&D Department, Shionogi & Co., Ltd., 3-1-1 Futaba-Cho, Toyonaka, Osaka 561-0825 Japan
| | - Keiko Matsunaga
- Department of Molecular Imaging in Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Miwa Ito
- Biomarker R&D Department, Shionogi & Co., Ltd., 3-1-1 Futaba-Cho, Toyonaka, Osaka 561-0825 Japan
| | - Hitoshi Iimori
- Laboratory for Advanced Medicine Research, Shionogi & Co., Ltd., Osaka, Japan
| | - Ippei Morita
- Laboratory for Advanced Medicine Research, Shionogi & Co., Ltd., Osaka, Japan
| | - Jun Nakamura
- Laboratory for Advanced Medicine Research, Shionogi & Co., Ltd., Osaka, Japan
| | - Eku Shimosegawa
- Department of Molecular Imaging in Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Kohji Abe
- Biomarker R&D Department, Shionogi & Co., Ltd., 3-1-1 Futaba-Cho, Toyonaka, Osaka 561-0825 Japan
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13
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Yin C. Endothelin Signaling Mediates Biliary-Endothelial Crosstalk in Primary Sclerosing Cholangitis. Cell Mol Gastroenterol Hepatol 2023; 16:643-645. [PMID: 37517802 PMCID: PMC10511926 DOI: 10.1016/j.jcmgh.2023.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 07/10/2023] [Indexed: 08/01/2023]
Affiliation(s)
- Chunyue Yin
- Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
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14
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Owen T, Carpino G, Chen L, Kundu D, Wills P, Ekser B, Onori P, Gaudio E, Alpini G, Francis H, Kennedy L. Endothelin Receptor-A Inhibition Decreases Ductular Reaction, Liver Fibrosis, and Angiogenesis in a Model of Cholangitis. Cell Mol Gastroenterol Hepatol 2023; 16:513-540. [PMID: 37336290 PMCID: PMC10462792 DOI: 10.1016/j.jcmgh.2023.06.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 06/09/2023] [Accepted: 06/09/2023] [Indexed: 06/21/2023]
Abstract
BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) leads to ductular reaction and fibrosis and is complicated by vascular dysfunction. Cholangiocyte and endothelial cell crosstalk modulates their proliferation in cholestatic models. Endothelin (ET)-1 and ET-2 bind to their receptor, ET-A, and cholangiocytes are a key source of ET-1 after bile duct ligation. We aimed to evaluate the therapeutic potential of ET-A inhibition in PSC and biliary-endothelial crosstalk mediated by this pathway. METHODS Wild-type and multidrug resistance 2 knockout (Mdr2-/-) mice at 12 weeks of age were treated with vehicle or Ambrisentan (ET-A antagonist) for 1 week by daily intraperitoneal injections. Human control and PSC samples were used. RESULTS Mdr2-/- mice at 4, 8, and 12 weeks displayed angiogenesis that peaked at 12 weeks. Mdr2-/- mice at 12 weeks had enhanced biliary ET-1/ET-2/ET-A expression and secretion, whereas human PSC had enhanced ET-1/ET-A expression and secretion. Ambrisentan reduced biliary damage, immune cell infiltration, and fibrosis in Mdr2-/- mice. Mdr2-/- mice had squamous cholangiocytes with blunted microvilli and dilated arterioles lacking cilia; however, Ambrisentan reversed these alterations. Ambrisentan decreased cholangiocyte expression of pro-angiogenic factors, specifically midkine, through the regulation of cFOS. In vitro, ET-1/ET-A caused cholangiocyte senescence, endothelial cell angiogenesis, and macrophage inflammation. In vitro, human PSC cholangiocyte supernatants increased endothelial cell migration, which was blocked with Ambrisentan treatment. CONCLUSIONS ET-A inhibition reduced biliary and liver damage in Mdr2-/- mice. ET-A promotes biliary angiocrine signaling that may, in turn, enhance angiogenesis. Targeting ET-A may prove therapeutic for PSC, specifically patients displaying vascular dysfunction.
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Affiliation(s)
- Travis Owen
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Guido Carpino
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Lixian Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Debjyoti Kundu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Payton Wills
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana.
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15
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Miao M, Miao J, Zhang Y, Zhang J, She M, Zhao M, Miao Q, Yang L, Zhou K, Li Q. An activatable near-infrared molecular reporter for fluoro-photoacoustic imaging of liver fibrosis. Biosens Bioelectron 2023; 235:115399. [PMID: 37210842 DOI: 10.1016/j.bios.2023.115399] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 05/09/2023] [Accepted: 05/13/2023] [Indexed: 05/23/2023]
Abstract
Noninvasive and accurate detection of liver fibrosis is extremely significant for well-timed intervention and treatment to prevent or reverse its progression. Fluorescence imaging probes hold great potential for imaging of liver fibrosis, but they always encounter the inherent limitation of shallow penetration depth, which compromises their ability of in vivo detection. To overcome this issue, an activatable fluoro-photoacoustic bimodal imaging probe (IP) is herein developed for specific visualization of liver fibrosis. The probe IP is constructed on a near-infrared thioxanthene-hemicyanine dye that is caged with gamma-glutamyl transpeptidase (GGT) responsive substrate and linked with integrin-targeted peptide (cRGD). Such molecular design permits IP to effectively accumulate in the liver fibrosis region through specific recognition of cRGD towards integrin and activate its fluoro-photoacoustic signal after interaction with overexpressed GGT to precisely monitor the liver fibrosis. Thus, our study presents a potential strategy to design dual-target fluoro-photoacoustic imaging probes for noninvasive detection of early-stage liver fibrosis.
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Affiliation(s)
- Minqian Miao
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China
| | - Jia Miao
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China
| | - Yuan Zhang
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China
| | - Jinglin Zhang
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China
| | - Meng She
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China
| | - Min Zhao
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China
| | - Qingqing Miao
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China
| | - Li Yang
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China.
| | - Kailong Zhou
- Department of Hand and Foot Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
| | - Qing Li
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China.
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16
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Brooks S, Mittler S, Hamilton DW. Contact Guidance of Connective Tissue Fibroblasts on Submicrometer Anisotropic Topographical Cues Is Dependent on Tissue of Origin, β1 Integrins, and Tensin-1 Recruitment. ACS APPLIED MATERIALS & INTERFACES 2023; 15:19817-19832. [PMID: 37067372 PMCID: PMC10141244 DOI: 10.1021/acsami.2c22381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/03/2023]
Abstract
The substratum topography of both natural and synthetic materials is a prominent regulator of cell behaviors including adhesion, migration, matrix fibrillogenesis, and cell phenotype. Connective tissue fibroblasts are known to respond to repeating groove topographical modifications by aligning and exhibiting directed migration, a phenomenon termed contact guidance. Although both reside in collagen rich connective tissues, dermal and gingival fibroblasts are known to exhibit differences in phenotype during wound healing, with gingival tissue showing a fetal-like scarless response. Differences in adhesion formation and maturation are known to underlie both a scarring phenotype and cell response to topographical features. Utilizing repeating groove substrates with periodicities of 600, 900, and 1200 nm (depth, 100 nm), we investigated the roles of integrins αvβ3 and β1 associated adhesions on contact guidance of human gingival (HGFs) and dermal fibroblasts (HDFs). HGFs showed a higher degree of orientation with the groove long axis than HDFs, with alignment of both vinculin and tensin-1 evident on 600 and 900 nm periodicities in both cell types. Orientation with grooves of any periodicity in HGFs and HDFs did not alter the adhesion number or area compared to smooth control surfaces. Growth of both cell types on all periodicities reduced fibronectin fibrillogenesis compared to control surfaces. Independent inhibition of integrin αvβ3 and β1 in both cell types induced changes in spreading up to 6 h and reduced alignment with the groove long axis. At 24 h post-seeding with blocking antibodies, HGFs recovered orientation, but in HDFs, blocking of β1, but not αvβ3 integrins, inhibited alignment. Blocking of β1 and αvβ3 in HDFs, but not HGFs, inhibited tensin-1-associated fibrillar adhesion formation. Furthermore, inhibition of β1 integrins in HDFs, but not HGFs, resulted in recruitment of tensin-1 to αvβ3 focal adhesions, preventing HDFs from aligning with the groove long axis. Our work demonstrates that tensin-1 localization with specific integrins in adhesion sites is an important determinant of contact guidance. This work emphasizes further the need for tissue-specific biomaterials, when integration into host tissues is required.
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Affiliation(s)
- Sarah Brooks
- School
of Biomedical Engineering, Western University, London, ON N6A 5C1, Canada
| | - Silvia Mittler
- School
of Biomedical Engineering, Western University, London, ON N6A 5C1, Canada
- Department
of Physics and Astronomy, Faculty of Science, Western University, London, ON N6A 3K7, Canada
| | - Douglas W. Hamilton
- School
of Biomedical Engineering, Western University, London, ON N6A 5C1, Canada
- Department
of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A
5C1, Canada
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17
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Bansal R, Poelstra K. Hepatic Stellate Cell Targeting Using Peptide-Modified Biologicals. Methods Mol Biol 2023; 2669:269-284. [PMID: 37247067 DOI: 10.1007/978-1-0716-3207-9_17] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Liver diseases are a leading cause of death worldwide and are rising exponentially due to increasing prevalence of metabolic disorders. Hepatic stellate cells (HSCs) are recognized as a key therapeutic target in liver diseases as these cells, upon activation during liver damage and ongoing liver inflammation, secrete excessive amounts of extracellular matrix that leads to liver tissue scarring (fibrosis) responsible for liver dysfunction (end-stage liver disease) and desmoplasia in hepatocellular carcinoma. Targeting of HSCs to reverse fibrosis progression has been realized by several experts in the field, including us. We have developed strategies to target activated HSCs by utilizing the receptors overexpressed on the surface of activated HSCs. One well-known receptor is platelet derived growth factor receptor-beta (PDGFR-β). Using PDGFR-β recognizing peptides (cyclic PPB or bicyclic PPB), we can deliver biologicals, e.g., interferon gamma (IFNγ) or IFNγ activity domain (mimetic IFNγ), to the activated HSCs that can inhibit their activation and reverse liver fibrosis. In this chapter, we provide the detailed methods and the principles involved in the synthesis of these targeted (mimetic) IFNγ constructs. These methods can be adapted for synthesizing constructs for targeted/cell-specific delivery of peptides/proteins, drugs, and imaging agents useful for various applications including diagnosis and treatment of inflammatory and fibrotic diseases and cancer.
