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Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis
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Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 21881

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Sabrina Lisi

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Guest Editor
Department of Basic Medical Sciences, Neurosciences and Sensory Organs (SMBNOS), Section of Human Anatomy and Histology, University of Bari “Aldo Moro”, Bari, Italy
Interests: autoimmunity; Sjogren’s syndrome; inflammation; salivary gland dysfunction; epithelial–mesenchymal transition; fibrosis
Special Issues, Collections and Topics in MDPI journals
Dr. Margherita Sisto

E-Mail Website
Guest Editor
Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Medical School, Bari, Italy
Interests: pathophysiology and molecular immunology applied to immunological research lines; molecular processes underlying the interaction between receptors of the immune response, inflammation and characterization of new anti-inflammatory molecules; novel therapies for Sjögren’s syndrome autoimmune disease; evaluation of the molecular mechanisms linking chronic inflammation to fibrosis in Sjögren’s syndrome and others autoimmune diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The process known as epithelial–mesenchymal transition (EMT), essential for accurate development during embryogenesis, is involved in many pathological processes, such as degenerative fibrosis and cancer. EMT is a biological process that allows epithelial cells to assume a mesenchymal phenotype with enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, stem-like features, and the increased production of ECM components.

During EMT, distinct molecular processes are activated: the loss of junctions and apical–basal polarity by epithelial cells, the activation of transcription factors, the downregulation of epithelial cell-surface proteins and up-regulation of mesenchymal markers, and the reorganization and expression of cytoskeletal proteins.

EMT is linked to wound healing, tissue regeneration, and organ fibrosis. During the course of fibrosis, EMT can lead to organ failure following the persistent release of a variety of inflammatory signals.

EMT is now considered a converging point among inflammation, fibrotic diseases, cancer, and pathologies characterized by chronic inflammation, such as autoimmune diseases. However, despite intense investigation in recent years, relatively little is known about the mechanisms of fibrosis pathogenesis and how all of these events are integrated and participate in the same process, and how the mesenchymal state is maintained. Deep knowledge of these aspects will help to exploit the plasticity of this process to reverse the metastatic phenotype of many cancers and design potential therapeutic approaches.

Papers related to any aspect of EMT and fibrosis will be considered for this Special Issue.

Dr. Sabrina Lisi
Dr. Margherita Sisto
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • inflammation
  • cancer
  • EMT
  • autoimmunity
  • fibrosis
  • salivary glands
 

Published Papers (16 papers)

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Editorial

Jump to: Research, Review

5 pages, 172 KiB  
Editorial
Special Issue “Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis”
by Margherita Sisto and Sabrina Lisi
Int. J. Mol. Sci. 2024, 25(7), 3808; https://doi.org/10.3390/ijms25073808 - 29 Mar 2024
Viewed by 435
Abstract
The process known as epithelial-mesenchymal transition (EMT), fundamental for accurate development during embryogenesis, is involved in several pathological mechanisms, such as severe fibrosis and cancer [...] Full article
(This article belongs to the Special Issue Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis)

