Database : MEDLINE
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[PMID]: 29523787
[Au] Autor:Ferreira-Gonzalez S; Lu WY; Raven A; Dwyer B; Man TY; O'Duibhir E; Lewis PJS; Campana L; Kendall TJ; Bird TG; Tarrats N; Acosta JC; Boulter L; Forbes SJ
[Ad] Address:MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK.
[Ti] Title:Paracrine cellular senescence exacerbates biliary injury and impairs regeneration.
[So] Source:Nat Commun;9(1):1020, 2018 Mar 09.
[Is] ISSN:2041-1723
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Cellular senescence is a mechanism that provides an irreversible barrier to cell cycle progression to prevent undesired proliferation. However, under pathological circumstances, senescence can adversely affect organ function, viability and regeneration. We have developed a mouse model of biliary senescence, based on the conditional deletion of Mdm2 in bile ducts under the control of the Krt19 promoter, that exhibits features of biliary disease. Here we report that senescent cholangiocytes induce profound alterations in the cellular and signalling microenvironment, with recruitment of myofibroblasts and macrophages causing collagen deposition, TGFß production and induction of senescence in surrounding cholangiocytes and hepatocytes. Finally, we study how inhibition of TGFß-signalling disrupts the transmission of senescence and restores liver function. We identify cellular senescence as a detrimental mechanism in the development of biliary injury. Our results identify TGFß as a potential therapeutic target to limit senescence-dependent aggravation in human cholangiopathies.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:In-Data-Review
[do] DOI:10.1038/s41467-018-03299-5

  2 / 8961 MEDLINE  
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[PMID]: 29458061
[Au] Autor:Tsutsumi-Kuroda U; Inoue T; Futakuchi A; Shobayashi K; Takahashi E; Kojima S; Inoue-Mochita M; Fujimoto T; Tanihara H
[Ad] Address:Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Japan.
[Ti] Title:Decreased MCP-1/CCR2 axis-mediated chemotactic effect of conjunctival fibroblasts after transdifferentiation into myofibroblasts.
[So] Source:Exp Eye Res;170:76-80, 2018 Feb 17.
[Is] ISSN:1096-0007
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:The purpose of this study is to investigate the change in chemotactic effects of human conjunctival fibroblasts (HConFs) after transdifferentiation into myofibroblasts, and to explore related molecular mechanisms. HConFs were treated with 5 ng/mL transforming growth factor (TGF)-ß2 for 48 h to induce transdifferentiation into myofibroblasts. The cytokine concentrations in the conditioned media of HConFs were measured by multiplex bead-based immunoassays. The Boyden chamber assay was used to assess the chemotactic effects using the monocyte cell line, THP-1 cells. The concentration of monocyte chemoattractant protein (MCP)-1 in the conditioned media was decreased after transdifferentiation into myofibroblasts (P < 0.001). The conditioned media of HConFs exerted a chemotactic effect on THP-1 cells, but this effect decreased after transdifferentiation into myofibroblasts (P = 0.032). The number of migrated THP-1 cells decreased significantly upon treatment with neutralizing anti-MCP-1 antibodies (P = 0.006) and tended to decrease upon treatment with C-C chemokine receptor (CCR) 2 antagonist. The chemotactic effect of HConFs mediated by the MCP-1/CCR2 axis was decreased after transdifferentiation into myofibroblasts.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:Publisher

  3 / 8961 MEDLINE  
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[PMID]: 29421383
[Au] Autor:Thomasy SM; Raghunathan VK; Miyagi H; Evashenk AT; Sermeno JC; Tripp GK; Morgan JT; Murphy CJ
[Ad] Address:Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, USA; Department of Ophthalmology & Vision Science, School of Medicine, University of California, Davis, Davis, CA, USA. Electronic address: smthomasy@ucdavis.edu.
[Ti] Title:Latrunculin B and substratum stiffness regulate corneal fibroblast to myofibroblast transformation.
[So] Source:Exp Eye Res;170:101-107, 2018 Feb 06.
