The tankyrase inhibitor G007-LK inhibits small intestine LGR5+ stem cell proliferation without altering tissue morphology
Abstract Background The WNT pathway regulates intestinal stem cells and is frequently disrupted in intestinal adenomas. The pathway contains several potential biotargets for interference, including the poly-ADP ribosyltransferase enzymes tankyrase1 and 2. LGR5 is a known WNT pathway target gene and...
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Sociedad de Biología de Chile
2018
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oai:scielo:S0716-976020180001002032018-03-09The tankyrase inhibitor G007-LK inhibits small intestine LGR5+ stem cell proliferation without altering tissue morphologyNorum,Jens HenrikSkarpen,EllenBrech,AndreasKuiper,RaoulWaaler,JoKrauss,StefanSørlie,Therese Tankyrase inhibitor LGR5 WNT signalling Intestine Lineage tracing Stem cell Abstract Background The WNT pathway regulates intestinal stem cells and is frequently disrupted in intestinal adenomas. The pathway contains several potential biotargets for interference, including the poly-ADP ribosyltransferase enzymes tankyrase1 and 2. LGR5 is a known WNT pathway target gene and marker of intestinal stem cells. The LGR5+ stem cells are located in the crypt base and capable of regenerating all intestinal epithelial cell lineages. Results We treated Lgr5-EGFP-Ires-CreERT2;R26R-Confetti mice with the tankyrase inhibitor G007-LK for up to 3 weeks to assess the effect on duodenal stem cell homeostasis and on the integrity of intestinal epithelium. At the administered doses, G007-LK treatment inhibited WNT signalling in LGR5+ stem cells and reduced the number and distribution of cells traced from duodenal LGR5+ stem cells. However, the gross morphology of the duodenum remained unaltered and G007-LK-treated mice showed no signs of weight loss or any other visible morphological changes. The inhibitory effect on LGR5+ stem cell proliferation was reversible. Conclusion We show that the tankyrase inhibitor G007-LK is well tolerated by the mice, although proliferation of the LGR5+ intestinal stem cells was inhibited. Our observations suggest the presence of a tankyrase inhibitor-resistant cell population in the duodenum, able to rescue tissue integrity in the presence of G007-LK-mediated inhibition of the WNT signalling dependent LGR5+ intestinal epithelial stem cells.info:eu-repo/semantics/openAccessSociedad de Biología de ChileBiological Research v.51 20182018-01-01text/htmlhttp://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602018000100203en10.1186/s40659-017-0151-6 |
| institution |
Scielo Chile |
| collection |
Scielo Chile |
| language |
English |
| topic |
Tankyrase inhibitor LGR5 WNT signalling Intestine Lineage tracing Stem cell |
| spellingShingle |
Tankyrase inhibitor LGR5 WNT signalling Intestine Lineage tracing Stem cell Norum,Jens Henrik Skarpen,Ellen Brech,Andreas Kuiper,Raoul Waaler,Jo Krauss,Stefan Sørlie,Therese The tankyrase inhibitor G007-LK inhibits small intestine LGR5+ stem cell proliferation without altering tissue morphology |
| description |
Abstract Background The WNT pathway regulates intestinal stem cells and is frequently disrupted in intestinal adenomas. The pathway contains several potential biotargets for interference, including the poly-ADP ribosyltransferase enzymes tankyrase1 and 2. LGR5 is a known WNT pathway target gene and marker of intestinal stem cells. The LGR5+ stem cells are located in the crypt base and capable of regenerating all intestinal epithelial cell lineages. Results We treated Lgr5-EGFP-Ires-CreERT2;R26R-Confetti mice with the tankyrase inhibitor G007-LK for up to 3 weeks to assess the effect on duodenal stem cell homeostasis and on the integrity of intestinal epithelium. At the administered doses, G007-LK treatment inhibited WNT signalling in LGR5+ stem cells and reduced the number and distribution of cells traced from duodenal LGR5+ stem cells. However, the gross morphology of the duodenum remained unaltered and G007-LK-treated mice showed no signs of weight loss or any other visible morphological changes. The inhibitory effect on LGR5+ stem cell proliferation was reversible. Conclusion We show that the tankyrase inhibitor G007-LK is well tolerated by the mice, although proliferation of the LGR5+ intestinal stem cells was inhibited. Our observations suggest the presence of a tankyrase inhibitor-resistant cell population in the duodenum, able to rescue tissue integrity in the presence of G007-LK-mediated inhibition of the WNT signalling dependent LGR5+ intestinal epithelial stem cells. |
| author |
Norum,Jens Henrik Skarpen,Ellen Brech,Andreas Kuiper,Raoul Waaler,Jo Krauss,Stefan Sørlie,Therese |
| author_facet |
Norum,Jens Henrik Skarpen,Ellen Brech,Andreas Kuiper,Raoul Waaler,Jo Krauss,Stefan Sørlie,Therese |
| author_sort |
Norum,Jens Henrik |
| title |
The tankyrase inhibitor G007-LK inhibits small intestine LGR5+ stem cell proliferation without altering tissue morphology |
| title_short |
The tankyrase inhibitor G007-LK inhibits small intestine LGR5+ stem cell proliferation without altering tissue morphology |
| title_full |
The tankyrase inhibitor G007-LK inhibits small intestine LGR5+ stem cell proliferation without altering tissue morphology |
| title_fullStr |
The tankyrase inhibitor G007-LK inhibits small intestine LGR5+ stem cell proliferation without altering tissue morphology |
| title_full_unstemmed |
The tankyrase inhibitor G007-LK inhibits small intestine LGR5+ stem cell proliferation without altering tissue morphology |
| title_sort |
tankyrase inhibitor g007-lk inhibits small intestine lgr5+ stem cell proliferation without altering tissue morphology |
| publisher |
Sociedad de Biología de Chile |
| publishDate |
2018 |
| url |
http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602018000100203 |
| work_keys_str_mv |
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| _version_ |
1718441568780681216 |