Abstract

The regular anatomy and simple cellular organisation of the intestine provides a powerful model for understanding self-renewal. Our approach is to functionally test the clonogenic potential of populations with different properties and in an agnostic way describe in quantitative terms their net contribution to the stem cell pool as whole. We have previously developed strategies to identify and clonally mark quiescent cells to follow their fate over time. In intestine these are now recognised as committed secretory progenitors but with regenerative potential following injury and are not therefore the steady state stem cells acting to maintain the tissue. In developing methods for lineage tracing that reflects the activity of functional stem cells we have identified that much smaller numbers of stem cells maintain the epithelium before and after transformation than previously suspected. In determining the probabilities of single cells 'winning' in clonal competition with their neighbours we have been able to demonstrate and quantitatively measure the altered probabilities of stem cells carrying defined oncogenic mutations. A continuing challenge is to apply these approaches through the various stages of cancer progression and contexts.