Lung development and repair: Contribution of the ciliated lineage

Abstract

The identity of the endogenous epithelial cells in the adult lung that are responsible for normal turnover and repair after injury is still controversial. In part, this is due to a paucity of highly specific genetic lineage tools to follow efficiently the fate of the major epithelial cell populations: the basal, secretory, ciliated, neuroendocrine, and alveolar cells. As part of a program to address this problem we have used a 1-kb FOXJ1 promoter to drive CreER in the ciliated cells of the embryonic and adult lung. Analysis of FOXJ1-GFP transgenic lungs shows that labeled cells appear in a proximaldistal pattern during embryogenesis and that the promoter drives expression in all ciliated cells. Using FOXJ1CreER adult mice, we have followed the fate of ciliated cells after epithelial injury by naphthalene or sulfur dioxide. From quantitative analysis and confocal microscopy we conclude that ciliated cells transiently change their morphology in response to lung injury but do not proliferate or transdifferentiate as part of the repair process.ciliated cell ͉ injury ͉ lung stem cells

Elf3 plays a role in regulating bronchiolar epithelial repair kinetics following Clara cell-specific injury

“…33 These findings are in accordance with a previous study, which utilized transgenic lineage tracing experiments in order to follow the fate of ciliated cells and provided strong evidence that ciliated cells do not proliferate or transdifferentiate into different epithelial cell types during repair of the naphthalene-injured mouse airway epithelium. 10 In addition, we found that many of the proliferating (ie, Ki-67-positive) cells detected within the regenerating airway epithelium were also dually positive for CC10/CCSP in both Elf3 þ / þ and Elf3À/À mice. We speculate that these cells may represent a naphthalene-resistant sub-population of CC10/CCSPexpressing progenitor cells, which are also known as vCE cells.…”

Expression of CFTR from a ciliated cell-specific promoter is ineffective at correcting nasal potential difference in CF mice

“…In this study, a fragment of the FOXJ1 promoter that has previously been shown to drive expression specifically in ciliated cells 15,28,29 was used to target the expression of CFTR in a murine model of CF. RNA analysis demonstrated that the FOXJ1 promoter successfully targeted the expression of CFTR to the ciliated epithelium of the airways, and the level of mRNA was greater than or equal to the level of endogenous mouse CFTR.…”

The building blocks of mammalian lung development

“…Differentiation of the airway epithelium has been observed to move down the airways from the proximal to the more distal regions (McDowell et al, 1994;Toskala et al, 2005). Molecular markers for NE cell fate specification (for example, the transcription factor Ascl1) and Clara and ciliated cell differentiation (Secretoglobin1a1 and the transcription factor Foxj1) are first observed at E12.5 (NE cells) and E14.5, or 15.5 (ciliated and Clara cells), always at least one airway generation from the multipotent progenitors in the distal tip (Rawlins et al, 2007;McGovern et al, 2010).…”