Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2015 Dec 22;112(51):E7148-54. doi: 10.1073/pnas.1509249112. Epub 2015 Dec 7.

Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival.

Author information

1
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110;
2
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
3
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110;
4
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110;
5
Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, MO 63130;
6
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;
7
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 dpiwnica-worms@mdanderson.org hpiwnica-worms@mdanderson.org.
8
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110; dpiwnica-worms@mdanderson.org hpiwnica-worms@mdanderson.org.

Abstract

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 stem cells were lost in fed mice, 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.

KEYWORDS:

DNA damage; chemotherapy; fasting; stem cells

PMID:
26644583
PMCID:
PMC4697381
DOI:
10.1073/pnas.1509249112
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center