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Affiliation(s)
- Ruchi Bansal
- Translational Liver Research, Department of Medical Cell BioPhysics, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.
| | - Klaas Poelstra
- Department of Nanomedicine and Drug Targeting, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands.
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18
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Tie Y, Tang F, Peng D, Zhang Y, Shi H. TGF-beta signal transduction: biology, function and therapy for diseases. MOLECULAR BIOMEDICINE 2022; 3:45. [PMID: 36534225 PMCID: PMC9761655 DOI: 10.1186/s43556-022-00109-9] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 11/15/2022] [Indexed: 12/23/2022] Open
Abstract
The transforming growth factor beta (TGF-β) is a crucial cytokine that get increasing concern in recent years to treat human diseases. This signal controls multiple cellular responses during embryonic development and tissue homeostasis through canonical and/or noncanonical signaling pathways. Dysregulated TGF-β signal plays an essential role in contributing to fibrosis via promoting the extracellular matrix deposition, and tumor progression via inducing the epithelial-to-mesenchymal transition, immunosuppression, and neovascularization at the advanced stage of cancer. Besides, the dysregulation of TGF-beta signal also involves in other human diseases including anemia, inflammatory disease, wound healing and cardiovascular disease et al. Therefore, this signal is proposed to be a promising therapeutic target in these diseases. Recently, multiple strategies targeting TGF-β signals including neutralizing antibodies, ligand traps, small-molecule receptor kinase inhibitors targeting ligand-receptor signaling pathways, antisense oligonucleotides to disrupt the production of TGF-β at the transcriptional level, and vaccine are under evaluation of safety and efficacy for the forementioned diseases in clinical trials. Here, in this review, we firstly summarized the biology and function of TGF-β in physiological and pathological conditions, elaborated TGF-β associated signal transduction. And then, we analyzed the current advances in preclinical studies and clinical strategies targeting TGF-β signal transduction to treat diseases.
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Affiliation(s)
- Yan Tie
- grid.13291.380000 0001 0807 1581Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.37 Guo Xue Xiang, Chengdu, 610041 China
| | - Fan Tang
- grid.13291.380000 0001 0807 1581Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.37 Guo Xue Xiang, Chengdu, 610041 China ,grid.13291.380000 0001 0807 1581Orthopaedic Research Institute, Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu, China
| | - Dandan Peng
- grid.13291.380000 0001 0807 1581Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.37 Guo Xue Xiang, Chengdu, 610041 China
| | - Ye Zhang
- grid.506261.60000 0001 0706 7839Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
| | - Huashan Shi
- grid.13291.380000 0001 0807 1581Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.37 Guo Xue Xiang, Chengdu, 610041 China
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19
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Wang Y, Liu X, Quan X, Qin X, Zhou Y, Liu Z, Chao Z, Jia C, Qin H, Zhang H. Pigment epithelium-derived factor and its role in microvascular-related diseases. Biochimie 2022; 200:153-171. [DOI: 10.1016/j.biochi.2022.05.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 05/19/2022] [Accepted: 05/30/2022] [Indexed: 01/02/2023]
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20
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Li X, Lu Z. Role of von Willebrand factor in the angiogenesis of lung adenocarcinoma (Review). Oncol Lett 2022; 23:198. [PMID: 35572495 PMCID: PMC9100484 DOI: 10.3892/ol.2022.13319] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/19/2022] [Indexed: 11/06/2022] Open
Affiliation(s)
- Xin Li
- Department of Oncology, Affiliated Hospital of Weifang Medical College, Weifang, Shandong 261053, P.R. China
| | - Zhong Lu
- Department of Oncology, Affiliated Hospital of Weifang Medical College, Weifang, Shandong 261053, P.R. China
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21
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Rahman SR, Roper JA, Grove JI, Aithal GP, Pun KT, Bennett AJ. Integrins as a drug target in liver fibrosis. Liver Int 2022; 42:507-521. [PMID: 35048542 DOI: 10.1111/liv.15157] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 12/30/2021] [Indexed: 02/06/2023]
Abstract
As the worldwide prevalence of chronic liver diseases is high and continuing to increase, there is an urgent need for treatment to prevent cirrhosis-related morbidity and mortality. Integrins are heterodimeric cell-surface proteins that are promising targets for therapeutic intervention. αv integrins are central in the development of fibrosis as they activate latent TGFβ, a known profibrogenic cytokine. The αv subunit can form heterodimers with β1, β3, β5, β6 or β8 subunits and one or more of these integrins are central to the development of liver fibrosis, however, their relative importance is not understood. This review summarises the current knowledge of αv integrins and their respective β subunits in different organs, with a focus on liver fibrosis and the emerging preclinical and clinical data with regards to αv integrin inhibitors.
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Affiliation(s)
- Syedia R Rahman
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.,FRAME Alternatives Laboratory, Life Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK.,Nottingham Digestive Diseases Centre, Translational Medical Sciences, Medicine, University of Nottingham, Nottingham, UK
| | - James A Roper
- Novel Human Genetics Research Unit, GlaxoSmithKline, Stevenage, UK
| | - Jane I Grove
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.,Nottingham Digestive Diseases Centre, Translational Medical Sciences, Medicine, University of Nottingham, Nottingham, UK
| | - Guruprasad P Aithal
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.,Nottingham Digestive Diseases Centre, Translational Medical Sciences, Medicine, University of Nottingham, Nottingham, UK
| | - K Tao Pun
- Novel Human Genetics Research Unit, GlaxoSmithKline, Stevenage, UK
| | - Andrew J Bennett
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.,FRAME Alternatives Laboratory, Life Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK.,Nottingham Digestive Diseases Centre, Translational Medical Sciences, Medicine, University of Nottingham, Nottingham, UK
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22
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Coll M, Ariño S, Mártinez-Sánchez C, Garcia-Pras E, Gallego J, Moles A, Aguilar-Bravo B, Blaya D, Vallverdú J, Rubio-Tomás T, Lozano JJ, Pose E, Graupera I, Fernández-Vidal A, Pol A, Bataller R, Geng JG, Ginès P, Fernandez M, Sancho-Bru P. Ductular reaction promotes intrahepatic angiogenesis through Slit2-Roundabout 1 signaling. Hepatology 2022; 75:353-368. [PMID: 34490644 PMCID: PMC8766889 DOI: 10.1002/hep.32140] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 07/08/2021] [Accepted: 08/06/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND AND AIMS Ductular reaction (DR) expands in chronic liver diseases and correlates with disease severity. Besides its potential role in liver regeneration, DR plays a role in the wound-healing response of the liver, promoting periductular fibrosis and inflammatory cell recruitment. However, there is no information regarding its role in intrahepatic angiogenesis. In the current study we investigated the potential contribution of DR cells to hepatic vascular remodeling during chronic liver disease. APPROACH AND RESULTS In mouse models of liver injury, DR cells express genes involved in angiogenesis. Among angiogenesis-related genes, the expression of Slit2 and its receptor Roundabout 1 (Robo1) was localized in DR cells and neoangiogenic vessels, respectively. The angiogenic role of the Slit2-Robo1 pathway in chronic liver disease was confirmed in ROBO1/2-/+ mice treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which displayed reduced intrahepatic neovascular density compared to wild-type mice. However, ROBO1/2 deficiency did not affect angiogenesis in partial hepatectomy. In patients with advanced alcohol-associated disease, angiogenesis was associated with DR, and up-regulation of SLIT2-ROBO1 correlated with DR and disease severity. In vitro, human liver-derived organoids produced SLIT2 and induced tube formation of endothelial cells. CONCLUSIONS Overall, our data indicate that DR expansion promotes angiogenesis through the Slit2-Robo1 pathway and recognize DR cells as key players in the liver wound-healing response.
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MESH Headings
- Animals
- Blood Vessels/metabolism
- Chronic Disease
- Disease Progression
- Gene Expression
- Gene Ontology
- Hepatitis, Alcoholic/pathology
- Hepatitis, Alcoholic/physiopathology
- Humans
- Intercellular Signaling Peptides and Proteins/genetics
- Intercellular Signaling Peptides and Proteins/metabolism
- Liver/metabolism
- Liver/physiopathology
- Liver Diseases, Alcoholic/genetics
- Liver Diseases, Alcoholic/metabolism
- Liver Diseases, Alcoholic/pathology
- Liver Diseases, Alcoholic/physiopathology
- Mice
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/pathology
- Neovascularization, Physiologic/genetics
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism
- Organoids
- Patient Acuity
- Receptors, Immunologic/genetics
- Receptors, Immunologic/metabolism
- Signal Transduction/genetics
- Stem Cells
- Up-Regulation
- Vascular Remodeling
- Wound Healing
- Roundabout Proteins
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Affiliation(s)
- Mar Coll
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Medicine department, Faculty of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
| | - Silvia Ariño
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Celia Mártinez-Sánchez
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Ester Garcia-Pras
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
| | - Javier Gallego
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
| | - Anna Moles
- Cell Death and Proliferation, Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Catalonia, Spain
- Liver Unit, Hospital Clínic, Barcelona, Catalonia, Spain
| | - Beatriz Aguilar-Bravo
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Delia Blaya
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Julia Vallverdú
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Teresa Rubio-Tomás
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Juan Jose Lozano
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
| | - Elisa Pose
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
- Liver Unit, Hospital Clínic, Barcelona, Catalonia, Spain
| | - Isabel Graupera
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Medicine department, Faculty of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
- Liver Unit, Hospital Clínic, Barcelona, Catalonia, Spain
| | - Andrea Fernández-Vidal
- Cell compartments and Signaling Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Albert Pol
- Cell compartments and Signaling Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Department of Biomedical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain
| | - Ramón Bataller
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Jian-Guo Geng
- Department of Biologic and Material Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA
| | - Pere Ginès
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Medicine department, Faculty of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
- Liver Unit, Hospital Clínic, Barcelona, Catalonia, Spain
| | - Mercedes Fernandez
- Medicine department, Faculty of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
| | - Pau Sancho-Bru
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Medicine department, Faculty of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
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23
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Connective Tissue Disorders and Cardiovascular Complications: The Indomitable Role of Transforming Growth Factor-β Signaling. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1348:161-184. [PMID: 34807419 DOI: 10.1007/978-3-030-80614-9_7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Marfan Syndrome (MFS) and Loeys-Dietz Syndrome (LDS) represent heritable connective tissue disorders that segregate with a similar pattern of cardiovascular defects (thoracic aortic aneurysm, mitral valve prolapse/regurgitation, and aortic dilatation with regurgitation). This pattern of cardiovascular defects appears to be expressed along a spectrum of severity in many heritable connective tissue disorders and raises suspicion of a relationship between the normal development of connective tissues and the cardiovascular system. With overwhelming evidence of the involvement of aberrant Transforming Growth Factor-beta (TGF-β) signaling in MFS and LDS, this signaling pathway may represent the common link in the relationship between connective tissue disorders and their associated cardiovascular complications. To further explore this hypothetical link, this chapter will review the TGF-β signaling pathway, the heritable connective tissue syndromes related to aberrant TGF-β signaling, and will discuss the pathogenic contribution of TGF-β to these syndromes with a primary focus on the cardiovascular system.
