Every day, billions of new cells are produced in the intestine of a mouse. The generation of these cells is driven by adult stem cells, which residue in the intestinal epithelium. These stem cells divide every day, but they also differentiate towards distinct cell types that are involves in processes such as nutrient uptake and secretion of mucus and hormones. Intestinal organoid cultures recently emerged as a paradigm to study adult stem cell maintenance and differentiation. These ‘miniguts’ can be cultured in vitro and contain all the different cell types that present in the mouse small intestinal epithelium. Recently it was shown that small-molecule driven perturbations can be used to obtain organoids, which are strongly enriched for specific intestinal cell types. This system thus provides a perfect opportunity to study, for the first time, adult stem cell maintenance and (de)differentiation in a controlled manner. Using small molecule-driven perturbations and a unique combination of ‘omics’ technologies this project has provided a systems-wide view of the molecular (epigenetic) mechanisms that orchestrate cell fate changes in intestinal organoids. Our integrative approach has identified the major regulatory networks that define the remarkable cellular plasticity and homeostasis of the mouse small intestinal epithelium. The technologies and computational infrastructure that we developed in the project have also been and will be further applied to other organoid models, including cancer organoids. Insights from these studies may eventually result in new treatments for colon cancer.
