Fate plasticity in the intestine: The devil is in the detail

Abstract

The intestinal epithelium possesses a remarkable ability for both proliferation and regeneration. The last two decades have generated major advances in our understanding of the stem cell populations responsible for its maintenance during homeostasis and more recently the events that occur during injury induced regeneration. These fundamental discoveries have capitalised on the use of transgenic mouse models and in vivo lineage tracing to make their conclusions. It is evident that maintenance is driven by rapidly proliferating crypt base stem cells, but complexities associated with the technicality of mouse modelling have led to several overlapping populations being held responsible for the same behaviour. Similarly, it has been shown that essentially any population in the intestinal crypt can revert to a stem cell state given the correct stimulus during epithelial regeneration. Whilst these observations are profound it is uncertain how relevant they are to human intestinal homeostasis and pathology. Here, these recent studies are presented, in context with technical considerations of the models used, to argue that their conclusions may indeed not be applicable in understanding “homeostatic regeneration” and experimental suggestions presented for validating their results in human tissue.

Keywords: Intestinal stem cell; Plasticity; Lgr5; Regeneration

Core tip: Recent advances, using transgenic mice, in understanding cellular hierarchies in the intestinal epithelium have identified numerous cell populations which retain the ability to change their fate in response to injury. Here, these new studies are presented in the context of a discussion about what represents a relevant epithelial injury to understand “homeostatic regeneration”. Experimental suggestions are proposed for validating animal findings to translate our current knowledge to better understand human intestinal epithelial maintenance.