Krüppel-like factor 4 modulates development of BMI1⁺ intestinal stem cell-derived lineage following γ-radiation-induced gut injury in mice

In response to ionizing radiation-induced injury, the normally quiescent intestinal stem cells marked by BMI1 participate in the regenerative response. Previously, we established a protective role for Krüppel-like factor 4 (KLF4) in the intestinal epithelium where it reduces senescence, apoptosis, and crypt atrophy following γ-radiation-induced gut injury. We also described a pro-proliferative function for KLF4 during the regenerative phase post irradiation. In the current study, using a mouse model in which Klf4 is deleted from quiescent BMI1⁺ intestinal stem cells, we observed increased proliferation from the BMI1⁺ lineage during homeostasis. In contrast, following irradiation, Bmi1-specific Klf4 deletion leads to decreased expansion of the BMI1⁺ lineage due to a combination of reduced proliferation and increased apoptosis. Our results support a critical role for KLF4 in modulating BMI1⁺ intestinal stem cell fate in both homeostasis and the regenerative response to radiation injury.