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24
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Decaris ML, Schaub JR, Chen C, Cha J, Lee GG, Rexhepaj M, Ho SS, Rao V, Marlow MM, Kotak P, Budi EH, Hooi L, Wu J, Fridlib M, Martin SP, Huang S, Chen M, Muñoz M, Hom TF, Wolters PJ, Desai TJ, Rock F, Leftheris K, Morgans DJ, Lepist EI, Andre P, Lefebvre EA, Turner SM. Dual inhibition of α vβ 6 and α vβ 1 reduces fibrogenesis in lung tissue explants from patients with IPF. Respir Res 2021; 22:265. [PMID: 34666752 PMCID: PMC8524858 DOI: 10.1186/s12931-021-01863-0] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 10/10/2021] [Indexed: 12/11/2022] Open
Abstract
RATIONALE αv integrins, key regulators of transforming growth factor-β activation and fibrogenesis in in vivo models of pulmonary fibrosis, are expressed on abnormal epithelial cells (αvβ6) and fibroblasts (αvβ1) in fibrotic lungs. OBJECTIVES We evaluated multiple αv integrin inhibition strategies to assess which most effectively reduced fibrogenesis in explanted lung tissue from patients with idiopathic pulmonary fibrosis. METHODS Selective αvβ6 and αvβ1, dual αvβ6/αvβ1, and multi-αv integrin inhibitors were characterized for potency, selectivity, and functional activity by ligand binding, cell adhesion, and transforming growth factor-β cell activation assays. Precision-cut lung slices generated from lung explants from patients with idiopathic pulmonary fibrosis or bleomycin-challenged mouse lungs were treated with integrin inhibitors or standard-of-care drugs (nintedanib or pirfenidone) and analyzed for changes in fibrotic gene expression or TGF-β signaling. Bleomycin-challenged mice treated with dual αvβ6/αvβ1 integrin inhibitor, PLN-74809, were assessed for changes in pulmonary collagen deposition and Smad3 phosphorylation. MEASUREMENTS AND MAIN RESULTS Inhibition of integrins αvβ6 and αvβ1 was additive in reducing type I collagen gene expression in explanted lung tissue slices from patients with idiopathic pulmonary fibrosis. These data were replicated in fibrotic mouse lung tissue, with no added benefit observed from inhibition of additional αv integrins. Antifibrotic efficacy of dual αvβ6/αvβ1 integrin inhibitor PLN-74809 was confirmed in vivo, where dose-dependent inhibition of pulmonary Smad3 phosphorylation and collagen deposition was observed. PLN-74809 also, more potently, reduced collagen gene expression in fibrotic human and mouse lung slices than clinically relevant concentrations of nintedanib or pirfenidone. CONCLUSIONS In the fibrotic lung, dual inhibition of integrins αvβ6 and αvβ1 offers the optimal approach for blocking fibrogenesis resulting from integrin-mediated activation of transforming growth factor-β.
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Affiliation(s)
| | | | - Chun Chen
- Pliant Therapeutics, South San Francisco, CA, USA
| | - Jacob Cha
- Pliant Therapeutics, South San Francisco, CA, USA
| | - Gail G Lee
- Pliant Therapeutics, South San Francisco, CA, USA
| | | | - Steve S Ho
- Pliant Therapeutics, South San Francisco, CA, USA
| | - Vikram Rao
- Pliant Therapeutics, South San Francisco, CA, USA
| | | | - Prerna Kotak
- Pliant Therapeutics, South San Francisco, CA, USA
| | - Erine H Budi
- Pliant Therapeutics, South San Francisco, CA, USA
| | - Lisa Hooi
- Pliant Therapeutics, South San Francisco, CA, USA
| | - Jianfeng Wu
- Pliant Therapeutics, South San Francisco, CA, USA
| | | | | | - Shaoyi Huang
- Pliant Therapeutics, South San Francisco, CA, USA
| | - Ming Chen
- Pliant Therapeutics, South San Francisco, CA, USA
| | - Manuel Muñoz
- Pliant Therapeutics, South San Francisco, CA, USA
| | | | - Paul J Wolters
- Department of Medicine, University of California, San Francisco, CA, USA
| | - Tushar J Desai
- Department of Medicine, Stanford University, Stanford, CA, USA
| | | | | | - David J Morgans
- Pliant Therapeutics, South San Francisco, CA, USA
- Maze Therapeutics, South San Francisco, CA, USA
| | | | - Patrick Andre
- Pliant Therapeutics, South San Francisco, CA, USA
- Acceleron Pharma, Cambridge, MA, USA
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25
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Turaga RC, Satyanarayana G, Sharma M, Yang JJ, Wang S, Liu C, Li S, Yang H, Grossniklaus H, Farris AB, Gracia-Sancho J, Liu ZR. Targeting integrin αvβ3 by a rationally designed protein for chronic liver disease treatment. Commun Biol 2021; 4:1087. [PMID: 34531529 PMCID: PMC8445973 DOI: 10.1038/s42003-021-02611-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 08/26/2021] [Indexed: 12/22/2022] Open
Abstract
Chronic Liver Diseases (CLD) are characterized by abnormal accumulation of collagen fibrils, neo-angiogenesis, and sinusoidal remodeling. Collagen deposition along with intrahepatic angiogenesis and sinusoidal remodeling alters sinusoid structure resulting in portal hypertension, liver failure, and other complications. Efforts were made to develop treatments for CLDs. However, the success of such treatments is limited and unpredictable. We report a strategy for CLD treatment by induction of integrin αvβ3 mediated cell apoptosis using a rationally designed protein (ProAgio). ProAgio is designed to target integrin αvβ3 at a novel site. Integrin αvβ3 is highly expressed in activated Hepatic Stellate Cells (HSC), angiogenic endothelium, and capillarized Liver Sinusoidal Endothelial Cells (LSEC). ProAgio induces apoptosis of these disease causative cells. Tests with liver fibrosis mouse models demonstrate that ProAgio reverses liver fibrosis and relieves blood flow resistance by depleting activated HSC and capillarized LSEC. Our studies demonstrate an effective approach for CLD treatment.
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Affiliation(s)
- Ravi Chakra Turaga
- Department of Biology, Georgia State University, Atlanta, GA, 30324, USA
| | | | - Malvika Sharma
- Department of Biology, Georgia State University, Atlanta, GA, 30324, USA
| | - Jenny J Yang
- Department of Chemistry, Georgia State University, Atlanta, USA
| | | | | | - Sun Li
- Department of Chemistry, Georgia State University, Atlanta, USA
| | - Hua Yang
- Department Ophthalmology, Emory University, Atlanta, GA, 30322, USA
| | | | | | | | - Zhi-Ren Liu
- Department of Biology, Georgia State University, Atlanta, GA, 30324, USA.
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26
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Yin GN, Piao S, Liu Z, Wang L, Ock J, Kwon MH, Kim DK, Gho YS, Suh JK, Ryu JK. RNA-sequencing profiling analysis of pericyte-derived extracellular vesicle-mimetic nanovesicles-regulated genes in primary cultured fibroblasts from normal and Peyronie's disease penile tunica albuginea. BMC Urol 2021; 21:103. [PMID: 34362357 PMCID: PMC8344132 DOI: 10.1186/s12894-021-00872-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 07/20/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Peyronie's disease (PD) is a severe fibrotic disease of the tunica albuginea that causes penis curvature and leads to penile pain, deformity, and erectile dysfunction. The role of pericytes in the pathogenesis of fibrosis has recently been determined. Extracellular vesicle (EV)-mimetic nanovesicles (NVs) have attracted attention regarding intercellular communication between cells in the field of fibrosis. However, the global gene expression of pericyte-derived EV-mimetic NVs (PC-NVs) in regulating fibrosis remains unknown. Here, we used RNA-sequencing technology to investigate the potential target genes regulated by PC-NVs in primary fibroblasts derived from human PD plaque. METHODS Human primary fibroblasts derived from normal and PD patients was cultured and treated with cavernosum pericytes isolated extracellular vesicle (EV)-mimetic nanovesicles (NVs). A global gene expression RNA-sequencing assay was performed on normal fibroblasts, PD fibroblasts, and PD fibroblasts treated with PC-NVs. Reverse transcription polymerase chain reaction (RT-PCR) was used for sequencing data validation. RESULTS A total of 4135 genes showed significantly differential expression in the normal fibroblasts, PD fibroblasts, and PD fibroblasts treated with PC-NVs. However, only 91 contra-regulated genes were detected among the three libraries. Furthermore, 20 contra-regulated genes were selected and 11 showed consistent changes in the RNA-sequencing assay, which were validated by RT-PCR. CONCLUSION The gene expression profiling results suggested that these validated genes may be good targets for understanding potential mechanisms and conducting molecular studies into PD.
