Editors' ChoiceLUNG INJURY

Breathing fresh: Rare stems cells repair injured lung

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Science Translational Medicine  21 Jan 2015:
Vol. 7, Issue 271, pp. 271ec12
DOI: 10.1126/scitranslmed.aaa6669

Patients who survive an acute lung injury are able to recover their lung function, suggesting 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, Vaughan et al. describe another cell type involved in the repair process in mouse models lung damage from influenza virus infection or bleomycin inhalation: the rare lineage-negative epithelial progenitor (LNEP).

LNEP cells are quiescently present within normal distal mouse lung and do not express mature lineage markers, such as club cell 10 (CC10) protein and surfactant protein C (SPC). However, the authors demonstrate that these cells are activated to proliferate and migrate to damaged sites and mediate lung remodeling following major injury. Using lineage tracing approaches and cell transplantation, Vaughan et al. showed that LNEP cells, but not mature epithelial lineage cells, were multipotent in their ability to give rise to both club cells and alveolar cells. Interestingly, acute Notch signaling promoted the initial activation of LNEP cells, 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). Strikingly, fibrotic lungs from patients with idiopathic pulmonary fibrosis or scleroderma show evidence of hyperactive Notch signaling and similar presence of honeycomb cysts, suggesting that dynamic Notch signaling could also regulate the function and differentiation of LNEP-analogous human lung progenitor cells. Modulating Notch signaling and, in turn, LNEP activity may therefore provide beneficial effects on halting the development of lung fibrosis in humans.

A. E. Vaughan et al., Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature 10.1038/nature14112 (2014). [Abstract]

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