[Is] ISSN:1096-0007
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:The transformation of keratocytes and fibroblasts to myofibroblasts is important to corneal wound healing as well as formation of stromal haze. The purpose of this study was to determine the effect of latrunculin B, an actin cytoskeleton disruptor in conjunction with a fundamental biophysical cue, substrate stiffness, on myofibroblast transformation in vitro and in vivo. Rabbit corneal fibroblasts were cultured on substrates of differing compliance (1.5, 22, and 71 kPa) and tissue culture plastic (TCP; > 1 GPa) in media containing 0 or 10 ng/ml TGFß1 for 72 h. Cells were treated with 0.4 µM Lat-B or DMSO for 30 min every 24 h for 72 h. RNA was collected from cells and expression of alpha-smooth muscle actin (α-SMA), keratocan, and ALDH1A1 determined using qPCR; immunocytochemistry was used to assess α-SMA protein expression. A rabbit phototherapeutic keratectomy (PTK) model was used to assess the impact of 0.1% Lat-B (n = 3) or 25% DMSO (vehicle control, n = 3) on corneal wound healing by assessment of epithelial wound size with fluorescein stain and semi-quantitative stromal haze scoring by an observer masked to treatment group as well as Fourier-domain optical coherence tomography (FD-OCT) at set time points. Statistical analysis was completed using one-way or two-way analysis of variance. Treatment with Lat-B versus DMSO resulted in significantly less αSMA mRNA (P ≤ 0.007) for RCF cells grown on 22 and 71 kPa substrates as well as TCP without or with TGFß1, and significantly decreased α-SMA protein expression in RCFs cultured on the intermediate (22 kPa) stiffness in the absence (P = 0.028) or presence (P = 0.018) of TGFß1. Treatment with Lat-B versus DMSO but did not significantly alter expression of keratocan or ALDH1A1 mRNA in RCFs (P > 0.05) in the absence or presence of TGFß1, but RCFs grown on stiff hydrogels (71 kPa) had significantly more keratocan mRNA expression versus the 22 kPa hydrogel or TCP (P < 0.001) without TGFß1. Administration of topical Lat-B BID was well tolerated by rabbits post-PTK but did not significantly alter epithelial wound closure, stromal haze score, stromal haze thickness as measured by FD-OCT in comparison to DMSO-treated rabbits. When corneal stromal cells are cultured on substrates possessing biologically relevant substratum stiffnesses, Lat-B modulates mRNA and protein expression of α-SMA and thus modulates myofibroblast transformation. At a dose and dose-frequency that reduced IOP in human glaucoma patients, Lat-B treatment did not substantially impact corneal epithelial or stromal wound healing in a rabbit PTK model. While a significant impact on wound healing was observed at the concentration and dose frequency reported here was not found, encouraging in vitro data support further investigations of topically applied Lat-B to determine if this compound can reduce stromal fibrosis.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:Publisher

  4 / 8961 MEDLINE  
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[PMID]: 29320561
[Au] Autor:Zhao W; Wang X; Sun KH; Zhou L
[Ad] Address:Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
[Ti] Title:α-smooth muscle actin is not a marker of fibrogenic cell activity in skeletal muscle fibrosis.
