Morphogen regulation of stem cell plasticity in intestinal regeneration and carcinogenesis.
Eggington HR., Mulholland EJ., Leedham SJ.
The intestinal epithelium is a tissue with high cell turnover, supported by adult intestinal stem cells. Intestinal homeostasis is underpinned by crypt basal columnar stem cells, marked by expression of the LGR5 gene. However, recent research has demonstrated considerable stem cell plasticity following injury, with dedifferentiation of a range of other intestinal cell populations, induced by a permissive microenvironment in the regenerating mucosa. The regulation of this profound adaptive cell reprogramming response is the subject of current research. There is a demonstrable contribution from disruption of key homeostatic signaling pathways such as wingless-related integration site and bone morphogenetic protein, and an emerging signaling hub role for the mechanoreceptor transducers Yes-associated protein 1/transcriptional coactivator with PDZ-binding motif, negatively regulated by the Hippo pathway. However, a number of outstanding questions remain, including a need to understand how tissues sense damage, and how pathways intersect to mediate dynamic changes in the stem cell population. Better understanding of these pathways, associated functional redundancies, and how they may be both enhanced for recovery of inflammatory diseases, and co-opted in neoplasia development, may have significant clinical implications, and could lead to development of more targeted molecular therapies which target individual stem or stem-like cell populations.