Even in steady state conditions, some signaling pathway interconversion occurs between Lgr5+ cells and cells residing at higher crypt levels, defined by Hopx expression indicating a ready accessibility of early committed cells to the stem compartment [20]. Recent discoveries indicate more dramatic plasticity within the absorptive lineage (Figure 3). Hyperactivation of pathways synergising with Wnt signalling are apparently able to generate stem cells as part of an oncogenic process even within terminally differentiated villus cells [21••]. Hyper-elevation of NF-κB

signalling, by deletion of negative regulators of the pathway, synergises with Wnt signalling, elevating targets such as Ascl2 and leading to ectopic formation in villi of crypt-like structures expressing stem cell markers [21•• and 22]. Further 3-D spheroid culture of isolated villi confirms the potential of these cells to proliferate over several passages and show multilineage differentiation in xenografts. Evidence that secretory progenitors can also contribute to regeneration comes from functional studies of cells expressing Delta-like 1 (see below). Lineage tracing in Dll1-CreER mice following Tamoxifen treatment demonstrates that single Dll1+ cells in the steady state give rise

mainly to short lived secretory clones [13•]. Equivalent lineage tracing following damage shows that many Dll1+ cells can give rise to long lived clones comprising both absorptive UK-371804 price and secretory lineages, demonstrating that they have regained stem cell activity [13•]. Further, elevated Notch signalling in intestinal villi can cause phenotypic

switching of mature differentiated cells from an absorptive to secretory lineage [23]. Subsequently the status of quiescent or label-retaining cells (LRCs) in the epithelium was investigated using a conditionally expressed, histone-conjugated fluorescent protein (H2BYFP) that could be widely induced initially and subsequently retained in cells that are quiescent [24••]. Characterisation Protein kinase N1 of isolated YFP-LRCs shows these cells have a secretory signature associated with Paneth and enteroendocrine cells. Moreover, inheritance of the label into these cell types is observed over time. Functional lineage tracing of these YFP-LRCs shows that they do not normally give rise to multilineage clones but do so after regenerative stimuli. Together these findings suggest that quiescent cells are committed to become Paneth and enteroendocrine cells but after damage and regeneration are capable of reacquiring stem cell potential. In summary both absorptive and secretory lineages display plasticity in experimental settings. For cells of either type, plasticity requires responsive cells not only to proliferate but also to demonstrate acquisition of the opposing phenotype, that is, multipotentiality.