[So] Source:PLoS One;13(1):e0191031, 2018.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:α-Smooth muscle actin (α-SMA) is used as a marker for a subset of activated fibrogenic cells, myofibroblasts, which are regarded as important effector cells of tissue fibrogenesis. We address whether α-SMA-expressing myofibroblasts are detectable in fibrotic muscles of mdx5cv mice, a mouse model for Duchenne muscular dystrophy (DMD), and whether the α-SMA expression correlates with the fibrogenic function of intramuscular fibrogenic cells. α-SMA immunostaining signal was not detected in collagen I (GFP)-expressing cells in fibrotic muscles of ColI-GFP/mdx5cv mice, but it was readily detected in smooth muscle cells lining intramuscular blood vessel walls. α-SMA expression was detected by quantitative RT-PCR and Western blot in fibrogenic cells sorted from diaphragm and quadriceps muscles of the ColI-GFP/mdx5cv mice. Consistent with the more severe fibrosis in the ColI-GFP/mdx5cv diaphragm, the fibrogenic cells in the diaphragm exerted a stronger fibrogenic function than the fibrogenic cells in the quadriceps as gauged by their extracellular matrix gene expression. However, both gene and protein expression of α-SMA was lower in the diaphragm fibrogenic cells than in the quadriceps fibrogenic cells in the ColI-GFP/mdx5cv mice. We conclude that myofibroblasts are present in fibrotic skeletal muscles, but their expression of α-SMA is not detectable by immunostaining. The level of α-SMA expression by intramuscular fibrogenic cells does not correlate positively with the level of collagen gene expression or the severity of skeletal muscle fibrosis in the mdx5cv mice. α-SMA is not a functional marker of fibrogenic cells in skeletal muscle fibrosis associated with muscular dystrophy.
[Mh] MeSH terms primary: Actins/metabolism
Biomarkers/metabolism
Muscle, Skeletal/metabolism
[Mh] MeSH terms secundary: Animals
Blotting, Western
Fibrosis
Mice
Mice, Inbred C57BL
Muscle, Skeletal/pathology
Real-Time Polymerase Chain Reaction
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (Actins); 0 (Biomarkers); 0 (alpha-smooth muscle actin, mouse)
[Em] Entry month:1803
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[Js] Journal subset:IM
[Da] Date of entry for processing:180111
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191031

  5 / 8961 MEDLINE  
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[PMID]: 28457748
[Au] Autor:Schneider RK; Mullally A; Dugourd A; Peisker F; Hoogenboezem R; Van Strien PMH; Bindels EM; Heckl D; Büsche G; Fleck D; Müller-Newen G; Wongboonsin J; Ventura Ferreira M; Puelles VG; Saez-Rodriguez J; Ebert BL; Humphreys BD; Kramann R
[Ad] Address:Department of Hematology, Erasmus MC Cancer Institute, 3015CN Rotterdam, the Netherlands; Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, RWTH Aachen University, 52074 Aachen, Germany. Electronic address: r.k.schneider@erasmusmc.nl.
[Ti] Title:Gli1 Mesenchymal Stromal Cells Are a Key Driver of Bone Marrow Fibrosis and an Important Cellular Therapeutic Target.
[So] Source:Cell Stem Cell;20(6):785-800.e8, 2017 Jun 01.
[Is] ISSN:1875-9777
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Bone marrow fibrosis (BMF) develops in various hematological and non-hematological conditions and is a central pathological feature of myelofibrosis. Effective cell-targeted therapeutics are needed, but the cellular origin of BMF remains elusive. Here, we show using genetic fate tracing in two murine models of BMF that Gli1 mesenchymal stromal cells (MSCs) are recruited from the endosteal and perivascular niche to become fibrosis-driving myofibroblasts in the bone marrow. Genetic ablation of Gli1 cells abolished BMF and rescued bone marrow failure. Pharmacological targeting of Gli proteins with GANT61 inhibited Gli1 cell expansion and myofibroblast differentiation and attenuated fibrosis severity. The same pathway is also active in human BMF, and Gli1 expression in BMF significantly correlates with the severity of the disease. In addition, GANT61 treatment reduced the myofibroblastic phenotype of human MSCs isolated from patients with BMF, suggesting that targeting of Gli proteins could be a relevant therapeutic strategy.
