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Gamma radiation is a commonly used adjuvant treatment for abdominally localized cancer. Since its therapeutic potential is limited due to gastrointestinal (GI) syndrome, elucidation of the regenerative response following radiation-induced gut injury is needed to develop a preventive treatment. Previously, we showed that Krüppel-like factor 4 (KLF4) activates certain quiescent intestinal stem cells (ISCs) marked by  Bmi1-Cre   ER   to give rise to regenerating crypts following γ irradiation. In the current study, we showed that γ radiation-induced expression of p21 Waf1/Cip1  in  Bmi1-Cre   ER   cells is likely mitigated by MUSASHI-1 (MSI1) acting as a negative regulator of p21 Waf1/Cip1  mRNA translation, which promotes exit of the  Bmi1-Cre   ER   cells from a quiescent state. Additionally,  Bmi1 -specific  Klf4  deletion resulted in decreased numbers of MSI1 +  cells in regenerating crypts compared to those of control mice. We showed that KLF4 binds to the  Msi1  promoter and activates its expression in vitro. Since MSI1 has been shown to be crucial for crypt regeneration, this finding elucidates a pro-proliferative role of KLF4 during the postirradiation regenerative response. Taken together, our data suggest that the interplay among p21 Waf1/Cip1 , MSI1 and KLF4 regulates  Bmi1-Cre   ER   cell survival, exit from quiescence and regenerative potential upon γ radiation-induced injury.

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Interplay among p21Waf1/Cip1, MUSASHI-1 and Krüppel-like factor 4 in activation of Bmi1-CreER reserve intestinal stem cells after gamma radiation-induced injury