The small and large intestines are essential in the sustenance of an organism, mediating the absorption of water and nutrients from the diet and the excretion of resulting waste. In humans, these essential functions are carried out by a simple columnar epithelium that has been estimated to cover the surface area of a small apartment. Remarkably, the epithelial cells that compose this lining turnover on a weekly basis due to the presence of the most active stem cell population in the adult organism, the intestinal stem cell (ISC). ISCs not only maintain intestinal homeostasis but also regenerate the intestinal epithelium in the case of injury and are susceptible to neoplastic transformation due to their longevity, which has been suggested to be the lifetime of the organism. This longevity coupled with proliferative capacity implicates ISCs as potential cells of origin for tumorigenesis in colorectal cancer (CRC). In the past decade, the ISC field has exploded with the identification of robust phenotypic markers and experimental models that enable study of ISC dynamics.
The intestinal epithelial receptor guanylyl cyclase C (GC-C) is expressed along the entire length of the intestines and maintains homeostasis of the epithelium through coordination of numerous processes, including preservation of genomic integrity, restriction of cell proliferation, and appropriate cell specification. Moreover, GC-C mediates susceptibility to intestinal injury and tumorigenesis, with absence of GC-C in mice resulting in increased mortality in irradiation and colitis models and exacerbated tumorigenesis in both genetic and sporadic models of CRC. These roles of GC-C combined with ISCs being both the cells responsible for maintaining the intestinal epithelium and the cells of origin in CRC highlight the potential of a previously unappreciated role for GC-C in the regulation of ISCs. Emerging experimental models enable the exploration of the GC-C signaling axis in relation to ISCs for the first time in this study, to investigate the hypothesis that GC-C defends the integrity of the ISC compartment.
Intestinal stem cells
Once thought to be limited to embryonic tissues, stem cells have emerged as necessary cell populations for the maintenance of various tissues in adult organisms. Advances in the field have been spurred in part by elucidation of somatic stem cells (SSC) markers and the development of complex transgenic reporter mice, and hold promise not only for increased understanding of biology but also for applications in regenerative medicine. SSCs are characterized by their longevity, multipotency and capacity for self-renewal. Epithelial SSCs are critical to the maintenance of numerous tissues, including the intestine, liver, lungs, stomach, pancreas, and adrenal cortex.
The intestinal epithelium is a particularly useful model for studying stem cell dynamics, due to the weekly turnover of the entire tissue and the identification of numerous cell types that exhibit stem-like capacity. These intestinal stem cells (ISCs) not only fuel the steady-state turnover of the gut epithelium but also regenerate the epithelium in the case of injury, indicating a potential use for disease treatment or regenerative medicine. Over the past decade, innovative models have facilitated a significant expansion of our understanding of ISCs and intestinal crypt dynamics. Indeed, the ISC niche is much more dynamic and plastic than previously thought. Although this plasticity makes experimental interpretation more difficult, it also has promising implications for ISCs as therapeutic targets.
A brief history of ISC models
The existence of cells at the crypt base that drive continuous renewal and regeneration of the intestinal epithelium has long been suspected, but the lack of adequate culture systems and molecular markers made these cells difficult to study. McMinn concluded in 1954 that cell divisions in the crypt base give rise to non-mitotic cells that populate the villus. Further, Behnke and Moe used electron microscopy to identify undifferentiated cells in the crypt base between Paneth cells in the small intestine. These studies were later unified when it was observed that the undifferentiated cells were proliferative and that all the differentiated epithelial cell lineages arose from the crypt base. These observations ultimately gave rise to the stem-cell zone model. According to this model, CBC stem cells reside in a stem-cell-permissive environment. These cycling stem cells generate progeny that exit the niche and pass through the ‘common origin of differentiation’ around position +5, where they commit to individual lineages. Chang and Leblond also posited that a pluripotent precursor cell generated the differentiated cell types of the colonic epithelium.
In parallel with these CBC findings, Potten and other researchers expanded the stem cell field by introducing another school of thought: the +4 position model. This model was born from identification of a cell population in the +4 crypt position that retained incorporated DNA label, or label-retaining cells (LRCs), in the small intestine. Further, irradiation studies also suggested that there was a cryptogenic cell population distinct from the proliferative CBC cells and TA cells in the stem-cell zone. These insightful studies and others laid the groundwork for more recent molecular studies, which have further defined ISC populations in the crypt base. Current studies support an ISC model in which other cells in the crypt have stem potential depending on tissue requirements. Active, proliferating CBC cells that drive the continual, homeostatic turnover of the intestinal epithelium, but there are also a number of quiescent, reserve ISC populations that are recruited for tissue regeneration in the case of injury.