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MUCOSAL BIOLOGY

Loss of p21^{Waf1/Cip1/Sdi1} enhances intestinal stem cell survival following radiation injury

¹Department of Medicine, Division of Digestive Diseases and Nutrition, and ²Department of Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; ³Department of Internal Medicine, Division of Gastroenterology, and ⁴Department of Surgery, Washington University School of Medicine, St. Louis, Missouri; ⁵OU Cancer Institute, Oklahoma City; and ⁶Department of Veteran Affairs Medical Center, Oklahoma City, Oklahoma

Submitted 16 January 2008 ; accepted in final form 22 November 2008

The microcolony assay following gamma irradiation (IR) is a functional assay of intestinal stem cell fate. The cyclin-dependent kinase (CDK) inhibitor p21^{Waf1/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 Musashi-1 (Msi-1) and the antiapoptotic gene survivin. Intestinal stem cell survival in adult wild-type (WT) and p21^–/– mice was measured using the microcolony assay. Msi-1, p21, and survivin mRNA were measured using 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^–/– compared with WT mice 3.5 days after 13 Gy. Msi-1 and survivin mRNA were elevated 12- and 7.5-fold, respectively, in LCM-dissected crypts of p21^–/– compared with WT mice. 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.

Musashi-1; gamma irradiation; survivin; crypt survival