Research

Jump to: Editorial, Review

12 pages, 3121 KiB  
Article
Regulation of STAT1 and STAT4 Expression by Growth Factor and Interferon Supplementation in Sjögren’s Syndrome Cell Culture Models
by Jean-Luc C. Mougeot, Thomas E. Thornburg, Braxton D. Noll, Michael T. Brennan and Farah Bahrani Mougeot
Int. J. Mol. Sci. 2024, 25(6), 3166; https://doi.org/10.3390/ijms25063166 - 9 Mar 2024
Viewed by 655
Abstract
Our goal was to investigate the effects of epidermal growth factor (EGF) and interferons (IFNs) on signal transducer and activator of transcription STAT1 and STAT4 mRNA and active phosphorylated protein expression in Sjögren’s syndrome cell culture models. iSGECs (immortalized salivary gland epithelial cells) [...] Read more.
Our goal was to investigate the effects of epidermal growth factor (EGF) and interferons (IFNs) on signal transducer and activator of transcription STAT1 and STAT4 mRNA and active phosphorylated protein expression in Sjögren’s syndrome cell culture models. iSGECs (immortalized salivary gland epithelial cells) and A253 cells were treated with EGF, IFN-alpha, -beta, -gamma, or mitogen-activated protein kinase p38 alpha (p38-MAPK) inhibitor for 0–24–48–72 h. STAT1 and STAT4 mRNA expression was quantified by qRT-PCR. Untreated and treated cells were compared using the delta-delta-CT method based on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) normalized relative fold changes. phospho-tyrosine-701-STAT1 and phospho-serine-721-STAT4 were detected by Western blot analysis. STAT4 mRNA expression decreased 48 h after EGF treatment in A253 cells, immortalized salivary gland epithelial cells iSGECs nSS2 (sicca patient origin), and iSGECs pSS1 (anti-SSA negative Sjögren’s Syndrome patient origin). EGF and p38-MAPK inhibitor decreased A253 STAT4 mRNA levels. EGF combined with IFN-gamma increased phospho-STAT4 and phospho-STAT1 after 72 h in all cell lines, suggesting additive effects for phospho-STAT4 and a major effect from IFN-gamma for phospho-STAT1. pSS1 and nSS2 cells responded differently to type I and type II interferons, confirming unique functional characteristics between iSGEC cell lines. EGF/Interferon related pathways might be targeted to regulate STAT1 and STAT4 expression in salivary gland epithelial cells. Further investigation is required learn how to better target the Janus kinases/signal transducer and activator of transcription proteins (JAK/STAT) pathway-mediated inflammatory response in Sjögren’s syndrome. Full article
(This article belongs to the Special Issue Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis)
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16 pages, 5781 KiB  
Article
Machine Learning and Single-Cell Analysis Identify Molecular Features of IPF-Associated Fibroblast Subtypes and Their Implications on IPF Prognosis
by Jiwei Hou, Yanru Yang and Xin Han
Int. J. Mol. Sci. 2024, 25(1), 94; https://doi.org/10.3390/ijms25010094 - 20 Dec 2023
Viewed by 1267
Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown cause, and the involvement of fibroblasts in its pathogenesis is well recognized. However, a comprehensive understanding of fibroblasts’ heterogeneity, their molecular characteristics, and their clinical relevance in IPF is lacking. In this [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown cause, and the involvement of fibroblasts in its pathogenesis is well recognized. However, a comprehensive understanding of fibroblasts’ heterogeneity, their molecular characteristics, and their clinical relevance in IPF is lacking. In this study, we aimed to systematically classify fibroblast populations, uncover the molecular and biological features of fibroblast subtypes in fibrotic lung tissue, and establish an IPF-associated, fibroblast-related predictive model for IPF. Herein, a meticulous analysis of scRNA-seq data obtained from lung tissues of both normal and IPF patients was conducted to identify fibroblast subpopulations in fibrotic lung tissues. In addition, hdWGCNA was utilized to identify co-expressed gene modules associated with IPF-related fibroblasts. Furthermore, we explored the prognostic utility of signature genes for these IPF-related fibroblast subtypes using a machine learning-based approach. Two predominant fibroblast subpopulations, termed IPF-related fibroblasts, were identified in fibrotic lung tissues. Additionally, we identified co-expressed gene modules that are closely associated with IPF-fibroblasts by utilizing hdWGCNA. We identified gene signatures that hold promise as prognostic markers in IPF. Moreover, we constructed a predictive model specifically focused on IPF-fibroblasts which can be utilized to assess disease prognosis in IPF patients. These findings have the potential to improve disease prediction and facilitate targeted interventions for patients with IPF. Full article
(This article belongs to the Special Issue Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis)
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14 pages, 7603 KiB  
Article