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Affiliation(s)
- Guo Nan Yin
- Department of Urology and National Research Center for Sexual Medicine, Inha University School of Medicine, 7-206, 3rd St, Shinheung-Dong, Jung-Gu, Incheon, 22332, Republic of Korea
| | - Shuguang Piao
- Department of Urology at Changhai Hospital Affiliated with the Naval Medicine University, Shanghai, 200433, People's Republic of China
| | - Zhiyong Liu
- Department of Urology at Changhai Hospital Affiliated with the Naval Medicine University, Shanghai, 200433, People's Republic of China
| | - Lei Wang
- Department of Urology at Changhai Hospital Affiliated with the Naval Medicine University, Shanghai, 200433, People's Republic of China
| | - Jiyeon Ock
- Department of Urology and National Research Center for Sexual Medicine, Inha University School of Medicine, 7-206, 3rd St, Shinheung-Dong, Jung-Gu, Incheon, 22332, Republic of Korea
| | - Mi-Hye Kwon
- Department of Urology and National Research Center for Sexual Medicine, Inha University School of Medicine, 7-206, 3rd St, Shinheung-Dong, Jung-Gu, Incheon, 22332, Republic of Korea
| | - Do-Kyun Kim
- Korea Zoonosis Research Institute, Jeonbuk National University, Iksan, Jeonbuk, 54531, Korea
| | - Yong Song Gho
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Kyeongsangbuk-do, 37673, Korea
| | - Jun-Kyu Suh
- Department of Urology and National Research Center for Sexual Medicine, Inha University School of Medicine, 7-206, 3rd St, Shinheung-Dong, Jung-Gu, Incheon, 22332, Republic of Korea.
| | - Ji-Kan Ryu
- Department of Urology and National Research Center for Sexual Medicine, Inha University School of Medicine, 7-206, 3rd St, Shinheung-Dong, Jung-Gu, Incheon, 22332, Republic of Korea.
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27
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Liebold I, Jawazneh AA, Hamley M, Bosurgi L. Apoptotic cell signals and heterogeneity in macrophage function: Fine-tuning for a healthy liver. Semin Cell Dev Biol 2021; 119:72-81. [PMID: 34246569 DOI: 10.1016/j.semcdb.2021.06.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 06/11/2021] [Accepted: 06/18/2021] [Indexed: 12/13/2022]
Abstract
Functional heterogeneity in tissue macrophage populations has often been traced to developmental and spatial cues. Upon tissue damage, macrophages are exposed to soluble mediators secreted by activated cells, which shape their polarisation. Interestingly, macrophages are concomitantly exposed to a variety of different dying cells, which carry miscellaneous signals and that need to be recognised and promptly up-taken by professional phagocytes. This review discusses how differences in the nature of the dying cells, like their morphological and biochemical features as well as the specificity of phagocytic receptor usage on macrophages, might contribute to the transcriptional and functional heterogeneity observed in phagocytic cells in the tissue.
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Affiliation(s)
- Imke Liebold
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Amirah Al Jawazneh
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Madeleine Hamley
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Lidia Bosurgi
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
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28
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Zhu Y, Xu W, Hu W, Wang F, Zhou Y, Xu J, Gong W. Discovery and validation of novel protein markers in mucosa of portal hypertensive gastropathy. BMC Gastroenterol 2021; 21:214. [PMID: 33971821 PMCID: PMC8111717 DOI: 10.1186/s12876-021-01787-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 04/22/2021] [Indexed: 11/10/2022] Open
Abstract
Background Portal hypertension induced esophageal and gastric variceal bleeding is the main cause of death among patients of decompensated liver cirrhosis. Therefore, a standardized, biomarker-based test, to make an early-stage non-invasive risk assessment of portal hypertension, is highly desirable. However, no fit-for-purpose biomarkers have yet been identified. Methods We conducted a pilot study consisting of 5 portal hypertensive gastropathy (PHG) patients and 5 normal controls, sampling the gastric mucosa of normal controls and PHG patients before and after endoscopic cyanoacrylate injection, using label-free quantitative (LFQ) mass spectrometry, to identify potential biomarker candidates in gastric mucosa from PHG patients and normal controls. Then we further used parallel reaction monitoring (PRM) to verify the abundance of the targeted protein. Results LFQ analyses identified 423 significantly differentially expressed proteins. 17 proteins that significantly elevated in the gastric mucosa of PHG patients were further validated using PRM. Conclusions This is the first application of an LFQ-PRM workflow to identify and validate PHG–specific biomarkers in patient gastric mucosa samples. Our findings lay the foundation for comprehending the molecular mechanisms of PHG pathogenesis, and provide potential applications for useful biomarkers in early diagnosis and treatment. Trial registration and ethics approval: Trial registration was completed (ChiCTR2000029840) on February 25, 2020. Ethics Approvals were completed on July 17, 2017 (NYSZYYEC20180003) and February 15, 2020 (NYSZYYEC20200005). Supplementary Information The online version contains supplementary material available at 10.1186/s12876-021-01787-5.
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Affiliation(s)
- Ying Zhu
- Department of Gastroenterology, Shenzhen Hospital of Southern Medical University, Shenzhen, 518000, Guangdong, China
| | - Wen Xu
- Department of Gastroenterology, Shenzhen Hospital of Southern Medical University, Shenzhen, 518000, Guangdong, China
| | - Wei Hu
- Department of Gastroenterology, Shenzhen Hospital of Southern Medical University, Shenzhen, 518000, Guangdong, China
| | - Fang Wang
- Department of Gastroenterology, Shenzhen Hospital of Southern Medical University, Shenzhen, 518000, Guangdong, China
| | - Yan Zhou
- Information Management Section, Bethune International Peace Hospital, Shijiazhuang City, Hebei Province, China
| | - Jianguo Xu
- Department of Liver Disease Center, Shenzhen Hospital of Southern Medical University, Shenzhen, 518000, Guangdong, China.
| | - Wei Gong
- Department of Gastroenterology, Shenzhen Hospital of Southern Medical University, Shenzhen, 518000, Guangdong, China.
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29
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Li H. Angiogenesis in the progression from liver fibrosis to cirrhosis and hepatocelluar carcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:217-233. [PMID: 33131349 DOI: 10.1080/17474124.2021.1842732] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: Persistent inflammation and hypoxia are strong stimulus for pathological angiogenesis and vascular remodeling, and are also the most important elements resulting in liver fibrosis. Sustained inflammatory process stimulates fibrosis to the end-point of cirrhosis and sinusoidal portal hypertension is an important feature of cirrhosis. Neovascularization plays a pivotal role in collateral circulation formation of portal vein, mesenteric congestion, and high perfusion. Imbalance of hepatic artery and portal vein blood flow leads to the increase of hepatic artery inflow, which is beneficial to the formation of nodules. Angiogenesis contributes to progression from liver fibrosis to cirrhosis and hepatocellular carcinoma (HCC) and anti-angiogenesis therapy can improve liver fibrosis, reduce portal pressure, and prolong overall survival of patients with HCC. Areas covers: This paper will try to address the difference of the morphological characteristics and mechanisms of neovascularization in the process from liver fibrosis to cirrhosis and HCC and further compare the different efficacy of anti-angiogenesis therapy in these three stages. Expert opinion: More in-depth understanding of the role of angiogenesis factors and the relationship between angiogenesis and other aspects of the pathogenesis and transformation may be the key to enabling future progress in the treatment of patients with liver fibrosis, cirrhosis, and HCC.
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Affiliation(s)
- Hui Li
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine , Chengdu, Sichuan Province, P. R. China
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Extracellular Matrix Remodeling in Chronic Liver Disease. CURRENT TISSUE MICROENVIRONMENT REPORTS 2021; 2:41-52. [PMID: 34337431 PMCID: PMC8300084 DOI: 10.1007/s43152-021-00030-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 05/09/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE OF THE REVIEW This review aims to summarize the current knowledge of the extracellular matrix remodeling during hepatic fibrosis. We discuss the diverse interactions of the extracellular matrix with hepatic cells and the surrounding matrix in liver fibrosis, with the focus on the molecular pathways and the mechanisms that regulate extracellular matrix remodeling. RECENT FINDINGS The extracellular matrix not only provides structure and support for the cells, but also controls cell behavior by providing adhesion signals and by acting as a reservoir of growth factors and cytokines. SUMMARY Hepatic fibrosis is characterized by an excessive accumulation of extracellular matrix. During fibrogenesis, the natural remodeling process of the extracellular matrix varies, resulting in the excessive accumulation of its components, mainly collagens. Signals released by the extracellular matrix induce the activation of hepatic stellate cells, which are the major source of extracellular matrix and most abundant myofibroblasts in the liver. GRAPHICAL ABSTRACT
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Zhang T, Li Y, Song Y, Chen X, Li J, Peng Q, He J, Fei X. Curcumin- and Cyclopamine-Loaded Liposomes to Enhance Therapeutic Efficacy Against Hepatic Fibrosis. Drug Des Devel Ther 2020; 14:5667-5678. [PMID: 33380787 PMCID: PMC7767702 DOI: 10.2147/dddt.s287442] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 12/11/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND AND PURPOSE Hepatic fibrosis is a public health problem characterized by activation of hepatic stellate cells (HSCs), which triggers excessive production of extracellular matrix (ECM). Inhibition of HSC activation may be an effective treatment. Since various pathways control HSC activation, a combination of drugs with different mechanisms may be more effective than monotherapy. METHODS Here, we prepared liposomes loaded with curcumin and cyclopamine to inhibit HSC activation. We systematically analyzed the physicochemical characteristics of liposomes loaded with the two drugs, as well as their effects on HSC proliferation, activation and collagen production on gene, protein and cellular levels. RESULTS The prepared liposomes helped solubilize both drugs, contributing to their uptake by cells. Liposomes loaded with both drugs inhibited cell proliferation, migration and invasion, as well as induced more apoptosis and perturbed the cell cycle more than the free combination of both drugs in solution or liposomes loaded with either drug alone. Liposomes loaded with both drugs strongly suppressed HSC activation and collagen secretion. CONCLUSION Our results suggest that liposome encapsulation can increase the uptake of curcumin and cyclopamine as well as the synergism between them in anti-fibrosis. This approach shows potential for treating hepatic fibrosis.