[Mh] MeSH terms primary: Cell Differentiation/drug effects
Cell Proliferation/drug effects
Mesenchymal Stromal Cells/metabolism
Myofibroblasts/metabolism
Primary Myelofibrosis/drug therapy
Pyridines/pharmacology
Pyrimidines/pharmacology
Zinc Finger Protein GLI1/antagonists & inhibitors
[Mh] MeSH terms secundary: Animals
Cell Differentiation/genetics
Humans
Mesenchymal Stromal Cells/pathology
Mice
Mice, Transgenic
Myofibroblasts/pathology
Primary Myelofibrosis/genetics
Primary Myelofibrosis/metabolism
Primary Myelofibrosis/pathology
Zinc Finger Protein GLI1/genetics
Zinc Finger Protein GLI1/metabolism
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (GANT 61); 0 (Gli protein, mouse); 0 (Pyridines); 0 (Pyrimidines); 0 (Zinc Finger Protein GLI1)
[Em] Entry month:1803
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[Js] Journal subset:IM
[Da] Date of entry for processing:170502
[St] Status:MEDLINE

  6 / 8961 MEDLINE  
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[PMID]: 29393433
[Au] Autor:Hu J; Wang X; Tang YH; Shan YG; Zou Q; Wang ZQ; Huang CX
[Ad] Address:Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
[Ti] Title:Activin A inhibition attenuates sympathetic neural remodeling following myocardial infarction in rats.
[So] Source:Mol Med Rep;17(4):5074-5080, 2018 Apr.
[Is] ISSN:1791-3004
[Cp] Country of publication:Greece
[La] Language:eng
[Ab] Abstract:Inflammation serves a critical role in driving sympathetic neural remodeling following myocardial infarction (MI), and activin A has been implicated as an important mediator of the inflammatory response post­MI. However, whether activin A impacts sympathetic neural remodeling post­MI remains unclear. In the present study, the authors assessed the effects of activin A on sympathetic neural remodeling in a rat model of MI. Rats were randomly divided into sham, MI, and MI + follistatin­300 (FS, activin A inhibitor) groups. Cardiac tissues from the peri­infarct zone were assessed for expression of sympathetic neural remodeling and inflammatory factors in rats 4 weeks post­MI by western blotting and immunohistochemical methods. Heart function was assessed by echocardiography. It is demonstrated that FS administration significantly reduced post­MI upregulation of activin A, nerve growth factor protein lever, and the density of nerve fibers with positive and protein expression of sympathetic neural remodeling markers in nerve fibers, which included growth associated protein 43 and tyrosine hydroxylase. In addition, inhibition of activin A reduced cardiac inflammation post­MI based on the reduction of i) interleukin­1 and tumor necrosis factor­α protein expression, ii) numbers and/or proportional area of infiltrating macrophages and myofibroblasts and iii) phosphorylated levels of p65 and IκBα. Furthermore, activin A inhibition lessened heart dysfunction post­MI. These results suggested that activin A inhibition reduced sympathetic neural remodeling post­MI in part through inhibition of the inflammatory response. The current study implicates activin A as a potential therapeutic target to circumvent sympathetic neural remodeling post-MI.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:In-Process
[do] DOI:10.3892/mmr.2018.8496

  7 / 8961 MEDLINE  
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[PMID]: 29393272
[Au] Autor:Tognetto D; De Giacinto C; D'Aloisio R; Papagno C; Pastore M; Zweyer M
[Ad] Address:Eye Clinic, University of Trieste, Trieste, Italy.
[Ti] Title:The Combination of Trypan Blue and Brilliant Blue G-Assisted Vitrectomy for Macular Pucker: Histopathological Findings.
[So] Source:Ophthalmologica;239(2-3):167-175, 2018.
