Rare Pulmonary Neuroendocrine Cells Are Stem Cells Regulated by Rb, p53, and Notch

Abstract

Pulmonary neuroendocrine (NE) cells are neurosensory cells sparsely distributed throughout the bronchial epithelium, many in innervated clusters of 20–30 cells. Following lung injury, NE cells proliferate and generate other cell types to promote epithelial repair. Here we show that only a subpopulation of NE cells, typically 2–4 cells per cluster, function as stem cells. These differentiated cells display the key features of classical stem cells. Most proliferate (self-renew) following injury, and some migrate into the injured area. Rare cells, often just one per cluster, lose NE identity, transit amplify, and reprogram to other fates, creating a large clonal patch of regenerated epithelium. Small cell lung cancer (SCLC) tumor suppressors regulate the stem cell program: Rb/p53 suppress self-renewal, whereas Notch initiates deprogramming and transit amplification. We propose that NE stem cells are tumor-initiating cells for SCLC, and transformation results from constitutive activation of stem cell renewal and inhibition of deprogramming.