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Affiliation(s)
- Ting Zhang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu610041, People’s Republic of China
| | - Yanping Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, People’s Republic of China
| | - Yi Song
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu610041, People’s Republic of China
| | - Xiaoshuang Chen
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu610041, People’s Republic of China
| | - Jing Li
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu610041, People’s Republic of China
| | - Qiang Peng
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu610041, People’s Republic of China
| | - Jinhan He
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu610041, People’s Republic of China
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, People’s Republic of China
| | - Xiaofan Fei
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu610041, People’s Republic of China
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Ritzenthaler JD, Zhang M, Torres-Gonzalez E, Roman J. The Integrin Inhibitor Cilengitide and Bleomycin-Induced Pulmonary Fibrosis : Cilengitide and Bleomycin-Induced Pulmonary Fibrosis. Lung 2020; 198:947-955. [PMID: 33146772 DOI: 10.1007/s00408-020-00400-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 10/18/2020] [Indexed: 12/22/2022]
Abstract
PURPOSE Fibroproliferation and excess deposition of extracellular matrix (ECM) are the pathologic hallmarks of idiopathic pulmonary fibrosis (IPF), a chronic progressive disorder with high mortality and suboptimal treatment options. Although the etiologic mechanisms responsible for the development and progression of IPF remain unclear, cell-ECM interactions and growth factors are considered important. Cilengitide is a cyclic RGD pentapeptide with anti-angiogenic activity that targets αvβ3, αvβ5 and α5β1, integrins known to mediate cell-ECM interactions and activate the pro-fibrotic growth factor Transforming Growth Factor beta (TGF-β). METHODS Cilengitide was studied in vitro with the use of NIH/3T3 cells and primary lung fibroblasts, and in vivo in the well-characterized bleomycin-induced lung injury model. The extent of ECM deposition was determined by RT-PCR, Western blot, histologic analysis and hydroxyproline assay of lung tissue. Bronchoalveolar lavage analysis was used to determine cell counts. RESULTS Cilengitide treatment of cultured fibroblasts showed decreased adhesion to vitronectin and fibronectin, both integrin-dependent events. Cilengitide also inhibited TGF-β-induced fibronectin gene expression and reduced the accumulation of mRNAs and protein for fibronectin and collagen type I. Both preventive and treatment effects of daily injections of cilengitide (20 mg/kg) failed to inhibit the development of pulmonary fibrosis as determined by histological analysis (Ashcroft scoring), bronchoalveolar lavage (BAL) fluid cell counts, and hydroxyproline content. CONCLUSIONS Overall, our data suggest that, despite its in vitro activity in fibroblasts, daily injections of cilengitide (20 mg/kg) did not inhibit the development of or ameliorate bleomycin-induced pulmonary fibrosis in mice.
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Affiliation(s)
- Jeffrey D Ritzenthaler
- Department of Medicine, Division of Pulmonary, Allergy and Critical Medicine, Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Jefferson Alumni Hall, 381, Philadelphia, PA, 19107, USA.
| | - Michael Zhang
- Department of Pharmacology & Toxicology, University of Louisville Health Sciences Center, Louisville, KY, USA.,University of Minnesota Medical School, Minneapolis, MN, USA
| | - Edilson Torres-Gonzalez
- Department of Medicine, Division of Pulmonary, Allergy and Critical Medicine, Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Jefferson Alumni Hall, 381, Philadelphia, PA, 19107, USA
| | - Jesse Roman
- Department of Pharmacology & Toxicology, University of Louisville Health Sciences Center, Louisville, KY, USA.,Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Louisville Health Sciences Center, Louisville, KY, USA.,Department of Medicine, Division of Pulmonary, Allergy and Critical Medicine, Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Jefferson Alumni Hall, 381, Philadelphia, PA, 19107, USA.,Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA
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Targeting Cancer Associated Fibroblasts in Liver Fibrosis and Liver Cancer Using Nanocarriers. Cells 2020; 9:cells9092027. [PMID: 32899119 PMCID: PMC7563527 DOI: 10.3390/cells9092027] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 08/26/2020] [Accepted: 08/31/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer associated fibroblasts (CAF) and the extracellular matrix (ECM) produced by them have been recognized as key players in cancer biology and emerged as important targets for cancer treatment and drug discovery. Apart from their presence in stroma rich tumors, such as biliary, pancreatic and subtypes of hepatocellular cancer (HCC), both CAF and certain ECM components are also present in cancers without an overt intra-tumoral desmoplastic reaction. They support cancer development, growth, metastasis and resistance to chemo- or checkpoint inhibitor therapy by a multitude of mechanisms, including angiogenesis, ECM remodeling and active immunosuppression by secretion of tumor promoting and immune suppressive cytokines, chemokines and growth factors. CAF resemble activated hepatic stellate cells (HSC)/myofibroblasts, expressing α-smooth muscle actin and especially fibroblast activation protein (FAP). Apart from FAP, CAF also upregulate other functional cell surface proteins like platelet-derived growth factor receptor β (PDGFRβ) or the insulin-like growth factor receptor II (IGFRII). Notably, if formulated with adequate size and zeta potential, injected nanoparticles home preferentially to the liver. Several nanoparticular formulations were tested successfully to deliver dugs to activated HSC/myofibroblasts. Thus, surface modified nanocarriers with a cyclic peptide binding to the PDGFRβ or with mannose-6-phosphate binding to the IGFRII, effectively directed drug delivery to activated HSC/CAF in vivo. Even unguided nanohydrogel particles and lipoplexes loaded with siRNA demonstrated a high in vivo uptake and functional siRNA delivery in activated HSC, indicating that liver CAF/HSC are also addressed specifically by well-devised nanocarriers with optimized physicochemical properties. Therefore, CAF have become an attractive target for the development of stroma-based cancer therapies, especially in the liver.
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Turaga RC, Sharma M, Mishra F, Krasinskas A, Yuan Y, Yang JJ, Wang S, Liu C, Li S, Liu ZR. Modulation of Cancer-Associated Fibrotic Stroma by An Integrin α vβ 3 Targeting Protein for Pancreatic Cancer Treatment. Cell Mol Gastroenterol Hepatol 2020; 11:161-179. [PMID: 32810598 PMCID: PMC7674520 DOI: 10.1016/j.jcmgh.2020.08.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 08/11/2020] [Accepted: 08/12/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapeutics owing to dense fibrotic stroma orchestrated by cancer-associated pancreatic stellate cells (CAPaSC). CAPaSC also support cancer cell growth, metastasis, and resistance to apoptosis. Currently, there is no effective therapy for PDAC that specifically targets CAPaSC. We previously reported a rationally designed protein, ProAgio, that targets integrin αvβ3 at a novel site and induces apoptosis in integrin αvβ3-expressing cells. Because both CAPaSC and angiogenic endothelial cells express high levels of integrin αvβ3, we aimed to analyze the effects of ProAgio in PDAC tumor. METHODS Expression of integrin αvβ3 was examined in both patient tissue and cultured cells. The effects of ProAgio on CAPaSC were analyzed using an apoptosis assay kit. The effects of ProAgio in PDAC tumor were studied in 3 murine tumor models: subcutaneous xenograft, genetic engineered (KrasG12D; p53R172H; Pdx1-Cre, GEM-KPC) mice, and an orthotopic KrasG12D; p53R172H; Pdx1-Cre (KPC) model. RESULTS ProAgio induces apoptosis in CAPaSC. ProAgio treatment significantly prolonged survival of a genetically engineered mouse-KPC and orthotopic KPC mice alone or in combination with gemcitabine (Gem). ProAgio specifically induced apoptosis in CAPaSC, resorbed collagen, and opened collapsed tumor vessels without an increase in angiogenesis in PDAC tumor, enabling drug delivery into the tumor. ProAgio decreased intratumoral insulin-like growth factor 1 levels as a result of depletion of CAPaSC and consequently decreased cytidine deaminase, a Gem metabolism enzyme in cancer cells, and thereby reduced resistance to Gem-induced apoptosis. CONCLUSIONS Our study suggests that ProAgio is an effective PDAC treatment agent because it specifically depletes CAPaSC and eliminates tumor angiogenesis, thereby enhancing drug delivery and Gem efficacy in PDAC tumors.
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Affiliation(s)
| | - Malvika Sharma
- Department of Biology, Georgia State University, Atlanta, Georgia
| | - Falguni Mishra
- Department of Biology, Georgia State University, Atlanta, Georgia
| | | | - Yi Yuan
- Department of Biology, Georgia State University, Atlanta, Georgia
| | - Jenny J Yang
- Department of Chemistry, Georgia State University, Atlanta, Georgia
| | - Shiyuan Wang
- Research and Development Division, Amoytop Biotech, Inc, Xiamen, People's Republic of China
| | - Chunfeng Liu
- Research and Development Division, Amoytop Biotech, Inc, Xiamen, People's Republic of China
| | - Sun Li
- Research and Development Division, Amoytop Biotech, Inc, Xiamen, People's Republic of China
| | - Zhi-Ren Liu
- Department of Biology, Georgia State University, Atlanta, Georgia.
