Repair of naphthalene-induced acute tracheal injury by basal cells depends on β-catenin

J Thorac Cardiovasc Surg. 2014 Jul;148(1):322-32. doi: 10.1016/j.jtcvs.2013.10.039. Epub 2013 Nov 23.

Abstract

Objectives: Little is known about the role of Wnt/β-catenin in postnatal airway homeostasis and basal cell function. This study aimed to investigate the role of Wnt signaling in the self-renewal of basal cells and the involvement of β-catenin in tracheal repair after naphthalene-induced injury.

Methods: Mice were treated with naphthalene and injected with 4-hydroxytamoxifen. Injury and repair of the tracheal epithelium after naphthalene-mediated secretory cell depletion was assessed by a immunohistochemical study. The involvement of Wnt and β-catenin signaling in basal cell proliferation was investigated during in vitro expansion.

Results: Immunohistochemical analysis of tracheal epithelium in wild-type mice showed a reduction in the number of Clara cell secretory protein (CCSP+) and forkhead box transcription factor (Fox-J1+) cells on days 2 to 5 after naphthalene-induced injury; this cell population was regenerated by day 10. After flush labeling, bromodeoxyuridine-positive (BrdU+) cells and Ki67+ cells were observed in tracheal epithelium on days 2 to 5 but not on days 10 and 21. Confocal microscopy visualizing K5+ and BrdU+ cells showed that Wnt3a promotes proliferation of K5+ cells. Immunohistochemical analysis of K5+ and CCSP+ in tracheal epithelial cells from wild-type littermate and K5-Cre-mediated β-catenin knock-out mice showed that on day 3, the number of CCSP+ cells was decreased in all mice. On day 10, CCSP+ cells were present in wild-type littermate mice but absent in conditional knock-out mice.

Conclusions: Basal cells serve as stem cells in the tracheal epithelium, regenerating and maintaining tracheal epithelial cells in a mouse model of tracheal injury. β-Catenin is required for proliferation and self-renewal of tracheal epithelial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Forkhead Transcription Factors / metabolism
  • Keratin-15
  • Keratin-5 / genetics
  • Keratin-5 / metabolism
  • Ki-67 Antigen / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Naphthalenes / toxicity*
  • Regeneration / drug effects*
  • Respiratory Mucosa / drug effects*
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / pathology
  • Stem Cells / drug effects*
  • Stem Cells / metabolism
  • Stem Cells / pathology
  • Time Factors
  • Trachea / drug effects*
  • Trachea / metabolism
  • Trachea / pathology
  • Uteroglobin / metabolism
  • Wnt Signaling Pathway / drug effects
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • CTNNB1 protein, mouse
  • FOXJ1 protein, mouse
  • Forkhead Transcription Factors
  • Keratin-15
  • Keratin-5
  • Ki-67 Antigen
  • Krt15 protein, mouse
  • Naphthalenes
  • Scgb1a1 protein, mouse
  • beta Catenin
  • naphthalene
  • Uteroglobin