[Is] ISSN:1423-0267
[Cp] Country of publication:Switzerland
[La] Language:eng
[Ab] Abstract:PURPOSE: To report on the combined use of trypan blue (TB) and brilliant blue G (BBG) for staining the epiretinal membrane (ERM) and internal limiting membrane (ILM) during vitrectomy and to describe the histopathological findings. METHODS: 10 surgical specimens were removed from 10 eyes with macular pucker during vitrectomy using a commercially available combination of TB and BBG for ERM and ILM staining and peeling. Specimens were evaluated using light and transmission electron microscopy. RESULTS: In all cases the combination of TB and BBG was useful for identifying and delineating ERM and ILM. No complications related to the use of the dye were observed during or after surgery. Glial cells were present in all specimens. Hyalocytes were observed in 6 cases and myofibroblasts in 3 of them. In 7 cases native vitreous collagen fibrils were found on the ILM, while in 5 specimens newly formed collagen was present. No clinical evidence of toxicity was observed during the 3-month follow-up. CONCLUSION: The combined use of TB and BBG appeared to be very useful intraoperatively to improve the visualization of ERM and ILM, thus facilitating their complete removal. Anatomical and histopathological findings demonstrated the safety and the efficacy of this vital dye.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180308
[Lr] Last revision date:180308
[St] Status:In-Process
[do] DOI:10.1159/000485986

  8 / 8961 MEDLINE  
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[PMID]: 29513926
[Au] Autor:Walton KD; Mishkind D; Riddle MR; Tabin CJ; Gumucio DL
[Ad] Address:Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan.
[Ti] Title:Blueprint for an intestinal villus: Species-specific assembly required.
[So] Source:Wiley Interdiscip Rev Dev Biol;, 2018 Mar 07.
[Is] ISSN:1759-7692
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Efficient absorption of nutrients by the intestine is essential for life. In mammals and birds, convolution of the intestinal surface into finger-like projections called villi is an important adaptation that ensures the massive surface area for nutrient contact that is required to meet metabolic demands. Each villus projection serves as a functional absorptive unit: it is covered by a simple columnar epithelium that is derived from endoderm and contains a mesodermally derived core with supporting vasculature, lacteals, enteric nerves, smooth muscle, fibroblasts, myofibroblasts, and immune cells. In cross section, the consistency of structure in the billions of individual villi of the adult intestine is strikingly beautiful. Villi are generated in fetal life, and work over several decades has revealed that villus morphogenesis requires substantial "crosstalk" between the endodermal and mesodermal tissue components, with soluble signals, cell-cell contacts, and mechanical forces providing specific dialects for sequential conversations that orchestrate villus assembly. A key part of this process is the formation of subepithelial mesenchymal cell clusters that act as signaling hubs, directing overlying epithelial cells to cease proliferation, thereby driving villus emergence and simultaneously determining the location of future stem cell compartments. Interestingly, distinct species-specific differences govern how and when tissue-shaping signals and forces generate mesenchymal clusters and control villus emergence. As the details of villus development become increasingly clear, the emerging picture highlights a sophisticated local self-assembled cascade that underlies the reproducible elaboration of a regularly patterned field of absorptive villus units. This article is categorized under: Vertebrate Organogenesis > From a Tubular Primordium: Non-Branched Comparative Development and Evolution > Organ System Comparisons Between Species Early Embryonic Development > Development to the Basic Body Plan.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1803
[Cu] Class update date: 180307
[Lr] Last revision date:180307
[St] Status:Publisher
[do] DOI:10.1002/wdev.317

  9 / 8961 MEDLINE  
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[PMID]: 29415171
[Au] Autor:Zuo C; Li X; Huang J; Chen D; Ji K; Yang Y; Xu T; Zhu DL; Yan C; Gao P
[Ad] Address:Department of Hypertension, Ruijin Hospital and Shanghai Institute of Hypertension, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
[Ti] Title:Osteoglycin Attenuates Cardiac Fibrosis by Suppressing Cardiac myofibroblast proliferation and migration throughAntagonizing LPA3/MMP2/EGFR signaling.
[So] Source:Cardiovasc Res;, 2018 Feb 05.
