Airway Tissue Stem Cells Reutilize the Embryonic Proliferation Regulator, Tgfβ-Id2 Axis, for Tissue Regeneration

During development, quiescent basal stem cells are derived from proliferative primordial progenitors through the cell cycle slowdown. In contrast, quiescent basal cells contribute to tissue repair during adult tissue regeneration by shifting from slow-cycling to proliferating and subsequently back to slow-cycling. Although sustained basal cell proliferation results in tumorigenesis, the molecular mechanisms regulating these transitions remain unknown. Using temporal single-cell transcriptomics of developing murine airway progenitors and in vivo genetic validation experiments, we found that Tgfβ signaling slowed down cell cycle by inhibiting Id2 expression in airway progenitors and contributed to the specification of slow-cycling basal cell population during development. In adult tissue regeneration, reduced Tgfβ signaling restored Id2 expression and initiated epithelial regeneration. Id2 overexpression and Tgfbr2 knockout enhanced epithelial proliferation; however, persistent Id2 expression in basal cells drove hyperplasia at a rate that resembled a precancerous state. Together, the Tgfβ-Id2 axis commonly regulates the proliferation transitions in airway basal cells during development and regeneration, and its fine-tuning is critical for normal regeneration while avoiding basal cell hyperplasia.