ISCs in the maintenance of epithelial homeostasis

Principles of stem cell biology and cancer: future applications and therapeutics. Edited by T. Regad, T. J. Sayers and R. C. Rees. John Wiley & Sons (2015)

Part II. Cancer stem cells

Recent experimental evidence from genetically engineered mouse models (GEMs) shows that the epithelial homeostasis in the gut is preserved by ISCs that resides near the crypt base (Clevers, 2013). ISCs are able to self-renew, while at the same time generating TACs (Figure 9.1), which frequently undergo cell division at a lower segment of the intestinal crypt. Following cell division, TACs differentiate into mature distinct epithelial cell lineages as they migrate upward to the top of the vertical axis and shed into the lumen. By contrast, secretory Paneth cells present in the small intestine migrate down towards the bottom of the crypt. The intestinal epithelium has the ability to rapidly repair and compensate for cell loss as part of an injury-induced repair response that prevents loss of structural and functional integrity. This is due to a process called ‘epithelial restitution’, followed by epithelial cell proliferation and differentiation. The restitution process involves atrophic regions in the gastrointestinal epithelium being covered by neighbouring epithelial cells (Iizuka and Konno, 2011). Epithelial cells surrounding the injury undergo cell migration to cover the naked patch in the epithelial barrier, facilitate cell – cell interaction and reinstate a functional epithelial barrier in the gut. This process typically takes minutes to hours to complete and limits the loss of fluids and electrolytes, all while preserving the submucosal compartments from direct exposure to potential antigens present in the intestinal lumen. Epithelial proliferation and differentiation follow the restitution process to compensate for the loss of cellularity following injury and to restore the function of the gut. It is generally agreed that this process is ISC-driven and involves signalling to stimulate the stem cell pool through the Notch and Wnt pathways in the intestine. The restitution process is mainly dependent on compensatory expansion of the ISCs and epithelial progenitor cells of the gut. Subsequently, ISC cell therapy could potentially have therapeutic value for gastrointestinal disorders, such as inflammatory bowel disease (IBD) and colitis, that have been intimately linked to CRC.

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