[Is] ISSN:1755-3245
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Aims: Cardiac myofibroblasts (CMFs) play a crucial role in the progression of pathological fibrotic cardiac remodeling. The expression of osteoglycin (OGN) is increased in diseased hearts; however, the role of OGN in pathological cardiac remodeling is not understood. Here we sought to determine the effect of OGN on cardiac interstitial fibrosis and investigated the molecular mechanisms of OGN in CMF activation and matrix production. Methods and results: We found that OGN expression was significantly upregulated in mouse hearts in response to chronic 14-day angiotensin II (Ang II) infusion. Mice lacking OGN (OGN-/-) exhibited enhanced cardiac interstitial fibrosis and significantly more severe cardiac dysfunction following Ang II infusion compared to wild-type mice. OGN deficiency did not alter blood pressure, nor had effect on TGFß signaling activation, but presented with increased proliferative activity in hearts. In vitro studies with isolated CMFs revealed that OGN deficiency significantly increased proliferation and migration and enhanced the transactivation of epidermal growth factor receptor (EGFR) signaling by Ang II. On the other hand, OGN overexpression in CMFs decreased their proliferation and migration via reducing EGFR activation. Overexpression of OGN also suppressed the shedding of membrane anchored EGFR ligand. Moreover, OGN was found to interact with a lysophosphatidic acid (LPA) receptor isoform 3 and thus to attenuate EGFR transactivation through blocking cell surface translocation of membrane type 1 matrix metalloproteinase (MT1-MMP) and subsequent pro-MMP-2 activation in a RhoA/ROCK-dependent manner. Conclusion: These findings suggest that OGN negatively regulates cardiac fibrotic remodeling by attenuating CMF proliferation and migration through LPA3-mediated and Rho/ROCK-dependent inhibition of MT1-MMP translocation, MMP2 activation, and EGFR transactivation.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180308
[Lr] Last revision date:180308
[St] Status:Publisher
[do] DOI:10.1093/cvr/cvy035

  10 / 8961 MEDLINE  
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[PMID]: 29361086
[Au] Autor:Truffi M; Sorrentino L; Monieri M; Fociani P; Mazzucchelli S; Bonzini M; Zerbi P; Sampietro GM; Di Sabatino A; Corsi F
[Ad] Address:Department of Biomedical and Clinical Sciences "L. Sacco", University of Milan, Milan, Italy.
[Ti] Title:Inhibition of Fibroblast Activation Protein Restores a Balanced Extracellular Matrix and Reduces Fibrosis in Crohn's Disease Strictures Ex Vivo.
[So] Source:Inflamm Bowel Dis;24(2):332-345, 2018 Jan 18.
[Is] ISSN:1536-4844
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Background: Crohn's disease (CD) is a chronic bowel inflammation that ultimately leads to fibrosis, for which medical therapy is currently unavailable. Fibrotic strictures in CD are characterized by excessive extracellular matrix (ECM) deposition, altered balance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), and overexpression of fibroblast activation protein (FAP), a marker of active fibroblasts. Here we investigated the role of FAP-targeted therapy in ECM remodeling in CD strictures ex vivo. Methods: Bowel specimens were obtained from stenotic and nonstenotic ileal segments from 30 patients with fibrostenotic CD undergoing surgery. FAP expression was evaluated in isolated mucosal myofibroblasts by immunoblotting and flow cytometry. Bowel tissue cultures were treated with anti-FAP antibody, and soluble collagen, TIMP-1, and MMPs were measured in tissue culture supernatants by immunoblotting. Anti-FAP-treated myofibroblasts were analyzed for TIMP-1 expression by immunoblotting, for migratory potential by wound healing assay, and for apoptosis by Annexin V staining. Results: Myofibroblasts from stenotic CD mucosa showed upregulation of FAP expression when compared with nonstenotic mucosa. Treatment of stenotic tissues with anti-FAP antibody induced a dose-dependent decrease in collagen production, particularly affecting type I collagen. The treatment also reduced TIMP-1 production in CD strictures, without altering MMP-3 and MMP-12 secretion. Accordingly, anti-FAP treatment inhibited TIMP-1 expression in stenotic CD myofibroblasts and enhanced myofibroblast migration without affecting survival. Conclusions: FAP inhibition reduced type I collagen and TIMP-1 production by CD strictures ex vivo without compromising uninvolved bowel areas. These results suggest that targeting FAP could reconstitute ECM homeostasis in fibrostenotic CD.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180308
[Lr] Last revision date:180308
[St] Status:In-Data-Review
[do] DOI:10.1093/ibd/izx008


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