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Yoshimatsu Y, Wakabayashi I, Kimuro S, Takahashi N, Takahashi K, Kobayashi M, Maishi N, Podyma‐Inoue KA, Hida K, Miyazono K, Watabe T. TNF-α enhances TGF-β-induced endothelial-to-mesenchymal transition via TGF-β signal augmentation. Cancer Sci 2020; 111:2385-2399. [PMID: 32385953 PMCID: PMC7385392 DOI: 10.1111/cas.14455] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 04/05/2020] [Accepted: 04/08/2020] [Indexed: 12/15/2022] Open
Abstract
The tumor microenvironment (TME) consists of various components including cancer cells, tumor vessels, cancer-associated fibroblasts (CAFs), and inflammatory cells. These components interact with each other via various cytokines, which often induce tumor progression. Thus, a greater understanding of TME networks is crucial for the development of novel cancer therapies. Many cancer types express high levels of TGF-β, which induces endothelial-to-mesenchymal transition (EndMT), leading to formation of CAFs. Although we previously reported that CAFs derived from EndMT promoted tumor formation, the molecular mechanisms underlying these interactions remain to be elucidated. Furthermore, tumor-infiltrating inflammatory cells secrete various cytokines, including TNF-α. However, the role of TNF-α in TGF-β-induced EndMT has not been fully elucidated. Therefore, this study examined the effect of TNF-α on TGF-β-induced EndMT in human endothelial cells (ECs). Various types of human ECs underwent EndMT in response to TGF-β and TNF-α, which was accompanied by increased and decreased expression of mesenchymal cell and EC markers, respectively. In addition, treatment of ECs with TGF-β and TNF-α exhibited sustained activation of Smad2/3 signals, which was presumably induced by elevated expression of TGF-β type I receptor, TGF-β2, activin A, and integrin αv, suggesting that TNF-α enhanced TGF-β-induced EndMT by augmenting TGF-β family signals. Furthermore, oral squamous cell carcinoma-derived cells underwent epithelial-to-mesenchymal transition (EMT) in response to humoral factors produced by TGF-β and TNF-α-cultured ECs. This EndMT-driven EMT was blocked by inhibiting the action of TGF-βs. Collectively, our findings suggest that TNF-α enhances TGF-β-dependent EndMT, which contributes to tumor progression.
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Affiliation(s)
- Yasuhiro Yoshimatsu
- Department of BiochemistryGraduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
- Division of PharmacologyGraduate School of Medical and Dental SciencesNiigata UniversityNiigataJapan
| | - Ikumi Wakabayashi
- Department of BiochemistryGraduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
| | - Shiori Kimuro
- Department of BiochemistryGraduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
| | - Naoya Takahashi
- Department of BiochemistryGraduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
| | - Kazuki Takahashi
- Department of BiochemistryGraduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
| | - Miho Kobayashi
- Department of BiochemistryGraduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
| | - Nako Maishi
- Department of Vascular Biology and Molecular PathologyGraduate School of Dental MedicineHokkaido UniversitySapporoJapan
| | - Katarzyna A. Podyma‐Inoue
- Department of BiochemistryGraduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
| | - Kyoko Hida
- Department of Vascular Biology and Molecular PathologyGraduate School of Dental MedicineHokkaido UniversitySapporoJapan
| | - Kohei Miyazono
- Department of Molecular PathologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Tetsuro Watabe
- Department of BiochemistryGraduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
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Ortega‐Ribera M, Hunt NJ, Gracia‐Sancho J, Cogger VC. The Hepatic Sinusoid in Aging and Disease: Update and Advances From the 20th Liver Sinusoid Meeting. Hepatol Commun 2020; 4:1087-1098. [PMID: 32626839 PMCID: PMC7327202 DOI: 10.1002/hep4.1517] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 03/17/2020] [Accepted: 03/18/2020] [Indexed: 12/13/2022] Open
Abstract
This is a meeting report of the 2019 Liver Sinusoid Meeting, 20th International Symposium on Cells of the Hepatic Sinusoid, held in Sydney, Australia, in September 2019. The meeting, which was organized by the International Society for Hepatic Sinusoidal Research, provided an update on the recent advances in the field of hepatic sinusoid cells in relation to cell biology, aging, and liver disease, with particular focus on the molecular and cellular targets involved in hepatic fibrosis, nonalcoholic hepatic steatohepatitis, alcoholic liver disease, hepatocellular carcinoma, and cirrhosis. In addition, the meeting highlighted the recent advances in regenerative medicine, targeted nanotechnologies, therapeutics, and novel methodologies.
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Affiliation(s)
- Martí Ortega‐Ribera
- Liver Vascular Biology Research GroupBarcelona Hepatic Hemodynamic UnitInstitut d’Investigacions Biomèdiques August Pi i SunyerCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y DigestivasBarcelonaSpain
| | - Nicholas J. Hunt
- Centre for Education and Research on AgeingConcord Repatriation General HospitalANZAC Research InstituteAustralian Ageing and Alzheimers InstituteConcordSydneyNSWAustralia
- Faculty of Medicine and HealthUniversity of SydneySydneyNSWAustralia
| | - Jordi Gracia‐Sancho
- Liver Vascular Biology Research GroupBarcelona Hepatic Hemodynamic UnitInstitut d’Investigacions Biomèdiques August Pi i SunyerCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y DigestivasBarcelonaSpain
- HepatologyDepartment of Biomedical ResearchUniversity of BernInselspitalBernSwitzerland
| | - Victoria C. Cogger
- Centre for Education and Research on AgeingConcord Repatriation General HospitalANZAC Research InstituteAustralian Ageing and Alzheimers InstituteConcordSydneyNSWAustralia
- Faculty of Medicine and HealthUniversity of SydneySydneyNSWAustralia
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Lafoz E, Ruart M, Anton A, Oncins A, Hernández-Gea V. The Endothelium as a Driver of Liver Fibrosis and Regeneration. Cells 2020; 9:E929. [PMID: 32290100 PMCID: PMC7226820 DOI: 10.3390/cells9040929] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 04/05/2020] [Accepted: 04/06/2020] [Indexed: 02/07/2023] Open
Abstract
Liver fibrosis is a common feature of sustained liver injury and represents a major public health problem worldwide. Fibrosis is an active research field and discoveries in the last years have contributed to the development of new antifibrotic drugs, although none of them have been approved yet. Liver sinusoidal endothelial cells (LSEC) are highly specialized endothelial cells localized at the interface between the blood and other liver cell types. They lack a basement membrane and display open channels (fenestrae), making them exceptionally permeable. LSEC are the first cells affected by any kind of liver injury orchestrating the liver response to damage. LSEC govern the regenerative process initiation, but aberrant LSEC activation in chronic liver injury induces fibrosis. LSEC are also main players in fibrosis resolution. They maintain liver homeostasis and keep hepatic stellate cell and Kupffer cell quiescence. After sustained hepatic injury, they lose their phenotype and protective properties, promoting angiogenesis and vasoconstriction and contributing to inflammation and fibrosis. Therefore, improving LSEC phenotype is a promising strategy to prevent liver injury progression and complications. This review focuses on changes occurring in LSEC after liver injury and their consequences on fibrosis progression, liver regeneration, and resolution. Finally, a synopsis of the available strategies for LSEC-specific targeting is provided.
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Affiliation(s)
- Erica Lafoz
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), 08036 Barcelona, Spain; (E.L.); (M.R.); (A.A.); (A.O.)
| | - Maria Ruart
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), 08036 Barcelona, Spain; (E.L.); (M.R.); (A.A.); (A.O.)
| | - Aina Anton
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), 08036 Barcelona, Spain; (E.L.); (M.R.); (A.A.); (A.O.)
| | - Anna Oncins
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), 08036 Barcelona, Spain; (E.L.); (M.R.); (A.A.); (A.O.)
| | - Virginia Hernández-Gea
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), 08036 Barcelona, Spain; (E.L.); (M.R.); (A.A.); (A.O.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Zhang Y, Distler JHW. Therapeutic molecular targets of SSc-ILD. JOURNAL OF SCLERODERMA AND RELATED DISORDERS 2020; 5:17-30. [DOI: 10.1177/2397198319899013] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 11/26/2019] [Indexed: 12/16/2022]
Abstract
Systemic sclerosis is a fibrosing chronic connective tissue disease of unknown etiology. A major hallmark of systemic sclerosis is the uncontrolled and persistent activation of fibroblasts, which release excessive amounts of extracellular matrix, lead to organ dysfunction, and cause high mobility and motility of patients. Systemic sclerosis–associated interstitial lung disease is one of the most common fibrotic organ manifestations in systemic sclerosis and a major cause of death. Treatment options for systemic sclerosis–associated interstitial lung disease and other fibrotic manifestations, however, remain very limited. Thus, there is a huge medical need for effective therapies that target tissue fibrosis, vascular alterations, inflammation, and autoimmune disease in systemic sclerosis–associated interstitial lung disease. In this review, we discuss data suggesting therapeutic ways to target different genes in distinct tissues/organs that contribute to the development of SSc.
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Affiliation(s)
- Yun Zhang
- Department of Internal Medicine 3—Rheumatology and Immunology, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Jörg HW Distler
- Department of Internal Medicine 3—Rheumatology and Immunology, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
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Chen S, Fang H, Li J, Shi JH, Zhang J, Wen P, Wang Z, Cao S, Yang H, Pan J, Tang H, Zhang H, Guo W, Zhang S. Donor Brain Death Leads to a Worse Ischemia-Reperfusion Injury and Biliary Injury After Liver Transplantation in Rats. Transplant Proc 2020; 52:373-382. [PMID: 31955852 DOI: 10.1016/j.transproceed.2019.10.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 09/13/2019] [Accepted: 10/06/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND Brain-dead (BD) donor is the main source for liver transplantation (LT). We aim to investigate the effect of brain death on donor liver inflammatory activity and its association with ischemia-reperfusion (I/R) injury and biliary tract injury after LT. MATERIAL AND METHOD A brain death model using male Lewis rats was established, in both BD and non-BD groups; livers were harvested for transplantation using a 2-cuff technique. The rats were sacrificed 12 hours (n = 10) or 4 weeks (n = 10) after transplantation. I/R injury and long-term biliary tract injury were observed after transplantation. RESULTS All rats survived for 4 weeks after transplantation. At 12 hours after BD-donor LT (BDDLT), liver injury worsened; serum transaminases, bilirubin, oxidative stress, inflammatory responses and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining level substantially increased (P < .05). At 4 weeks after BDDLT, serum bilirubin and bile lactate dehydrogenase and γ-glutamyl transpeptidase levels were elevated (P < .05). Biliary fibrosis and epithelial-mesenchymal transition (EMT) were detectable and NDRG1 gene expression was decreased. CONCLUSIONS These results suggested that brain death-induced inflammatory response in donor organs and resulted in a worse I/R injury and biliary tract injury after LT in rats. The brain death-related biliary tract injury may be associated with the regulation of EMT through NDRG1.
