Stem cell control in the lung by an autocrine injury-activated Igf complex

Stem cells proliferate after injury to repair damaged tissue, and chronic injury can promote cancer. However, the injury-activated signals and regulatory mechanisms, and their relationship to cancer, are poorly understood. Here, we identified insulin-like growth factor 2 (Igf2) as an injury-activated mitogen for lung neuroendocrine stem cells, which are facultative airway progenitors and a cell of origin of small-cell lung cancer in mice. Igf2 was constitutively produced by the stem cells but sequestered in the niche by coexpressed Igf binding proteins (Igfbps). Airway injury released Igf2 and induced proliferation by transiently activating Igf2 receptors and repressing retinoblastoma (Rb) tumor suppressor. Permanent pathway activation by Rb deletion initiated continuous stem cell division. Thus, beyond their classical hormonal roles in physiology, growth, and aging, Igf proteins operate locally and rapidly with Igfbp and Rb to control injury-induced stem cell proliferation and tumor initiation.