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

Stem Cell Reports. 2016 Jun 14;6(6):815-824. doi: 10.1016/j.stemcr.2016.04.014. Epub 2016 May 26.

Abstract

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.

MeSH terms

  • Animals
  • Apoptosis / radiation effects
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Cell Count
  • Cell Proliferation / radiation effects
  • Gamma Rays
  • Gene Deletion
  • Gene Expression Regulation
  • Genes, Reporter
  • Intestinal Mucosa / metabolism
  • Intestines / cytology
  • Intestines / radiation effects*
  • Kruppel-Like Transcription Factors / deficiency
  • Kruppel-Like Transcription Factors / genetics*
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Polycomb Repressive Complex 1 / genetics*
  • Polycomb Repressive Complex 1 / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Radiation Injuries / genetics
  • Radiation Injuries / metabolism
  • Radiation Injuries / pathology
  • Radiation Injuries / rehabilitation*
  • Regeneration / genetics
  • Signal Transduction
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • Stem Cells / radiation effects*

Substances

  • Bacterial Proteins
  • Bmi1 protein, mouse
  • GKLF protein
  • Kruppel-Like Transcription Factors
  • Luminescent Proteins
  • Proto-Oncogene Proteins
  • yellow fluorescent protein, Bacteria
  • Polycomb Repressive Complex 1