title: Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions.
abstract: Peritoneal adhesions (PAs) are fibrotic bands formed between bowel loops, solid organs, and the parietal peritoneum, which may appear following surgery, infection or endometriosis. They represent an important health problem with no effective treatment. Mesothelial cells (MCs) line the peritoneal cavity and undergo a mesothelial-to-mesenchymal transition (MMT) under pathological conditions, transforming into myofibroblasts, which are abundant in peritoneal fibrotic tissue. The aim of this study was to investigate if peritoneal MCs undergo a MMT contributing to the formation of post-surgical adhesions. Biopsies from patients with PAs were analysed by immunohistochemistry, immunofluorescence, and quantitative RT-PCR. A mouse model of PAs based on ischaemic buttons was used to modulate MMT by blocking the transforming growth factor-beta (TGF-β) pathway. The severity of adhesions and MMT-related marker expression were studied. We observed myofibroblasts derived from the conversion of MCs in submesothelial areas of patients with PAs. In addition, MMT-related markers were dysregulated in adhesion zones when compared to distant normal peritoneal tissue of the same patient. In animal experiments, blockage of TGF-β resulted in molecular reprogramming of markers related to the mesenchymal conversion of MCs and in a significant decrease in the severity of the adhesions. These data indicate for the first time that MMT is involved in PA pathogenesis. This finding opens new therapeutic strategies to interfere with adhesion formation by modulating MMT with a wide range of pharmacological agents.
authors.affiliation: Centro de Biología Molecular-Severo Ochoa, CSIC. Cantoblanco, Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Sandoval
authors.affiliation: Departamento de Anatomía Patológica, Hospital Universitario La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Jiménez-Heffernan
authors.affiliation: Servicio de Cirugía, Clínica Quirón-San Camilo, Madrid, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Guerra-Azcona
authors.affiliation: Centro de Biología Molecular-Severo Ochoa, CSIC. Cantoblanco, Madrid, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: Pérez-Lozano
authors.affiliation: Centro de Biología Molecular-Severo Ochoa, CSIC. Cantoblanco, Madrid, Spain.
authors.forename: Ángela
authors.initials: Á
authors.lastname: Rynne-Vidal
authors.affiliation: Unidad de Biología Molecular y Servicio de Nefrología, Hospital Universitario La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Albar-Vizcaíno
authors.affiliation: Servicio de Cirugía, Clínica Quirón-San Camilo, Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Gil-Vera
authors.affiliation: Departamento de Anatomía Patológica, Hospital Universitario Puerta de Hierro, Madrid, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín
authors.affiliation: Unidad de Microscopía Confocal, Instituto de Investigación Sanitaria Hospital Puerta de Hierro, Madrid, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Coronado
authors.affiliation: Departamento de Anatomía Patológica, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Barcena
authors.affiliation: Digna Biotech, Zizur Mayor, Navarra, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Dotor
authors.affiliation: Unidad de Biología Molecular y Servicio de Nefrología, Hospital Universitario La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain.
authors.forename: Pedro Lorenzo
authors.initials: PL
authors.lastname: Majano
authors.affiliation: Unidad de Biología Molecular y Servicio de Nefrología, Hospital Universitario La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain.
authors.forename: Abelardo Aguilera
authors.initials: AA
authors.lastname: Peralta
authors.affiliation: Centro de Biología Molecular-Severo Ochoa, CSIC. Cantoblanco, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: López-Cabrera
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D064032:Calbindin 2 / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D007633:Keratins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010446:Peptide Fragments / Q000494:pharmacology; D010537:Peritoneum; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein / Q000378:metabolism; D000267:Tissue Adhesions / Q000209:etiology* / Q000473:pathology; D055815:Young Adult
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D064032:Calbindin 2; D010446:Peptide Fragments; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C504795:TGF-beta1 type III receptor (730-743), human; D007633:Keratins
keywords: TGF-β; mesothelial-to-mesenchymal transition; post-surgical adhesions