Corylin Attenuates CCl4-Induced Liver Fibrosis in Mice by Regulating the GAS6/AXL Signaling Pathway in Hepatic Stellate Cells
by Chin-Chuan Chen, Chi-Yuan Chen, Chau-Ting Yeh, Yi-Tsen Liu, Yann-Lii Leu, Wen-Yu Chuang, Yin-Hwa Shih, Li-Fang Chou, Tzong-Ming Shieh and Tong-Hong Wang
Int. J. Mol. Sci. 2023, 24(23), 16936; https://doi.org/10.3390/ijms242316936 - 29 Nov 2023
Cited by 1 | Viewed by 1164
Abstract
Liver fibrosis is reversible when treated in its early stages and when liver inflammatory factors are inhibited. Limited studies have investigated the therapeutic effects of corylin, a flavonoid extracted from Psoralea corylifolia L. (Fabaceae), on liver fibrosis. Therefore, we evaluated the anti-inflammatory activity [...] Read more.
Liver fibrosis is reversible when treated in its early stages and when liver inflammatory factors are inhibited. Limited studies have investigated the therapeutic effects of corylin, a flavonoid extracted from Psoralea corylifolia L. (Fabaceae), on liver fibrosis. Therefore, we evaluated the anti-inflammatory activity of corylin and investigated its efficacy and mechanism of action in ameliorating liver fibrosis. Corylin significantly inhibited inflammatory responses by inhibiting the activation of mitogen-activated protein kinase signaling pathways and the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha in human THP-1 and mouse RAW264.7 macrophages. Furthermore, corylin inhibited the expression of growth arrest-specific gene 6 in human hepatic stellate cells (HSCs) and the activation of the downstream phosphoinositide 3-kinase/protein kinase B pathway. This inhibited the activation of HSCs and the expression of extracellular matrix proteins, including α-smooth muscle actin and type I collagen. Additionally, corylin induced caspase 9 and caspase 3 activation, which promoted apoptosis in HSCs. Moreover, in vivo experiments confirmed the regulatory effects of corylin on these proteins, and corylin alleviated the symptoms of carbon tetrachloride-induced liver fibrosis in mice. These findings revealed that corylin has anti-inflammatory activity and inhibits HSC activation; thus, it presents as a potential adjuvant in the treatment of liver fibrosis. Full article
(This article belongs to the Special Issue Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis)
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12 pages, 1119 KiB  
Article
New Insights via RNA Profiling of Formalin-Fixed Paraffin-Embedded Lung Tissue of Pulmonary Fibrosis Patients
by Dymph Klay, Karin M. Kazemier, Joanne J. van der Vis, Hidde M. Smits, Jan C. Grutters and Coline H. M. van Moorsel
Int. J. Mol. Sci. 2023, 24(23), 16748; https://doi.org/10.3390/ijms242316748 - 25 Nov 2023
Viewed by 806
Abstract
In sporadic idiopathic pulmonary fibrosis (sIPF) and pulmonary fibrosis caused by a mutation in telomere (TRG-PF) or surfactant related genes (SRG-PF), there are a number of aberrant cellular processes known that can lead to fibrogenesis. We investigated whether RNA expression of genes involved [...] Read more.
In sporadic idiopathic pulmonary fibrosis (sIPF) and pulmonary fibrosis caused by a mutation in telomere (TRG-PF) or surfactant related genes (SRG-PF), there are a number of aberrant cellular processes known that can lead to fibrogenesis. We investigated whether RNA expression of genes involved in these processes differed between sIPF, TRG-PF, and SRG-PF and whether expression levels were associated with survival. RNA expression of 28 genes was measured in lung biopsies of 26 sIPF, 17 TRG-PF, and 6 SRG-PF patients. Significant differences in RNA expression of TGFBR2 (p = 0.02) and SFTPA2 (p = 0.02) were found between sIPF, TRG-PF, and SRG-PF. Patients with low (<median) expression of HSPA5 (p = 0.04), COL1A1 (p = 0.03), and ATF4 (0.005) had significantly longer survival rates than patients with high (≥median) expression of these genes. In addition, we scored for low (0) or high (1) expression of six endoplasmic reticulum (ER) stress genes (HSP90B1, DDIT3, EDEM1, HSPA5, ATF4, and XBP1) and found that patients with high expression in a low number of ER stress genes (total score 0–1) had longer survival rates than patients with high expression in a high number of ER stress genes (total score 2–6) (p = 0.03). In conclusion, there are minor differences between sIPF, TRG-PF, and SRG-PF and high expression in a high number of ER stress genes significantly associated with shorter survival time, suggesting that ER stress may be a target for therapy for PF. Full article
(This article belongs to the Special Issue Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis)
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13 pages, 2923 KiB  
Article
Novel Peritoneal Sclerosis Rat Model Developed by Administration of Bleomycin and Lansoprazole
by Kosei Kunitatsu, Yuta Yamamoto, Shota Nasu, Akira Taniji, Shuji Kawashima, Naoko Yamagishi, Takao Ito, Shigeaki Inoue and Yoshimitsu Kanai
Int. J. Mol. Sci. 2023, 24(22), 16108; https://doi.org/10.3390/ijms242216108 - 9 Nov 2023
Viewed by 744
Abstract
