Rare Stem Cell Heals Damaged Lungs; Notch Signaling May Hold the Key to Lung Fibrosis

Patients who survive an acute lung injury are able to recover their lung function, which suggests that adult lungs regenerate to a certain extent. Depending on the cause and severity of the injury, multiple progenitor cells, including alveolar type II cells and distal airway stem cells, have been shown to drive lung tissue regeneration in mice. Now, Andrew Vaughan and others have described another cell type in the lungs involved in the repair process in mice when mouse lungs are damaged from influenza virus infection or inhalation of the anticancer drug bleomycin.  This cell type is called the rare lineage-negative epithelial progenitor (LNEP).

LNEP cells are quiescently present within normal distal mouse lung and do not express mature lineage markers (for example, a protein called club cell 10 or CC10 or surfactant protein C, otherwise known as SPC).  However, Vaughan and others demonstrate that LNEPs are activated to proliferate and migrate to damaged sites and mediate lung remodeling following major injury.

Vaughan and others used lineage tracing approaches and cell transplantation strategies and showed that LNEP cells, but not mature epithelial lineage cells, are multipotent in their ability to give rise to both club cells and alveolar cells.  Interestingly, activation of the Notch signaling pathway in LNEP cells initially activated them, but persistent Notch activation inhibited subsequent alveolar differentiation, resulting in failed tissue regeneration (characterized by the formation of abnormal honeycomb cysts in the mouse lung).  Thus Notch signaling is only required at the beginning of their activation, and then must be down-regulated if the LNEP cells are to reconstruct normal lung tissue.  Interestingly, scarred over or fibrotic lungs from patients with idiopathic pulmonary fibrosis or a disease called scleroderma show evidence of hyperactive Notch signaling and their lungs also contain very similar-looking honeycomb cysts.  This strongly suggests that dynamic Notch signaling also regulates the function and differentiation of LNEP-analogous human lung progenitor cells.  Thus designing treatments that properly regulate Notch signaling and, consequently, LNEP activity may potentially halt the development of lung fibrosis in humans.