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Affiliation(s)
- Sanyang Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Henen Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery Digestive Organ Transplantation at Henan University, Zhengzhou, Henan Province, China; Zheng Zhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan Province, China
| | - Hongbo Fang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Jie Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Ji-Hua Shi
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Henen Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery Digestive Organ Transplantation at Henan University, Zhengzhou, Henan Province, China; Zheng Zhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan Province, China
| | - Jiakai Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Peihao Wen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Zhihui Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Shengli Cao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Han Yang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Jie Pan
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Hongwei Tang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Henen Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery Digestive Organ Transplantation at Henan University, Zhengzhou, Henan Province, China; Zheng Zhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan Province, China
| | - Huapeng Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Henen Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery Digestive Organ Transplantation at Henan University, Zhengzhou, Henan Province, China; Zheng Zhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan Province, China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Henen Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery Digestive Organ Transplantation at Henan University, Zhengzhou, Henan Province, China; Zheng Zhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan Province, China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Henen Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery Digestive Organ Transplantation at Henan University, Zhengzhou, Henan Province, China; Zheng Zhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan Province, China.
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40
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Hinz B, Lagares D. Evasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases. Nat Rev Rheumatol 2020; 16:11-31. [PMID: 31792399 PMCID: PMC7913072 DOI: 10.1038/s41584-019-0324-5] [Citation(s) in RCA: 363] [Impact Index Per Article: 72.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/04/2019] [Indexed: 12/15/2022]
Abstract
Organ fibrosis is a lethal outcome of autoimmune rheumatic diseases such as systemic sclerosis. Myofibroblasts are scar-forming cells that are ultimately responsible for the excessive synthesis, deposition and remodelling of extracellular matrix proteins in fibrosis. Advances have been made in our understanding of the mechanisms that keep myofibroblasts in an activated state and control myofibroblast functions. However, the mechanisms that help myofibroblasts to persist in fibrotic tissues remain poorly understood. Myofibroblasts evade apoptosis by activating molecular mechanisms in response to pro-survival biomechanical and growth factor signals from the fibrotic microenvironment, which can ultimately lead to the acquisition of a senescent phenotype. Growing evidence suggests that myofibroblasts and senescent myofibroblasts, rather than being resistant to apoptosis, are actually primed for apoptosis owing to concomitant activation of cell death signalling pathways; these cells are poised to apoptose when survival pathways are inhibited. This knowledge of apoptotic priming has paved the way for new therapies that trigger apoptosis in myofibroblasts by blocking pro-survival mechanisms, target senescent myofibroblast for apoptosis or promote the reprogramming of myofibroblasts into scar-resolving cells. These novel strategies are not only poised to prevent progressive tissue scarring, but also have the potential to reverse established fibrosis and to regenerate chronically injured tissues.
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Affiliation(s)
- Boris Hinz
- Laboratory of Tissue Repair and Regeneration, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada
| | - David Lagares
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Fibrosis Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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41
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Li J, Fukase Y, Shang Y, Zou W, Muñoz-Félix JM, Buitrago L, van Agthoven J, Zhang Y, Hara R, Tanaka Y, Okamoto R, Yasui T, Nakahata T, Imaeda T, Aso K, Zhou Y, Locuson C, Nesic D, Duggan M, Takagi J, Vaughan RD, Walz T, Hodivala-Dilke K, Teitelbaum SL, Arnaout MA, Filizola M, Foley MA, Coller BS. Novel Pure αVβ3 Integrin Antagonists That Do Not Induce Receptor Extension, Prime the Receptor, or Enhance Angiogenesis at Low Concentrations. ACS Pharmacol Transl Sci 2019; 2:387-401. [PMID: 32259072 PMCID: PMC7088984 DOI: 10.1021/acsptsci.9b00041] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Indexed: 01/12/2023]
Abstract
The integrin αVβ3 receptor has been implicated in several important diseases, but no antagonists are approved for human therapy. One possible limitation of current small-molecule antagonists is their ability to induce a major conformational change in the receptor that induces it to adopt a high-affinity ligand-binding state. In response, we used structural inferences from a pure peptide antagonist to design the small-molecule pure antagonists TDI-4161 and TDI-3761. Both compounds inhibit αVβ3-mediated cell adhesion to αVβ3 ligands, but do not induce the conformational change as judged by antibody binding, electron microscopy, X-ray crystallography, and receptor priming studies. Both compounds demonstrated the favorable property of inhibiting bone resorption in vitro, supporting potential value in treating osteoporosis. Neither, however, had the unfavorable property of the αVβ3 antagonist cilengitide of paradoxically enhancing aortic sprout angiogenesis at concentrations below its IC50, which correlates with cilengitide's enhancement of tumor growth in vivo.
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Affiliation(s)
- Jihong Li
- Allen and
Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, 1230 York Avenue, New York, New York 10065, United States
| | - Yoshiyuki Fukase
- Tri-Institutional
Therapeutics Discovery Institute, 413 East 69 Street, New York, New York 10021, United
States
| | - Yi Shang
- Department
of Pharmacological Sciences, Icahn School
of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1677, New York, New York 10029-6574, United States
| | - Wei Zou
- Washington
University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110, United States
| | - José M. Muñoz-Félix
- Adhesion
and Angiogenesis Laboratory, Centre for Tumour Biology, Barts Cancer Institute—a CR-UK Centre of Excellence,
Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, United Kingdom
| | - Lorena Buitrago
- Allen and
Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, 1230 York Avenue, New York, New York 10065, United States
| | - Johannes van Agthoven
- Leukocyte
Biology and Inflammation and Structural Biology Programs, Division
of Nephrology, Massachusetts General Hospital
and Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, United States
| | - Yixiao Zhang
- Laboratory
of Molecular Electron Microscopy, Rockefeller
University, 1230 York Avenue, New York, New York 10065, United
States
| | - Ryoma Hara
- Tri-Institutional
Therapeutics Discovery Institute, 413 East 69 Street, New York, New York 10021, United
States
| | - Yuta Tanaka
- Tri-Institutional
Therapeutics Discovery Institute, 413 East 69 Street, New York, New York 10021, United
States
| | - Rei Okamoto
- Tri-Institutional
Therapeutics Discovery Institute, 413 East 69 Street, New York, New York 10021, United
States
| | - Takeshi Yasui
- Tri-Institutional
Therapeutics Discovery Institute, 413 East 69 Street, New York, New York 10021, United
States
| | - Takashi Nakahata
- Tri-Institutional
Therapeutics Discovery Institute, 413 East 69 Street, New York, New York 10021, United
States
| | - Toshihiro Imaeda
- Tri-Institutional
Therapeutics Discovery Institute, 413 East 69 Street, New York, New York 10021, United
States
| | - Kazuyoshi Aso
- Tri-Institutional
Therapeutics Discovery Institute, 413 East 69 Street, New York, New York 10021, United
States
| | - Yuchen Zhou
- Department
of Pharmacological Sciences, Icahn School
of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1677, New York, New York 10029-6574, United States
| | - Charles Locuson
- Agios Pharmaceuticals, 88 Sidney Street, Cambridge, Massachusetts 02139-4169, United States
| | - Dragana Nesic
- Allen and
Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, 1230 York Avenue, New York, New York 10065, United States
| | - Mark Duggan
- LifeSci
Consulting, LLC, 18243
SE Ridgeview Drive, Tequesta, Florida 33469, United
States
| | - Junichi Takagi
- Laboratory
of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Roger D. Vaughan
- Rockefeller
University Center for Clinical and Translational Science, Rockefeller University, 2130 York Avenue, New York, New York 10065, United States
| | - Thomas Walz
- Laboratory
of Molecular Electron Microscopy, Rockefeller
University, 1230 York Avenue, New York, New York 10065, United
States
| | - Kairbaan Hodivala-Dilke
- Adhesion
and Angiogenesis Laboratory, Centre for Tumour Biology, Barts Cancer Institute—a CR-UK Centre of Excellence,
Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, United Kingdom
| | - Steven L. Teitelbaum
- Washington
University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110, United States
| | - M. Amin Arnaout
- Leukocyte
Biology and Inflammation and Structural Biology Programs, Division
of Nephrology, Massachusetts General Hospital
and Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, United States
| | - Marta Filizola
- Department
of Pharmacological Sciences, Icahn School
of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1677, New York, New York 10029-6574, United States
| | - Michael A. Foley
- Tri-Institutional
Therapeutics Discovery Institute, 413 East 69 Street, New York, New York 10021, United
States
| | - Barry S. Coller
- Allen and
Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, 1230 York Avenue, New York, New York 10065, United States
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Ramirez-Pedraza M, Fernández M. Interplay Between Macrophages and Angiogenesis: A Double-Edged Sword in Liver Disease. Front Immunol 2019; 10:2882. [PMID: 31921146 PMCID: PMC6927291 DOI: 10.3389/fimmu.2019.02882] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 11/25/2019] [Indexed: 12/19/2022] Open
Abstract
During chronic liver disease, macrophages support angiogenesis, not only by secreting proangiogenic growth factors and matrix-remodeling proteases, but also by physically interacting with the sprouting vasculature to assist the formation of complex vascular networks. In the liver, macrophages acquire specific characteristics becoming Kupffer cells and working to ensure protection and immunotolerance. Angiogenesis is another double-edged sword in health and disease and it is the biggest ally of macrophages allowing its dissemination. Angiogenesis and fibrosis may occur in parallel in several tissues as macrophages co-localize with newly formed vessels and secrete cytokines, interleukins, and growth factors that will activate other cell types in the liver such as hepatic stellate cells and liver sinusoidal endothelial cells, promoting extracellular matrix accumulation and fibrogenesis. Vascular endothelial growth factor, placental growth factor, and platelet-derived growth factor are the leading secreted factors driving pathological angiogenesis and consequently increasing macrophage infiltration. Tumor development in the liver has been widely linked to macrophage-mediated chronic inflammation in which epidermal growth factors, STAT3 and NF-kβ are some of the most relevant signaling molecules involved. In this article, we review the link between macrophages and angiogenesis at molecular and cellular levels in chronic liver disease.
