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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 297/3/G461    most recent 90446.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Dekaney, C. M. Articles by Henning, S. J. PubMed PubMed Citation Articles by Dekaney, C. M. Articles by Henning, S. J.

MUCOSAL BIOLOGY

Regeneration of intestinal stem/progenitor cells following doxorubicin treatment of mice

Departments of ¹Surgery, ²Pediatrics, ³Medicine, and ⁴Cell and Molecular Physiology, The University of North Carolina, Chapel Hill, North Carolina; and ⁵Michael E. DeBakey Department of Surgery, Departments of ⁶Pediatrics and ⁷Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas

Submitted 21 July 2008 ; accepted in final form 7 July 2009

The intestinal epithelium is in a constant state of renewal. The rapid turnover of cells is fed by a hierarchy of transit amplifying and stem/progenitor cells destined to give rise to the four differentiated epithelial lineages of the small intestine. Doxorubicin (Dox) is a commonly used chemotherapeutic agent that preferentially induces apoptosis in the intestinal stem cell zone (SCZ). We hypothesized that Dox treatment would initially decrease "+4" intestinal stem cell numbers with a subsequent expansion during mucosal repair. Temporal assessment following Dox treatment demonstrated rapid induction of apoptosis in the SCZ leading to a decrease in the number of intestinal stem/progenitor cells as determined by flow cytometry for CD45(–) SP cells, and immunohistochemistry of cells positive for putative +4 stem cell markers β-cat^Ser552 and DCAMKL1. Between 96 and 168 h postinjection, overall proliferation in the crypts increased concomitant with increases in both absolute and relative numbers of goblet, Paneth, and enteroendocrine cells. This regeneration phase was also associated with increases of CD45(–) SP cells, β-cat^Ser552-positive cells, crypt fission, and crypt number. We used Lgr5-lacZ mice to assess behavior of Lgr5-positive stem cells following Dox and found no change in this cell population. Lgr5 mRNA level was also measured and showed no change immediately after Dox but decreased during the regeneration phase. Together these data suggest that, following Dox-induced injury, expansion of intestinal stem cells occurs during mucosal repair. On the basis of available markers this expansion appears to be predominantly the +4 stem cell population rather than those of the crypt base.

crypt fission; apoptosis; Paneth cells; goblet cells; Lgr5