1. Regeneration of intestinal stem/progenitor cells following doxorubicin treatment of mice.
- Author
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Dekaney CM, Gulati AS, Garrison AP, Helmrath MA, and Henning SJ
- Subjects
- Animals, Antibiotics, Antineoplastic administration & dosage, Cell Lineage, Doublecortin-Like Kinases, Doxorubicin administration & dosage, Female, Injections, Intraperitoneal, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Intestine, Small metabolism, Intestine, Small pathology, Jejunum drug effects, Jejunum pathology, Leukocyte Common Antigens analysis, Mice, Mice, Inbred C57BL, Mice, Transgenic, Protein Serine-Threonine Kinases metabolism, RNA, Messenger metabolism, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Stem Cells metabolism, Stem Cells pathology, Time Factors, beta Catenin metabolism, Antibiotics, Antineoplastic toxicity, Apoptosis drug effects, Cell Proliferation drug effects, Doxorubicin toxicity, Intestinal Mucosa drug effects, Intestine, Small drug effects, Regeneration drug effects, Stem Cells drug effects
- Abstract
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 beta-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, beta-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.
- Published
- 2009
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