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Affiliation(s)
- Marta Ramirez-Pedraza
- Angiogenesis in Liver Disease Research Group, IDIBAPS Biomedical Research Institute, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Mercedes Fernández
- Angiogenesis in Liver Disease Research Group, IDIBAPS Biomedical Research Institute, Hospital Clinic, University of Barcelona, Barcelona, Spain.,Biomedical Research Networking Center on Hepatic and Digestive Disease (CIBEREHD), Institute of Health Carlos III, Madrid, Spain
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43
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The Many Roles of Cell Adhesion Molecules in Hepatic Fibrosis. Cells 2019; 8:cells8121503. [PMID: 31771248 PMCID: PMC6952767 DOI: 10.3390/cells8121503] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/17/2019] [Accepted: 11/18/2019] [Indexed: 01/09/2023] Open
Abstract
Fibrogenesis is a progressive scarring event resulting from disrupted regular wound healing due to repeated tissue injury and can end in organ failure, like in liver cirrhosis. The protagonists in this process, either liver-resident cells or patrolling leukocytes attracted to the site of tissue damage, interact with each other by soluble factors but also by direct cell–cell contact mediated by cell adhesion molecules. Since cell adhesion molecules also support binding to the extracellular matrix, they represent excellent biosensors, which allow cells to modulate their behavior based on changes in the surrounding microenvironment. In this review, we focus on selectins, cadherins, integrins and members of the immunoglobulin superfamily of adhesion molecules as well as some non-classical cell adhesion molecules in the context of hepatic fibrosis. We describe their liver-specific contributions to leukocyte recruitment, cell differentiation and survival, matrix remodeling or angiogenesis and touch on their suitability as targets in antifibrotic therapies.
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44
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Horst AK, Tiegs G, Diehl L. Contribution of Macrophage Efferocytosis to Liver Homeostasis and Disease. Front Immunol 2019; 10:2670. [PMID: 31798592 PMCID: PMC6868070 DOI: 10.3389/fimmu.2019.02670] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 10/29/2019] [Indexed: 12/21/2022] Open
Abstract
The clearance of apoptotic cells is pivotal for both maintaining tissue homeostasis and returning to homeostasis after tissue injury as part of the regenerative resolution response. The liver is known for its capacity to remove aged and damaged cells from the circulation and can serve as a graveyard for effector T cells. In particular Kupffer cells are active phagocytic cells, but during hepatic inflammatory responses incoming neutrophils and monocytes may contribute to pro-inflammatory damage. To stimulate resolution of such inflammation, myeloid cell function can change, via sensing of environmental changes in the inflammatory milieu. Also, the removal of apoptotic cells via efferocytosis and the signaling pathways that are activated in macrophages/phagocytes upon their engulfment of apoptotic cells are important for a return to tissue homeostasis. Here, we will discuss, how efferocytosis mechanisms in hepatic macrophages/phagocytes may regulate tissue homeostasis and be involved in tissue regeneration in liver disease.
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Affiliation(s)
- Andrea Kristina Horst
- Institute for Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Gisa Tiegs
- Institute for Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Linda Diehl
- Institute for Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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45
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Distler JHW, Györfi AH, Ramanujam M, Whitfield ML, Königshoff M, Lafyatis R. Shared and distinct mechanisms of fibrosis. Nat Rev Rheumatol 2019; 15:705-730. [PMID: 31712723 DOI: 10.1038/s41584-019-0322-7] [Citation(s) in RCA: 373] [Impact Index Per Article: 62.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/03/2019] [Indexed: 02/07/2023]
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46
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Feng J, Li S, Fan HJ, Lin Y, Lu Y. Dendritic polylysine based ανβ3 integrin targeted probe for near-infrared fluorescent imaging of glioma. Colloids Surf B Biointerfaces 2019; 178:146-152. [DOI: 10.1016/j.colsurfb.2019.01.059] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 01/10/2019] [Accepted: 01/28/2019] [Indexed: 10/27/2022]
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47
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Li Y, Pu S, Liu Q, Li R, Zhang J, Wu T, Chen L, Li H, Yang X, Zou M, Xiao J, Xie W, He J. An integrin-based nanoparticle that targets activated hepatic stellate cells and alleviates liver fibrosis. J Control Release 2019; 303:77-90. [PMID: 31004666 DOI: 10.1016/j.jconrel.2019.04.022] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Revised: 04/05/2019] [Accepted: 04/16/2019] [Indexed: 02/06/2023]
Abstract
Activation of hepatic stellate cells (HSCs) contributes to the development of liver fibrosis. Because of a relatively small population of HSCs in the liver and the lack of specific membrane targeting proteins, HSC-targeted therapy remains a major clinical challenge. Here we first showed that a hallmark of activated HSC (aHSC) is their increased expression of integrin αvβ3. Thus we established sterically stable liposomes that contain the cyclic peptides (cRGDyK) with a high affinity to αvβ3 to achieve aHSC-specific delivery. Our results showed that the cRGDyK-guided liposomes were preferentially internalized by activated HSCs in vitro and in vivo, and the internalization was abolished by excess free cRGDyK or knockdown of αvβ3. In contrast, quiescent HSCs, hepatocytes, Kupffer cells, sinusoidal endothelial cells, or biliary cells showed minimal uptake of the cRGDyK-guided liposomes. When loaded with the hedgehog inhibitor vismodegib, the cRGDyK-guided liposomes inhibited hedgehog pathway signaling specifically in activated HSCs. Moreover, treatment of mice with vismodegib-loaded cRGDyK-liposomes markedly inhibited the fibrogenic phenotype in bile duct ligation- or thioacetamide-treated mice. We conclude that the cRGDyK-guided liposomes can specifically target the activated HSCs, but not quiescent HSCs. This nanoparticle system showed great promise to deliver therapeutic agents to aHSC to treat liver fibrosis.
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Affiliation(s)
- Yanping Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China; Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Shiyun Pu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China; Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Qinhui Liu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China
| | - Rui Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China; Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Jinhang Zhang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China; Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Tong Wu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China; Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Lei Chen
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China; Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Hong Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China; Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Xuping Yang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China; Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Min Zou
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Jia Xiao
- Institute of Clinical Science, Guangzhou Overseas Chinese Hospital, Jinan University, Guangzhou, China
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Jinhan He
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China; Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China.
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48
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Hayashida M, Hashimoto K, Ishikawa T, Miyamoto Y. Vitronectin deficiency attenuates hepatic fibrosis in a non-alcoholic steatohepatitis-induced mouse model. Int J Exp Pathol 2019; 100:72-82. [PMID: 30887659 DOI: 10.1111/iep.12306] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 11/13/2018] [Accepted: 01/16/2019] [Indexed: 12/20/2022] Open
Abstract
Vitronectin (VN), an extracellular matrix protein, is a promising immune biomarker of non-alcoholic steatohepatitis (NASH); however, its precise function remains unclear. This study investigated how VN deficiency contributes to the development of NASH. Towards this aim, wild-type (WT) and VN-/- mice were fed with a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 6 and 10 weeks to induce NASH, and the livers were isolated. In WT mice fed with CDAHFD for 6 and 10 weeks, the expression of Vn mRNA and protein was up-regulated compared with that in mice fed with the MF control diet, indicating that VN is regulated in NASH condition. VN-/- mice showed decreased picrosirius red staining in the liver area and Col1a2 mRNA expression levels, compared with WT mice, indicating that the severity of hepatic fibrosis is attenuated in the CDAHFD-fed VN-/- mice. In addition, VN deficiency did not affect the area of lipid droplets in haematoxylin-eosin staining and the mRNA expression levels of fatty acid synthases, Srebp, Acc and Fas in the CDAHFD-fed mice. Moreover, VN deficiency decreased the inflammation score and the mRNA expression levels of Cd11b and F4/80, macrophage markers, as well as Tnf-α and Il-1β, inflammatory cytokines in the CDAHFD-fed mice. Furthermore, VN deficiency decreased the protein and mRNA expression levels of α-smooth muscle actin in the CDAHFD-fed mice, suggesting that VN deficiency inhibits the activation of hepatic stellate cells (HSCs). Our findings indicate that VN contributes to the development of fibrosis in the NASH model mice via modulation of the inflammatory reaction and activation of HSCs.
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Affiliation(s)
- Momoka Hayashida
- Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo, Japan.,Institute for Human Life Innovation, Ochanomizu University, Tokyo, Japan
| | - Kei Hashimoto
- Institute for Human Life Innovation, Ochanomizu University, Tokyo, Japan.,Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Tomoko Ishikawa
- Institute for Human Life Innovation, Ochanomizu University, Tokyo, Japan
| | - Yasunori Miyamoto
- Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo, Japan.,Institute for Human Life Innovation, Ochanomizu University, Tokyo, Japan
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49
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Györfi AH, Matei AE, Distler JH. Targeting TGF-β signaling for the treatment of fibrosis. Matrix Biol 2018; 68-69:8-27. [DOI: 10.1016/j.matbio.2017.12.016] [Citation(s) in RCA: 141] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 12/18/2017] [Indexed: 01/02/2023]
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50
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Angiogenesis and Hepatic Fibrosis: Western and Chinese Medicine Therapies on the Road. Chin J Integr Med 2018; 24:713-720. [DOI: 10.1007/s11655-018-3007-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/19/2016] [Indexed: 02/07/2023]
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