In our preliminary experiment, peritoneal sclerosis likely induced by peritoneal dialysis was unexpectedly observed in the livers of rats given bleomycin and lansoprazole. We examined whether this peritoneal thickening around the liver was time-dependently induced by administration of both drugs. Male Wistar rats [...] Read more.
In our preliminary experiment, peritoneal sclerosis likely induced by peritoneal dialysis was unexpectedly observed in the livers of rats given bleomycin and lansoprazole. We examined whether this peritoneal thickening around the liver was time-dependently induced by administration of both drugs. Male Wistar rats were injected with bleomycin and/or lansoprazole for 2 or 4 weeks. The 3YB-1 cell line derived from rat fibroblasts was treated by bleomycin and/or lansoprazole for 24 h. The administration of both drugs together, but not individually, thickened the peritoneal tissue around the liver. There was accumulation of collagen fibers, macrophages, and eosinophils under mesothelial cells. Expressions of Col1a1, Mcp1 and Mcp3 genes were increased in the peritoneal tissue around the liver and in 3YB-1 cells by the administration of both drugs together, and Opn genes had increased expressions in this tissue and 3YB-1 cells. Mesothelial cells indicated immunoreactivity against both cytokeratin, a mesothelial cell marker, and αSMA, a fibroblast marker, around the livers of rats given both drugs. Administration of both drugs induced the migration of macrophages and eosinophils and induced fibrosis associated with the possible activation of fibroblasts and the possible promotion of the mesothelial–mesenchymal transition. This might become a novel model of peritoneal sclerosis for peritoneal dialysis. Full article
(This article belongs to the Special Issue Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis)
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15 pages, 5753 KiB  
Article
The Role of STAT3 Signaling Pathway Activation in Subconjunctival Scar Formation after Glaucoma Filtration Surgery
by Yanxia Li, Jing Zhao, Yuan Yin, Chenchen Zhang, Zhaoying Zhang and Yajuan Zheng
Int. J. Mol. Sci. 2023, 24(15), 12210; https://doi.org/10.3390/ijms241512210 - 30 Jul 2023
Viewed by 839
Abstract
Scar formation resulting from overly active wound healing is a critical factor in the success rate of glaucoma filtration surgery (GFS). IL-6 and TGF-β have been implicated in the pathogenesis of fibrogenesis. In addition, the signal transducer and activator of transcription 3 (STAT3) [...] Read more.
Scar formation resulting from overly active wound healing is a critical factor in the success rate of glaucoma filtration surgery (GFS). IL-6 and TGF-β have been implicated in the pathogenesis of fibrogenesis. In addition, the signal transducer and activator of transcription 3 (STAT3) can be activated by numerous cytokines and growth factors, including IL-6 and TGF-β1. Thus, STAT3 activation may integrate common profibrotic pathways to promote fibrosis. In this study, an increase in p-STAT3 was observed in activated HTFs. Inhibiting STAT3 in cultured HTFs by pharmacological inactivation reversed the fibrotic responses, such as fibroblast migration, the differentiation of resting fibroblasts into myofibroblasts and the deposition of ECM, mediated by IL-6 and TGF-β1. Moreover, the expression of suppressor of cytokine signaling 3 (SOCS3) was decreased in HTFs cultured with IL-6 and TGF-β1, and SOCS3 overexpression rescued ECM deposition, α-SMA expression and migration in IL-6- and TGF-β1-stimulated HTFs by inactivating STAT3. Finally, S3I-201 treatment inhibited profibrotic gene expression and subconjunctival fibrosis in a rat model of GFS. In conclusion, our data suggests that STAT3 plays a central role in fibrosis induced by different profibrotic pathways and that STAT3 is a potential target for antifibrotic therapies following GFS. Full article
(This article belongs to the Special Issue Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis)
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18 pages, 7271 KiB  
Article
The Enzyme 15-Hydroxyprostaglandin Dehydrogenase Inhibits a Shift to the Mesenchymal Pattern of Trophoblasts and Decidual Stromal Cells Accompanied by Prostaglandin Transporter in Preeclampsia
by Huiyuan Pang, Di Lei, Tingting Chen, Yujie Liu and Cuifang Fan
Int. J. Mol. Sci. 2023, 24(6), 5111; https://doi.org/10.3390/ijms24065111 - 7 Mar 2023
Cited by 3 | Viewed by 1459
Abstract
Preeclampsia (PE) is a pregnancy complication beginning after 20 weeks of pregnancy that involves high blood pressure (systolic > 140 mmHg or diastolic > 90 mmHg), with or without proteinuria. Insufficient trophoblast invasion and abnormal decidualization are involved in PE development. However, whether [...] Read more.
