Plasticity of intestinal epithelial cells in regeneration and cancer

Paul W. Tetteh

Research output: PhD ThesisPhD thesis

Abstract

Cellular plasticity refers to the ability of a cell to change its fate or identity in response to external or intrinsic factors. Regeneration of the intestinal epithelium after injury is driven mainly by plasticity of crypt stem cells that can rapidly divide to replace all the lost cells. Stem cell plasticity also occurs in cancer where mutations transform them into cancer stem cells that drive tumor formation. Emerging evidence suggests that non-stem cells also play a role in regeneration and cancer. This thesis research describes the generation of novel mouse models, the Alpi-CreER model, to examine the plasticity of enterocytes in small intestine regeneration and cancer, and the Car1-CreER model, to study tumor formation from differentiated cells in the colon. Results from experiments with the Alpi-CreER mouse shows that after intestinal damage enterocytes progenitors are plastic, behaving like stem cells that can replace lost Lgr5+ stem cells both in mice or in cultured organoids in the lab. Enterocytes with mutations of both Apc and K-ras genes form tumors in organoid culture but do not form tumors in mice. Interestingly, Apc/-K-ras mutated tumors form tumors in mice when they gain access to the stem cell microenvironment. Experiments with the Car1-CreER model showed that Apc/K-ras mutations in differentiated epithelial cells leads to tumor formation in the colon. These results suggest that stem cell identity in crypts is not fixed ; rather the stem cell microenvironment can change the fate of crypt cells including enterocyte progenitors to become stem cells. In the colon, not only stem cells but also mutated differentiated cells can form tumors.
Original languageEnglish
Awarding Institution
Supervisors/Advisors
  • Clevers, Hans, Promotor
Award date09 Jun 2015
Publisher
Publication statusPublished - 09 Jun 2015

Keywords

  • Plasticity
  • Intestine
  • Epithelium
  • Stem Cells
  • differentiated cells
  • Mouse Model
  • cancer
  • Niche

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