期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 51, 页码 E7148-E7154出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1509249112
关键词
stem cells; DNA damage; chemotherapy; fasting
资金
- Department of Defense Prostate Cancer Research Program Training Award [PC101951]
- NIH National Institute of General Medical Sciences (NIGMS) [T32GM007200]
- NIH National Institute of Biomedical Imaging and Bioengineering (NIBIB) [T32EB018266]
- National Cancer Institute Cancer Center Support Grant [P30 CA91842]
- Institute for Clinical and Translational Science/Clinical and Translational Science Award from the National Center for Research Resources, a component of the National Institutes of Health [UL1RR024992]
- National Institutes of Health Roadmap for Medical Research
- [P50 CA94056]
- [P30 NS057105]
Short-term fasting protects mice from lethal doses of chemotherapy through undetermined mechanisms. Herein, we demonstrate that fasting preserves small intestinal (SI) architecture by maintaining SI stem cell viability and SI barrier function following exposure to high-dose etoposide. Nearly all SI stemcells were lost in fedmice, whereas fasting promoted sufficient SI stem cell survival to preserve SI integrity after etoposide treatment. Lineage tracing demonstrated that multiple SI stem cell populations, marked by Lgr5, Bmi1, or HopX expression, contributed to fasting-induced survival. DNA repair and DNA damage response genes were elevated in SI stem/progenitor cells of fasted etoposide-treated mice, which importantly correlated with faster resolution of DNA double-strand breaks and less apoptosis. Thus, fasting preserved SI stem cell viability as well as SI architecture and barrier function suggesting that fasting may reduce host toxicity in patients undergoing dose intensive chemotherapy.
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