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

• 成果类型: Article
• 署名作者: Zhang, Yue; Ouadah, Youcef; Liu, Yin; Kumar, Maya E.; Morck, Makenna M.; Krasnow, Mark A.
• 署名单位: Stanford Medicine; Stanford University; Stanford University; Stanford Medicine; Howard Hughes Medical Institute; Stanford University; Stanford University; Stanford Medicine; Stanford Medicine; Stanford University; California Institute of Technology; Howard Hughes Medical Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adt1310
• 发表日期: 2026-04-16
• 页码: eadt1310
• 关键词: pulmonary neuroendocrine cells; rna-seq; NEUROEPITHELIAL BODIES; RETINOBLASTOMA GENE; progenitor cells; insulin; cancer; receptor; p53; proliferation

摘要

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.