Preeclampsia (PE) is a pregnancy complication beginning after 20 weeks of pregnancy that involves high blood pressure (systolic > 140 mmHg or diastolic > 90 mmHg), with or without proteinuria. Insufficient trophoblast invasion and abnormal decidualization are involved in PE development. However, whether unhealthy placenta and decidua have the same biological activities is unclear. The enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH; encoded by HPGD) degrades prostaglandin, and prostaglandin transporter (PGT), as a candidate molecule of prostaglandin carriers, helps transport prostaglandin into cells. Whether 15-PGDH and PGT are involved in PE has not been researched. In this study, we investigated the shared pathogenesis of foetal placenta and maternal decidua from the perspective of epithelial–mesenchymal transition (EMT)/mesenchymal–epithelial transition (MET) and explored the combined effects of 15-PGDH and PGT on the EMT/MET of trophoblasts and decidual stromal cells (DSCs). Here, we demonstrated that placental development and decidualization both involved EMT/MET. In PE, both trophoblasts and DSCs show more epithelial patterns. Moreover, 15-PGDH expression was downregulated in the placentas but upregulated in the deciduas of PE patients. Inhibiting 15-PGDH promotes a shift to a mesenchymal pattern of trophoblasts and DSCs depending on the PGT-mediated transport of prostaglandin E2 (PGE2). In conclusion, our results showed that inhibiting 15-PGDH promotes a shift to the mesenchymal pattern of trophoblasts and DSCs and may provide a new and alternative therapy for the treatment of PE. Full article
(This article belongs to the Special Issue Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis)
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14 pages, 2059 KiB  
Article
Altered Mesenchymal Stem Cells Mechanotransduction from Oxidized Collagen: Morphological and Biophysical Observations
by Regina Komsa-Penkova, Adelina Yordanova, Pencho Tonchev, Stanimir Kyurkchiev, Svetla Todinova, Velichka Strijkova, Mario Iliev, Borislav Dimitrov and George Altankov
Int. J. Mol. Sci. 2023, 24(4), 3635; https://doi.org/10.3390/ijms24043635 - 11 Feb 2023
Viewed by 1432
Abstract
Extracellular matrix (ECM) provides various mechanical cues that are able to affect the self-renewal and differentiation of mesenchymal stem cells (MSC). Little is known, however, how these cues work in a pathological environment, such as acute oxidative stress. To better understand the behavior [...] Read more.
Extracellular matrix (ECM) provides various mechanical cues that are able to affect the self-renewal and differentiation of mesenchymal stem cells (MSC). Little is known, however, how these cues work in a pathological environment, such as acute oxidative stress. To better understand the behavior of human adipose tissue-derived MSC (ADMSC) in such conditions, we provide morphological and quantitative evidence for significantly altered early steps of mechanotransduction when adhering to oxidized collagen (Col-Oxi). These affect both focal adhesion (FA) formation and YAP/TAZ signaling events. Representative morphological images show that ADMSCs spread better within 2 h of adhesion on native collagen (Col), while they tended to round up on Col-Oxi. It also correlates with the lesser development of the actin cytoskeleton and FA formation, confirmed quantitatively by morphometric analysis using ImageJ. As shown by immunofluorescence analysis, oxidation also affected the ratio of cytosolic-to-nuclear YAP/TAZ activity, concentrating in the nucleus for Col while remaining in the cytosol for Col-Oxi, suggesting abrogated signal transduction. Comparative Atomic Force Microscopy (AFM) studies show that native collagen forms relatively coarse aggregates, much thinner with Col-Oxi, possibly reflecting its altered ability to aggregate. On the other hand, the corresponding Young’s moduli were only slightly changed, so viscoelastic properties cannot explain the observed biological differences. However, the roughness of the protein layer decreased dramatically, from RRMS equal to 27.95 ± 5.1 nm for Col to 5.51 ± 0.8 nm for Col-Oxi (p < 0.05), which dictates our conclusion that it is the most altered parameter in oxidation. Thus, it appears to be a predominantly topographic response that affects the mechanotransduction of ADMSCs by oxidized collagen. Full article
(This article belongs to the Special Issue Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis)
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15 pages, 28504 KiB  
Article
Evaluation of Epithelial–Mesenchymal Transition Markers in Autoimmune Thyroid Diseases
by Pablo Sacristán-Gómez, Ana Serrano-Somavilla, Lía Castro-Espadas, Nuria Sánchez de la Blanca Carrero, Miguel Sampedro-Núñez, José Luis Muñoz-De-Nova, Francisca Molina-Jiménez, Alejandra Rosell, Mónica Marazuela and Rebeca Martínez-Hernández
Int. J. Mol. Sci. 2023, 24(4), 3359; https://doi.org/10.3390/ijms24043359 - 8 Feb 2023
Cited by 1 | Viewed by 2225
Abstract
A state of chronic inflammation is common in organs affected by autoimmune disorders, such as autoimmune thyroid diseases (AITD). Epithelial cells, such as thyroid follicular cells (TFCs), can experience a total or partial transition to a mesenchymal phenotype under these conditions. One of [...] Read more.
