Abstract
The pseudostratified epithelium of the lung contains ciliated and secretory luminal cells and basal stem/progenitor cells. To identify signals controlling basal cell behavior we screened factors that alter their self-renewal and differentiation in a clonal organoid (tracheosphere) assay. This revealed that inhibitors of the canonical BMP signaling pathway promote proliferation but do not affect lineage choice, whereas exogenous Bmp4 inhibits proliferation and differentiation. We therefore followed changes in BMP pathway components in vivo in the mouse trachea during epithelial regeneration from basal cells after injury. The findings suggest that BMP signaling normally constrains proliferation at steady state and this brake is released transiently during repair by the upregulation of endogenous BMP antagonists. Early in repair, the packing of epithelial cells along the basal lamina increases, but density is later restored by active extrusion of apoptotic cells. Systemic administration of the BMP antagonist LDN-193189 during repair initially increases epithelial cell number but, following the shedding phase, normal density is restored. Taken together, these results reveal crucial roles for both BMP signaling and cell shedding in homeostasis of the respiratory epithelium.
Highlights
Lung function is highly dependent on the cellular composition and integrity of the mucociliary epithelium lining the airway tubes and its interactions with the underlying mesenchyme
BMP ligands and inhibitors regulate the formation of 3D tracheospheres from basal cells (BCs) To explore the signaling pathways that stimulate regeneration of airway progenitors we exploited a BC 3D organoid culture system (Fig. 1A) (Rock et al, 2009; Tadokoro et al, 2014)
By 7 dpi there is no statistical difference in epithelial cell numbers in treated versus untreated tissue. Here, we use both an in vitro clonal organoid culture system and an in vivo injury model in the mouse trachea to explore mechanisms involved in the maintenance and regeneration of the pseudostratified mucociliary airway epithelium from basal progenitors
Summary
Lung function is highly dependent on the cellular composition and integrity of the mucociliary epithelium lining the airway tubes and its interactions with the underlying mesenchyme. Received 19 May 2015; Accepted 19 January 2016 cells can produce immune modulators, a function shared with the monocyte-derived cells intercalated within the surface layer (Hallstrand et al, 2014; Hammad and Lambrecht, 2008; Persson et al, 2014). Given these multiple functions it is crucial that the cellular composition and architecture of the airway epithelium are quickly repaired after damage caused by viral or bacterial infection or by inhalation of smoke or toxic gases (reviewed by Hogan et al, 2014). There is experimental evidence that failure of epithelial repair can lead to dysregulation of the underlying stroma and fibrosis and bronchiolitis obliterans-like conditions (O’Koren et al, 2013)
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