Figure 12. Schematic representation of hypothetical IFN-γ etiology augmenting irradiation injury.

Upper images depict the course of crypt recovery from irradiation injury. Rapidly cycling ISCs that converted from quiescent ISCs after irradiation (center image, blue arrows) restore damaged crypts promptly (33, 34). Lower panel shows the hypothetical IFN-γ etiology. In the absence of niche signals previously derived from Paneth cells, Lgr5^loOlfm4^– cells, and TA cells become prevalent, and Lgr5^loOlfm4^– cells replace positions the base of the crypts that formerly were occupied by the depleted Paneth cells. The increase in Lgr5^loOlfm4^– cells relative to Lgr5⁺Olfm4⁺ ISCs may contribute to crypt hyperplasia. However, in crypts depleted of Paneth cells by IFN-γ exposure, Bmi1⁺ quiescent ISCs cannot convert to rapidly cycling ISCs in sufficient numbers to respond to irradiation, resulting in failure to repair and restore epithelial integrity. Blue arrows indicate ISC division.