A state of chronic inflammation is common in organs affected by autoimmune disorders, such as autoimmune thyroid diseases (AITD). Epithelial cells, such as thyroid follicular cells (TFCs), can experience a total or partial transition to a mesenchymal phenotype under these conditions. One of the major cytokines involved in this phenomenon is transforming growth factor beta (TGF-β), which, at the initial stages of autoimmune disorders, plays an immunosuppressive role. However, at chronic stages, TGF- β contributes to fibrosis and/or transition to mesenchymal phenotypes. The importance of primary cilia (PC) has grown in recent decades as they have been shown to play a key role in cell signaling and maintaining cell structure and function as mechanoreceptors. Deficiencies of PC can trigger epithelial–mesenchymal transition (EMT) and exacerbate autoimmune diseases. A set of EMT markers (E-cadherin, vimentin, α-SMA, and fibronectin) were evaluated in thyroid tissues from AITD patients and controls through RT-qPCR, immunohistochemistry (IHC), and western blot (WB). We established an in vitro TGF-β–stimulation assay in a human thyroid cell line to assess EMT and PC disruption. EMT markers were evaluated in this model using RT-qPCR and WB, and PC was evaluated with a time-course immunofluorescence assay. We found an increased expression of the mesenchymal markers α-SMA and fibronectin in TFCs in the thyroid glands of AITD patients. Furthermore, E-cadherin expression was maintained in these patients compared to the controls. The TGF-β-stimulation assay showed an increase in EMT markers, including vimentin, α-SMA, and fibronectin in thyroid cells, as well as a disruption of PC. The TFCs from the AITD patients experienced a partial transition to a mesenchymal phenotype, preserving epithelial characteristics associated with a disruption in PC, which might contribute to AITD pathogenesis. Full article
(This article belongs to the Special Issue Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis)
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18 pages, 2225 KiB  
Article
Cathelicidin Treatment Silences Epithelial–Mesenchymal Transition Involved in Pulmonary Fibrosis in a Murine Model of Hypersensitivity Pneumonitis
by Marta Kinga Lemieszek, Marcin Golec, Jacek Zwoliński, Jacek Dutkiewicz and Janusz Milanowski
Int. J. Mol. Sci. 2022, 23(21), 13039; https://doi.org/10.3390/ijms232113039 - 27 Oct 2022
Cited by 2 | Viewed by 1344
Abstract
Pulmonary fibrosis is becoming an increasingly common pathology worldwide. Unfortunately, this disorder is characterized by a bad prognosis: no treatment is known, and the survival rate is dramatically low. One of the most frequent reasons for pulmonary fibrosis is hypersensitivity pneumonitis (HP). As [...] Read more.
Pulmonary fibrosis is becoming an increasingly common pathology worldwide. Unfortunately, this disorder is characterized by a bad prognosis: no treatment is known, and the survival rate is dramatically low. One of the most frequent reasons for pulmonary fibrosis is hypersensitivity pneumonitis (HP). As the main mechanism of pulmonary fibrosis is a pathology of the repair of wounded pulmonary epithelium with a pivotal role in epithelial–mesenchymal transition (EMT), we assumed that EMT silencing could prevent disease development. Because of several biological features including wound healing promotion, an ideal candidate for use in the treatment of pulmonary fibrosis seems to be cathelicidin. The aim of the studies was to understand the influence of cathelicidin on the EMT process occurring during lung fibrosis development in the course of HP. Cathelicidin’s impact on EMT was examined in a murine model of HP, wherein lung fibrosis was induced by chronic exposure to extract of Pantoea agglomerans (SE-PA) by real-time PCR and Western blotting. Studies revealed that mouse exposure to cathelicidin did not cause any side changes in the expression of investigated genes/proteins. Simultaneously, cathelicidin administered together or after SE-PA decreased the elevated level of myofibroblast markers (Acta2/α-smooth muscle actin, Cdh2/N-cadherin, Fn1/Fibronectin, Vim/vimentin) and increased the lowered level of epithelial markers (Cdh1/E-cadherin, Ocln/occludin). Cathelicidin provided with SE-PA or after cessation of SE-PA inhalations reduced the expression of EMT-associated factors (Ctnnd1/β-catenin, Nfkb1/NFκB, Snail1/Snail, Tgfb1/TGFβ1 Zeb1/ZEB1, Zeb2/ZEB2) elevated by P. agglomerans. Cathelicidin’s beneficial impact on the expression of genes/proteins involved in EMT was observed during and after the HP development; however, cathelicidin was not able to completely neutralize the negative changes. Nevertheless, significant EMT silencing in response to cathelicidin suggested the possibility of its use in the prevention/treatment of pulmonary fibrosis. Full article
(This article belongs to the Special Issue Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis)
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Review

