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Am J Physiol Gastrointest Liver Physiol (December 4, 2008). doi:10.1152/ajpgi.00021.2008
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296/2/G245    most recent
00021.2008v1
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Submitted on January 16, 2008
Accepted on November 22, 2008

Loss of p21Waf1/cip1/Sdi1 enhances intestinal stem cell survival following radiation injury

Robert J George1, Mark A Sturmoski2, Randal May3, Sripathi M Sureban3, Brian K Dieckgraefe1, Shrikant Anant4, and Courtney W Houchen5*

1 Medicine / Gastroenterology, Washington University School of Medicine, Saint Louis, Missouri, United States
2 Surgery, Washington University School of Medicine, Saint Louis, Missouri, United States
3 Medicine / Digestive Diseases and Nutrition, Oklahoma University of Health Sciences Center, Oklahoma City, Oklahoma, United States
4 Medicine/Digestive Diseases and Nutrition, Oklahoma University Health Sciences Center, Oklahoma City, Oklahoma, United States; Cell Biology, Oklahoma University Health Sciences Center, Oklahoma City, Oklahoma, United States
5 Medicine / Digestive Disease and Nutrition, Oklahoma University Health Sciences Center, Oklahoma City, Oklahoma, United States

* To whom correspondence should be addressed. E-mail: courtney-houchen{at}ouhsc.edu.

The microcolony assay following {gamma}-irradiation (IR) is a functional assay of intestinal stem cell fate. The CDK inhibitor p21Waf1/cip1/Sdi1 (p21) regulates cell cycle arrest following DNA damage. To explore the role of p21 on stem cell fate, we examined the effects of p21 deletion on intestinal crypt survival following IR and expression of the stem/progenitor cell marker Msi-1 and the antiapoptotic gene survivin. Intestinal stem cell survival in adult wild-type (WT) and p21-/- mice was measured by the microcolony assay. Msi-1, p21 and survivin mRNA were measured by real time PCR and immunohistochemical analysis. Laser Capture Microdissection (LCM) was used to isolate mRNA from the crypt stem cell zone. No differences in radiation-induced apoptosis were observed between WT and p21-/- mice. However, increased crypt survival (3.0 fold) was observed in p21-/- mice compared to WT 3.5 d after 13 Gy. Msi-1 and survivin mRNA were elevated 12 and 7.5 fold respectively in LCM dissected crypts of p21-/- mice compared to WT. In conclusion, deletion of p21 results in protection of crypt stem/progenitor cells from IR induced cell death. Furthermore the increase in crypt survival is associated with increased numbers of Msi-1 and survivin expressing cells in regenerative crypts.






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