Crypt stem cell survival in the mouse intestinal epithelium is regulated by prostaglandins synthesized through cyclooxygenase-1

Steven Cohn, Suzanne Schloemann, Teresa Tessner, Karen Seibert, William F. Stenson

Research output: Contribution to journalArticle

185 Citations (Scopus)

Abstract

Prostaglandins (PGs) are important mediators of epithelial integrity and function in the gastrointestinal tract. Relatively little is known, however, about the mechanism by which PGs affect stem cells in the intestine during normal epithelial turnover, or during wound repair. PGs are synthesized from arachidonate by either of two cyclooxygenases, cyclooxygenase-1 (Cox-1) or cyclooxygenase-2 (Cox-2), which are present in a wide variety of mamalian cells. Cox-1 is thought to be a constitutively expressed enzyme, and the expression of Cox-2 is inducible by cytokines or other stimuli in a variety of cell types. We investigated the role of PGs in mouse intestinal stem cell survival and proliferation following radiation injury. The number of surviving crypt stem cells was determined 3.5 d after irradiation by the microcolony assay. Radiation injury induced a dose-dependent decrease in the number of surviving crypts. Indomethacin, an inhibitor of Cox-1 and Cox-2, further reduced the number of surviving crypts in irradiated mice. The indomethacin dose response for inhibition of PGE2 production and reduction of crypt survival were similar. DimethylPGE2 reversed the indomethacin- induced decrease in crypt survival. Selective Cox-2 inhibitors had no effect on crypt survival. PGE2, Cox-1 mRNA, and Cox-1 protein levels all increase in the 3 d after irradiation. Immunohistochemistry for Cox-1 demonstrated localization in epithelial cells of the crypt in the unirradiated mouse, and in the regenerating crypt epithelium in the irradiated mouse. We conclude that radiation injury results in increased Cox-1 levels in crypt stem cells and their progeny, and that PGE2 produced through Cox-1 promotes crypt stem cell survival and proliferation.

Original languageEnglish (US)
Pages (from-to)1367-1379
Number of pages13
JournalJournal of Clinical Investigation
Volume99
Issue number6
DOIs
StatePublished - Mar 15 1997
Externally publishedYes

Fingerprint

Cyclooxygenase 1
Intestinal Mucosa
Prostaglandins
Cell Survival
Stem Cells
Radiation Injuries
Cyclooxygenase 2
Dinoprostone
Indomethacin
Cell Proliferation
Cyclooxygenase 2 Inhibitors
Prostaglandin-Endoperoxide Synthases
Intestines
Gastrointestinal Tract
Epithelium
Epithelial Cells
Immunohistochemistry
Cytokines
Messenger RNA
Wounds and Injuries

Keywords

  • bromodeoxyuridine
  • epithelium
  • indomethacin
  • prostaglandin E2
  • wound healing

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Crypt stem cell survival in the mouse intestinal epithelium is regulated by prostaglandins synthesized through cyclooxygenase-1. / Cohn, Steven; Schloemann, Suzanne; Tessner, Teresa; Seibert, Karen; Stenson, William F.

In: Journal of Clinical Investigation, Vol. 99, No. 6, 15.03.1997, p. 1367-1379.

Research output: Contribution to journalArticle

Cohn, Steven ; Schloemann, Suzanne ; Tessner, Teresa ; Seibert, Karen ; Stenson, William F. / Crypt stem cell survival in the mouse intestinal epithelium is regulated by prostaglandins synthesized through cyclooxygenase-1. In: Journal of Clinical Investigation. 1997 ; Vol. 99, No. 6. pp. 1367-1379.
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AU - Stenson, William F.

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AB - Prostaglandins (PGs) are important mediators of epithelial integrity and function in the gastrointestinal tract. Relatively little is known, however, about the mechanism by which PGs affect stem cells in the intestine during normal epithelial turnover, or during wound repair. PGs are synthesized from arachidonate by either of two cyclooxygenases, cyclooxygenase-1 (Cox-1) or cyclooxygenase-2 (Cox-2), which are present in a wide variety of mamalian cells. Cox-1 is thought to be a constitutively expressed enzyme, and the expression of Cox-2 is inducible by cytokines or other stimuli in a variety of cell types. We investigated the role of PGs in mouse intestinal stem cell survival and proliferation following radiation injury. The number of surviving crypt stem cells was determined 3.5 d after irradiation by the microcolony assay. Radiation injury induced a dose-dependent decrease in the number of surviving crypts. Indomethacin, an inhibitor of Cox-1 and Cox-2, further reduced the number of surviving crypts in irradiated mice. The indomethacin dose response for inhibition of PGE2 production and reduction of crypt survival were similar. DimethylPGE2 reversed the indomethacin- induced decrease in crypt survival. Selective Cox-2 inhibitors had no effect on crypt survival. PGE2, Cox-1 mRNA, and Cox-1 protein levels all increase in the 3 d after irradiation. Immunohistochemistry for Cox-1 demonstrated localization in epithelial cells of the crypt in the unirradiated mouse, and in the regenerating crypt epithelium in the irradiated mouse. We conclude that radiation injury results in increased Cox-1 levels in crypt stem cells and their progeny, and that PGE2 produced through Cox-1 promotes crypt stem cell survival and proliferation.

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