Jump to: Editorial, Research

26 pages, 1126 KiB  
Review
Epigenetic Regulation of EMP/EMT-Dependent Fibrosis
by Margherita Sisto and Sabrina Lisi
Int. J. Mol. Sci. 2024, 25(5), 2775; https://doi.org/10.3390/ijms25052775 - 28 Feb 2024
Viewed by 737
Abstract
Fibrosis represents a process characterized by excessive deposition of extracellular matrix (ECM) proteins. It often represents the evolution of pathological conditions, causes organ failure, and can, in extreme cases, compromise the functionality of organs to the point of causing death. In recent years, [...] Read more.
Fibrosis represents a process characterized by excessive deposition of extracellular matrix (ECM) proteins. It often represents the evolution of pathological conditions, causes organ failure, and can, in extreme cases, compromise the functionality of organs to the point of causing death. In recent years, considerable efforts have been made to understand the molecular mechanisms underlying fibrotic evolution and to identify possible therapeutic strategies. Great interest has been aroused by the discovery of a molecular association between epithelial to mesenchymal plasticity (EMP), in particular epithelial to mesenchymal transition (EMT), and fibrogenesis, which has led to the identification of complex molecular mechanisms closely interconnected with each other, which could explain EMT-dependent fibrosis. However, the result remains unsatisfactory from a therapeutic point of view. In recent years, advances in epigenetics, based on chromatin remodeling through various histone modifications or through the intervention of non-coding RNAs (ncRNAs), have provided more information on the fibrotic process, and this could represent a promising path forward for the identification of innovative therapeutic strategies for organ fibrosis. In this review, we summarize current research on epigenetic mechanisms involved in organ fibrosis, with a focus on epigenetic regulation of EMP/EMT-dependent fibrosis. Full article
(This article belongs to the Special Issue Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis)
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13 pages, 646 KiB  
Review
Approach for Elucidating the Molecular Mechanism of Epithelial to Mesenchymal Transition in Fibrosis of Asthmatic Airway Remodeling Focusing on Cl− Channels
by Susumu Yoshie, Shigeyuki Murono and Akihiro Hazama
Int. J. Mol. Sci. 2024, 25(1), 289; https://doi.org/10.3390/ijms25010289 - 25 Dec 2023
Viewed by 899
Abstract
Airway remodeling caused by asthma is characterized by structural changes of subepithelial fibrosis, goblet cell metaplasia, submucosal gland hyperplasia, smooth muscle cell hyperplasia, and angiogenesis, leading to symptoms such as dyspnea, which cause marked quality of life deterioration. In particular, fibrosis exacerbated by [...] Read more.
Airway remodeling caused by asthma is characterized by structural changes of subepithelial fibrosis, goblet cell metaplasia, submucosal gland hyperplasia, smooth muscle cell hyperplasia, and angiogenesis, leading to symptoms such as dyspnea, which cause marked quality of life deterioration. In particular, fibrosis exacerbated by asthma progression is reportedly mediated by epithelial-mesenchymal transition (EMT). It is well known that the molecular mechanism of EMT in fibrosis of asthmatic airway remodeling is closely associated with several signaling pathways, including the TGF-β1/Smad, TGF-β1/non-Smad, and Wnt/β-catenin signaling pathways. However, the molecular mechanism of EMT in fibrosis of asthmatic airway remodeling has not yet been fully clarified. Given that Cl− transport through Cl− channels causes passive water flow and consequent changes in cell volume, these channels may be considered to play a key role in EMT, which is characterized by significant morphological changes. In the present article, we highlight how EMT, which causes fibrosis and carcinogenesis in various tissues, is strongly associated with activation or inactivation of Cl− channels and discuss whether Cl− channels can lead to elucidation of the molecular mechanism of EMT in fibrosis of asthmatic airway remodeling. Full article
(This article belongs to the Special Issue Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis)
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36 pages, 5469 KiB  
Review
The Nexus of Inflammation-Induced Epithelial-Mesenchymal Transition and Lung Cancer Progression: A Roadmap to Pentacyclic Triterpenoid-Based Therapies
by Kirill V. Odarenko, Marina A. Zenkova and Andrey V. Markov
Int. J. Mol. Sci. 2023, 24(24), 17325; https://doi.org/10.3390/ijms242417325 - 10 Dec 2023
Cited by 1 | Viewed by 1162
Abstract
Lung cancer is the leading cause of cancer-related death worldwide. Its high mortality is partly due to chronic inflammation that accompanies the disease and stimulates cancer progression. In this review, we analyzed recent studies and highlighted the role of the epithelial–mesenchymal transition (EMT) [...] Read more.
