title: Krüppel-like Factor 4 Modulates Development of BMI1(+) Intestinal Stem Cell-Derived Lineage Following γ-Radiation-Induced Gut Injury in Mice.
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.
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Jes G
authors.initials: JG
authors.lastname: Kuruvilla
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Chang-Kyung
authors.initials: CK
authors.lastname: Kim
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Amr M
authors.initials: AM
authors.lastname: Ghaleb
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Agnieszka B
authors.initials: AB
authors.lastname: Bialkowska
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Calvin J
authors.initials: CJ
authors.lastname: Kuo
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Stony Brook University Medical Center, HSC T-16, Room 020, Stony Brook, NY 11794-8160, USA. Electronic address: vincent.yang@stonybrookmedicine.edu.
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D049109:Cell Proliferation / Q000528:radiation effects; D005720:Gamma Rays; D017353:Gene Deletion; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000528:radiation effects*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000235:genetics*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D063150:Polycomb Repressive Complex 1 / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011832:Radiation Injuries / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000534:rehabilitation*; D012038:Regeneration / Q000235:genetics; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*
chemical_list: D001426:Bacterial Proteins; C489421:Bmi1 protein, mouse; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D008164:Luminescent Proteins; D011518:Proto-Oncogene Proteins; C054562:yellow fluorescent protein, Bacteria; D063150:Polycomb Repressive Complex 1