Abstract
In mouse pulmonary neuroepithelial bodies, few stem cells per cluster proliferate upon lung injury.
Major Finding: In mouse pulmonary neuroepithelial bodies, few stem cells per cluster proliferate upon lung injury.
Concept: NOTCH signaling triggered deprogramming of the stem cells, whereas Rb and p53 prevented proliferation.
Impact: Pulmonary neuroepithelial stem cells may be the progenitors of small-cell lung cancer cells.
Pulmonary neuroendocrine cells, which sense airway status and signal to other lung cells as well as the brain, rarely, if ever, divide under normal circumstances. However, following injury to the lung epithelium, pulmonary neuroepithelial cells proliferate to repair the damaged tissue. In mice, Ouadah and colleagues found that in each pulmonary neuroepithelial body (NEB), a cluster of around 20 to 30 cells, two to four cells proliferated in response to injury caused by naphthalene ablation, with each parental cell yielding one to three daughter cells. The neuroepithelial cells that proliferated upon injury, which the authors called NEstem, represented a unique subpopulation of the original NEB. In rare cases, lung injury also appeared to cause outward migration of some neuroendocrine cells toward the injured region. Neuroendocrine outgrowths derived from a single cell were able to restore injured portions of the lung epithelium. Single-cell mRNA-sequencing experiments revealed that neuroendocrine cells undergoing reprogramming exhibited specific activation of the NOTCH pathway, which is involved in cell-fate decisions. Further experiments showed that NOTCH signaling following lung injury triggered deprogramming of neuroendocrine cells, and NOTCH signaling was also able to cause deprogramming under normal conditions. Additionally, Notch2 expression was a marker of the NEstem state, and was inherited asymmetrically among daughter cells, allowing maintenance of a pool of NEstem cells. The cell-cycle proteins Rb and p53 prevented NEstem proliferation in the absence of injury and curtailed dispersal and reprogramming signals in NEBs following injury, allowing restoration of quiescence after injury. Given that Rb and p53 are almost uniformly inactivated in small-cell lung cancer (SCLC) and that there is some prior evidence that pulmonary neuroendocrine cells initiate SCLC, these findings suggest that NEstem cells may be the progenitors of SCLC and provide a possible mechanism by which SCLC development from NEstem cells may occur.
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