Krüppel-like Factor 4 Modulates Development of BMI1+ Intestinal Stem Cell-Derived Lineage Following γ-Radiation-Induced Gut Injury in Mice

•KLF4 is expressed in a subpopulation of quiescent BMI1+ intestinal stem cells (ISCs)•KLF4 restricts BMI1+ ISC proliferation at homeostasis•KLF4 promotes expansion of the BMI1+ lineage during radiation-induced regeneration•KLF4 exerts context-dependent activity in modulating BMI1+ ISC fate

SummaryIn 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.

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