Abstract
The bronchioles of the murine lung are lined by a simple columnar epithelium composed of ciliated, Clara, and goblet cells that together mediate barrier function, mucociliary clearance and innate host defense, vital for pulmonary homeostasis. In the present work, we demonstrate that expression of Sox2 in Clara cells is required for the differentiation of ciliated, Clara, and goblet cells that line the bronchioles of the postnatal lung. The gene was selectively deleted in Clara cells utilizing Scgb1a1-Cre, causing the progressive loss of Sox2 in the bronchioles during perinatal and postnatal development. The rate of bronchiolar cell proliferation was decreased and associated with the formation of an undifferentiated, cuboidal-squamous epithelium lacking the expression of markers of Clara cells (Scgb1a1), ciliated cells (FoxJ1 and α-tubulin), and goblet cells (Spdef and Muc5AC). By adulthood, bronchiolar cell numbers were decreased and Sox2 was absent in extensive regions of the bronchiolar epithelium, at which time residual Sox2 expression was primarily restricted to selective niches of CGRP staining neuroepithelial cells. Allergen-induced goblet cell differentiation and mucus production was absent in the respiratory epithelium lacking Sox2. In vitro, Sox2 activated promoter-luciferase reporter constructs for differentiation markers characteristic of Clara, ciliated, and goblet cells, Scgb1a1, FoxJ1, and Agr2, respectively. Sox2 physically interacted with Smad3 and inhibited TGF-β1/Smad3-mediated transcriptional activity in vitro, a pathway that negatively regulates proliferation. Sox2 is required for proliferation and differentiation of Clara cells that serve as the progenitor cells from which Clara, ciliated, and goblet cells are derived.
Highlights
The respiratory epithelium is lined by a diversity of distinct epithelial cell types that vary in abundance along its proximaldistal axis
The loss of Clara, ciliated and goblet cells in response to Sox2 deletion are consistent with the proposed role of Clara cells as progenitor cells in bronchioles, and show that Sox2 is necessary for normal proliferation and differentiation of the major epithelial cell types lining the bronchioles (Fig. 8)
Summary In summary, the expression of Sox2 in Clara cells of the bronchiolar epithelium was required for its normal differentiation and proliferation after birth
Summary
The respiratory epithelium is lined by a diversity of distinct epithelial cell types that vary in abundance along its proximaldistal axis. Cellular composition of conducting airways varies during development, and is highly responsive to acute and chronic injury in the postnatal lung. The diverse cell types lining the trachea, bronchi, bronchioles, and alveoli become highly differentiated in the perinatal and postnatal period, during which the respiratory epithelium is proliferative. Basal and Clara cells are known to serve as progenitor cells in the conducting airways, while type II epithelial cells proliferate during repair of the alveoli [3,4,7]. Clara cells are capable of self-renewal and differentiate into both ciliated cells and goblet cells, and there is evidence that the Clara cell serves as a common progenitor of the various cell types lining the peripheral conducting airways [16,17,18]
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