title: Cx26 regulates proliferation of repairing basal airway epithelial cells.
abstract: The recovery of an intact epithelium following injury is critical for restoration of lung homeostasis, a process that may be altered in cystic fibrosis (CF). In response to injury, progenitor cells in the undamaged areas migrate, proliferate and re-differentiate to regenerate an intact airway epithelium. The mechanisms regulating this regenerative response are, however, not well understood. In a model of circular wound injury of well-differentiated human airway epithelial cell (HAEC) cultures, we identified the gap junction protein Cx26 as an important regulator of cell proliferation. We report that induction of Cx26 in repairing HAECs is associated with cell proliferation. We also show that Cx26 is expressed in a population of CK14-positive basal-like cells. Cx26 silencing in immortalized cell lines using siRNA and in primary HAECs using lentiviral-transduced shRNA enhanced Ki67-labeling index and Ki67 mRNA, indicating that Cx26 acts a negative regulator of HAEC proliferation. Cx26 silencing also markedly decreased the transcription of KLF4 in immortalized HAECs. We further show that CF HAECs exhibited deregulated expression of KLF4, Ki67 and Cx26 as well enhanced rate of wound closure in the early response to injury. These results point to an altered repair process of CF HAECs characterized by rapid but desynchronized initiation of HAEC activation and proliferation.
authors.affiliation: Laboratory of Clinical Investigation III, Geneva University Hospitals and University of Geneva, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Crespin
authors.affiliation: Laboratory of Clinical Investigation III, Geneva University Hospitals and University of Geneva, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Bacchetta
authors.affiliation: Laboratory of Clinical Investigation III, Geneva University Hospitals and University of Geneva, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Bou Saab
authors.affiliation: Mahidol University, Bangkok, Thailand.
authors.forename: P
authors.initials: P
authors.lastname: Tantilipikorn
authors.affiliation: INSERM UMR 1064, CHU Nantes, ITUN, Nantes, France.
authors.forename: J
authors.initials: J
authors.lastname: Bellec
authors.affiliation: Laboratory of Clinical Investigation III, Geneva University Hospitals and University of Geneva, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Dudez
authors.affiliation: INSERM UMR 1064, CHU Nantes, ITUN, Nantes, France.
authors.forename: T H
authors.initials: TH
authors.lastname: Nguyen
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Switzerland; Department of Internal Medicine - Cardiology, University of Geneva, Switzerland.
authors.forename: B R
authors.initials: BR
authors.lastname: Kwak
authors.affiliation: Division of Otho-Rhino-Laryngology, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: J S
authors.initials: JS
authors.lastname: Lacroix
authors.affiliation: Epithelix Sàrl, Plan-les-Ouates, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Huang
authors.affiliation: Epithelix Sàrl, Plan-les-Ouates, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Wiszniewski
authors.affiliation: Laboratory of Clinical Investigation III, Geneva University Hospitals and University of Geneva, Switzerland. Electronic address: marc.chanson@hcuge.ch.
authors.forename: M
authors.initials: M
authors.lastname: Chanson
mesh_terms: D001980:Bronchi / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D000072259:Connexin 26; D017630:Connexins / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology*
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D000072259:Connexin 26
keywords: Cx26; Cystic fibrosis; Gap junctions; Mucilair; Proliferation; Repair