Journal Club

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

Science

16 Apr 2026

Vol 392, Issue 67

Structured Abstract

INTRODUCTION

Adult stem cells are rapidly, but transiently, activated by injury to repair damaged tissue. Repeated or chronic injury predisposes to cancer. Although there has been progress in identifying and characterizing mammalian stem cells and homeostatic mitogens that regulate their proliferation, injury-activated mitogens, the mechanisms that keep them inactive until injury, and whether and how these contribute to cancer is unclear. Here, we investigated these questions for a population of mouse lung epithelial stem cells called NE^stem. NE^stem are rare stem cells intermingled with other pulmonary neuroendocrine (NE) cells in innervated neurosensory clusters that monitor airway status and serve as a stem cell niche. NE^stem are facultative stem cells that proliferate extensively after airway injury, forming large clonal repair patches that restore the surrounding epithelium. NE^stem can also be activated permanently by compound deletion of tumor suppressors retinoblastoma (Rb) and p53. This initiates small-cell lung cancer (SCLC), one of the deadliest cancers.

RATIONALE

We sought to identify the injury-induced mitogen for NE^stem, the mechanisms by which injury activates the mitogen and stimulates stem cell proliferation, and the relationship of this tissue repair pathway to the SCLC tumor suppressors. We reasoned that this could reveal the molecular logic of how injury triggers the critical first step in stem cell activation (division) and answer questions in the fields of tissue repair, stem cells, and cancer.

RESULTS

To identify the mitogenic signal, we developed a mouse lung-slice culture assay and screened candidate ligands for an effect on NE^stem  proliferation. Only insulin-like growth factors 1 and 2 (Igf1 and Igf2), which are well-known hormones that regulate growth, physiology, and aging, induced their proliferation. Igf2 and its receptors were both expressed by and required for injury-induced activation of NE^stem, thus functioning in an autocrine fashion. Although Igf2 was produced constitutively by NE^stem, it was sequestered and stabilized in an inactive form in the niche by coexpressed Igf binding proteins (Igfbps). Pharmacologic release of Igf from latent Igf-Igfbp complexes, or destruction of Igfbp with PAPP-A (pregnancy-associated plasma protein A, also called pappalysin-1) and PAPP-A2 (pappalysin-2) proteases expressed by sensory neurons in the niche, immediately triggered NE^stem proliferation, as did injury. Igf signaling repressed Rb function, which normally enforces stem cell quiescence. Persistent pathway activation by Rb deletion resulted in continuous stem cell proliferation.

CONCLUSION

We have shown that in addition to its classical hormonal roles, Igf operates locally in a lung stem cell niche as a latent autocrine complex with Igfbp, poised for activation by injury. Injury releases Igf, presumably by proteolytic destruction of Igfbp by PAPP-A and/or PAPP-A2. Once freed, Igf activates its signaling pathway, which inhibits Rb and releases this cell-cycle checkpoint to initiate stem cell proliferation. This poised control pathway in tissue repair may be co-opted in cancer because Rb loss immediately initiates uncontrolled NE^stem proliferation and tumorigenesis. This local, rapidly activatable Igf-Rb stem cell control pathway may also operate in other neuroendocrine and neural stem cells and tumors of the body and brain.