Cx26 regulates proliferation of repairing basal airway epithelial cells

• Published in: The international journal of biochemistry & cell biology Vol. 52; pp. 152 - 160
• Main Authors: Crespin, S., Bacchetta, M., Bou Saab, J., Tantilipikorn, P., Bellec, J., Dudez, T., Nguyen, T.H., Kwak, B.R., Lacroix, J.S., Huang, S., Wiszniewski, L., Chanson, M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.07.2014; Elsevier
• Subjects: Airways; Biology; Bronchi - metabolism; Bronchi - pathology; Cell Differentiation - physiology; Cell Proliferation - physiology; Cells, Cultured; Connexin 26; Connexins - metabolism; Cx26; Cystic fibrosis; Cystic Fibrosis - metabolism; Cystic Fibrosis - pathology; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelium; Gap junctions; Human health and pathology; Humans; Injuries; Kruppel-Like Transcription Factors - metabolism; Life Sciences; Maintenance; Mucilair; Proliferation; Regulators; Repair; Repairing; Respiratory Mucosa - metabolism; Respiratory Mucosa - pathology; Mucilair; Cx26; Cystic fibrosis; Proliferation; Repair; Gap junctions
• ISSN: 1357-2725; 1878-5875
• DOI: 10.1016/j.biocel.2014.02.010

•Repair of human airway epithelial cells from control individuals and patients with cystic fibrosis (CF) in response to injury is investigated.•Connexin26, a gap junction protein, is transiently induced in a subpopulation of basal airway epithelial cells expressing keratin14.•Connexin26 is induced by cell division and acts as a negative regulator of proliferation.•Krüppel-like factor (KLF) 4, a known transcription factor controlling cell proliferation, is transiently up-regulated in response to injury but did not appear to regulate Connexin26 expression.•The up-regulation of KLF4 following injury is absent in CF airway epithelial cells, which also exhibit desynchronized induction of Connexin26 expression and proliferation. 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. This article is part of a Directed Issue entitled: Cystic fibrosis: From o-mics to cell biology, physiology, and therapeutic advances.