Intrinsic and extrinsic regulators of stem cell fate in the intestinal epithelium

HE Abud1,2,3, K Horvay1,2,3, T Jarde1,2,3, F Casagranda4, CM Nefzger2,3,5, R Akhtar1,2,3, JM Polo2,3,5 and GR Hime4

  1. Cancer Program, Monash Biomedicine Discovery Institute,
  2. Stem Cells and Development Program, Monash Biomedicine Discovery Institute
  3. Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia
  4. Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Australia
  5. Australian Regenerative Medicine Institute, Monash University, Clayton, Australia

Gastrointestinal diseases, infections and pathologies that manifest in the epithelial layer are very common clinical problems. Regulation of intestinal stem cell renewal and differentiation is required for daily maintenance of the intestinal epithelium. Stem cells also play a key role in rapidly regenerating the epithelium following damage. Our objective is to elucidate the molecular mechanisms and environmental influences that regulate cell fate within the intestinal epithelium. We have identified the Snai1 transcriptional regulator as a critical intrinsic regulator of stem cell fate. We have also identified some key environmental factors that influence stem cell behaviour. Snai1 is normally expressed in the intestinal epithelium with strong nuclear expression in crypt base columnar stem cells. Knockout and mechanistic studies in intestinal organoids demonstrate that Snai1 is required for survival and proliferation of stem cells and lineage specific differentiation of mature cell types. Snai1 is up-regulated in polyps and bowel tumours and has a potential role in regulating cancer stem cell populations. Snai1 importantly correlates with the expression of stem cell markers in tumours. We have also identified important environmental signals that can modify stem cell behaviour including factors that are specifically up-regulated in response to epithelial damage. In conclusion, both intrinsic and extrinsic signals regulate stem cell maintenance and cellular differentiation in the intestinal epithelium and manipulation of these signals can influence stem cell fate. These factors also contribute to pathological processes when unregulated.