Lung cancer is the leading cause of cancer-related death worldwide. Its high mortality is partly due to chronic inflammation that accompanies the disease and stimulates cancer progression. In this review, we analyzed recent studies and highlighted the role of the epithelial–mesenchymal transition (EMT) as a link between inflammation and lung cancer. In the inflammatory tumor microenvironment (iTME), fibroblasts, macrophages, granulocytes, and lymphocytes produce inflammatory mediators, some of which can induce EMT. This leads to increased invasiveness of tumor cells and self-renewal of cancer stem cells (CSCs), which are associated with metastasis and tumor recurrence, respectively. Based on published data, we propose that inflammation-induced EMT may be a potential therapeutic target for the treatment of lung cancer. This prospect is partially realized in the development of EMT inhibitors based on pentacyclic triterpenoids (PTs), described in the second part of our study. PTs reduce the metastatic potential and stemness of tumor cells, making PTs promising candidates for lung cancer therapy. We emphasize that the high diversity of molecular mechanisms underlying inflammation-induced EMT far exceeds those that have been implicated in drug development. Therefore, analysis of information on the relationship between the iTME and EMT is of great interest and may provide ideas for novel treatment approaches for lung cancer. Full article
(This article belongs to the Special Issue Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis)
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36 pages, 1563 KiB  
Review
Epithelial–Mesenchymal Transition Mechanisms in Chronic Airway Diseases: A Common Process to Target?
by Angélique Mottais, Luca Riberi, Andrea Falco, Simone Soccal, Sophie Gohy and Virginia De Rose
Int. J. Mol. Sci. 2023, 24(15), 12412; https://doi.org/10.3390/ijms241512412 - 3 Aug 2023
Cited by 5 | Viewed by 2559
Abstract
Epithelial-to-mesenchymal transition (EMT) is a reversible process, in which epithelial cells lose their epithelial traits and acquire a mesenchymal phenotype. This transformation has been described in different lung diseases, such as lung cancer, interstitial lung diseases, asthma, chronic obstructive pulmonary disease and other [...] Read more.
Epithelial-to-mesenchymal transition (EMT) is a reversible process, in which epithelial cells lose their epithelial traits and acquire a mesenchymal phenotype. This transformation has been described in different lung diseases, such as lung cancer, interstitial lung diseases, asthma, chronic obstructive pulmonary disease and other muco-obstructive lung diseases, such as cystic fibrosis and non-cystic fibrosis bronchiectasis. The exaggerated chronic inflammation typical of these pulmonary diseases can induce molecular reprogramming with subsequent self-sustaining aberrant and excessive profibrotic tissue repair. Over time this process leads to structural changes with progressive organ dysfunction and lung function impairment. Although having common signalling pathways, specific triggers and regulation mechanisms might be present in each disease. This review aims to describe the various mechanisms associated with fibrotic changes and airway remodelling involved in chronic airway diseases. Having better knowledge of the mechanisms underlying the EMT process may help us to identify specific targets and thus lead to the development of novel therapeutic strategies to prevent or limit the onset of irreversible structural changes. Full article
(This article belongs to the Special Issue Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis)
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21 pages, 934 KiB  
Review
Experimental Models to Study Epithelial-Mesenchymal Transition in Proliferative Vitreoretinopathy
by Azine Datlibagi, Anna Zein-El-Din, Maxime Frohly, François Willermain, Christine Delporte and Elie Motulsky
Int. J. Mol. Sci. 2023, 24(5), 4509; https://doi.org/10.3390/ijms24054509 - 24 Feb 2023
Cited by 6 | Viewed by 2245
Abstract
Proliferative vitreoretinal diseases (PVDs) encompass proliferative vitreoretinopathy (PVR), epiretinal membranes, and proliferative diabetic retinopathy. These vision-threatening diseases are characterized by the development of proliferative membranes above, within and/or below the retina following epithelial-mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) and/or endothelial-mesenchymal [...] Read more.
Proliferative vitreoretinal diseases (PVDs) encompass proliferative vitreoretinopathy (PVR), epiretinal membranes, and proliferative diabetic retinopathy. These vision-threatening diseases are characterized by the development of proliferative membranes above, within and/or below the retina following epithelial-mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) and/or endothelial-mesenchymal transition of endothelial cells. As surgical peeling of PVD membranes remains the sole therapeutic option for patients, development of in vitro and in vivo models has become essential to better understand PVD pathogenesis and identify potential therapeutic targets. The in vitro models range from immortalized cell lines to human pluripotent stem-cell-derived RPE and primary cells subjected to various treatments to induce EMT and mimic PVD. In vivo PVR animal models using rabbit, mouse, rat, and swine have mainly been obtained through surgical means to mimic ocular trauma and retinal detachment, and through intravitreal injection of cells or enzymes to induce EMT and investigate cell proliferation and invasion. This review offers a comprehensive overview of the usefulness, advantages, and limitations of the current models available to investigate EMT in PVD. Full article
(This article belongs to the Special Issue Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis)
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