title: Semaphorin 7A contributes to TGF-β-mediated liver fibrogenesis.
abstract: Semaphorin7A (SEMA7A) is a membrane-anchored protein involved in immune and inflammatory responses, exerting an effect on pulmonary fibrosis. Thus, we aimed to investigate the role of SEMA7A in hepatic fibrosis. Liver injury was induced in vivo by carbon tetrachloride i.p. injection or bile duct ligation in wild-type and SEMA7A knockout (KO) mice. Human and mouse liver samples and primary mouse hepatic cell populations were used for Western blot analysis, quantitative real-time RT-PCR, and immunohistochemistry. SEMA7A is highly expressed in hepatic stellate cells (HSCs). The expression of SEMA7A and its receptor β1-integrin subunit increase during liver injury and in activated HSCs. Transforming growth factor β-stimulated HSCs showed increased expression of SEMA7A in a SMAD2/3-independent manner, leading to increased expression of fibrogenic and inflammation markers. This pattern was significantly blunted in SEMA7A KO HSCs. Overexpression of SEMA7A in HSCs showed increased fibrogenic and inflammation markers expression. In vivo, SEMA7A KO mice treated with carbon tetrachloride and bile duct ligation developed reduced fibrosis versus wild-type mice. Moreover, SEMA7A expression increased in liver samples of patients with fibrosis versus healthy controls. SEMA7A was expressed in the liver and was increased in the course of liver fibrosis, both in mice and in humans. SEMA7A was mainly expressed in HSCs with respect to other cell types in the liver and plays a critical role in regulating fibrosis.
authors.affiliation: Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Samuele
authors.initials: S
authors.lastname: De Minicis
authors.forename: Chiara
authors.initials: C
authors.lastname: Rychlicki
authors.forename: Laura
authors.initials: L
authors.lastname: Agostinelli
authors.forename: Stefania
authors.initials: S
authors.lastname: Saccomanno
authors.forename: Luciano
authors.initials: L
authors.lastname: Trozzi
authors.forename: Cinzia
authors.initials: C
authors.lastname: Candelaresi
authors.forename: Ramon
authors.initials: R
authors.lastname: Bataller
authors.forename: Cristina
authors.initials: C
authors.lastname: Millán
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
authors.forename: Marco
authors.initials: M
authors.lastname: Vivarelli
authors.forename: Federico
authors.initials: F
authors.lastname: Mocchegiani
authors.forename: Marco
authors.initials: M
authors.lastname: Marzioni
authors.forename: Antonio
authors.initials: A
authors.lastname: Benedetti
authors.forename: Gianluca
authors.initials: G
authors.lastname: Svegliati-Baroni
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D039961:Semaphorins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; D058851:GPI-Linked Proteins; C118753:SEMA7A protein, human; C485571:Sema7a protein, mouse; D039961:Semaphorins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases