Abstract
BackgroundIn the human lung, epithelial progenitor cells in the airways give rise to the differentiated pseudostratified airway epithelium. In mice, emerging evidence confers a progenitor function to cytokeratin 5 (KRT5+) or cytokeratin 14 (KRT14+)-positive basal cells of the airway epithelium. Little is known, however, about the distribution of progenitor subpopulations in the human lung, particularly about aberrant epithelial differentiation in lung disease, such as idiopathic pulmonary fibrosis (IPF).MethodsHere, we used multi-color immunofluorescence analysis to detect and quantify the distribution of airway epithelial progenitor subpopulations in human lungs obtained from healthy donors or IPF patients.ResultsIn lungs from both, healthy donors and IPF patients, we detected KRT5+KRT14-, KRT5-KRT14+ and KRT5+KRT14+ populations in the proximal airways. KRT14+ cells, however, were absent in the distal airways of healthy lungs. In IPF, we detected a dramatic increase in the amount of KRT5+ cells and the emergence of a frequent KRT5+KRT14+ epithelial population, in particular in distal airways and alveolar regions. While the KRT14- progenitor population exhibited signs of proper epithelial differentiation, as evidenced by co-staining with pro-SPC, aquaporin 5, CC10, or MUC5B, the KRT14+ cell population did not co-stain with bronchial/alveolar differentiation markers in IPF.ConclusionsWe provide, for the first time, a quantitative profile of the distribution of epithelial progenitor populations in human lungs. We show compelling evidence for dysregulation and aberrant differentiation of these populations in IPF.
Highlights
In the human lung, epithelial progenitor cells in the airways give rise to the differentiated pseudostratified airway epithelium
All p63+ basal cells/mm basement membrane were Keratin 5 (KRT5)+, while 14 % of all basal cells were KRT5+p63- (Fig. 3). This fraction localized luminal to the basal KRT5+p63+ population in the stratified bronchial epithelium (Fig. 2a, left panel)
A costaining for KRT5 and Keratin 14 (KRT14) revealed the existence of a KRT5+KRT14+ subpopulation that was restricted to the basal layer of the healthy conducting airways (Figs. 1a and 2a, right panel)
Summary
Epithelial progenitor cells in the airways give rise to the differentiated pseudostratified airway epithelium. In mice, emerging evidence confers a progenitor function to cytokeratin 5 (KRT5+) or cytokeratin 14 (KRT14+)-positive basal cells of the airway epithelium. The pseudostratified airway epithelial layer continues into a flat epithelial layer composed of alveolar type 1 (AT1) or Recently, lung epithelial progenitor cells have attracted significant interest, as they serve as stem cells for differentiated lung epithelial cell types, such as secretory, ciliated, or AT1 cells in mice [3]. Basal cells are relatively undifferentiated epithelial cells, which are located attached to the basal lamina of the stratified and pseudostratified airway epithelium [5]. Basal cells participate in anchoring of the airway epithelium to the basement membrane and separate the underlying stroma from the epithelial tubes.
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