An enteroendocrine cell‐based model for a quiescent intestinal stem cell niche

Abstract

We have shown that the kinetics of conversion of intestinal crypt cell populations to a partially or wholly mutant phenotype are consistent with a model in which each crypt contains an infrequently dividing 'deep' stem cell that is the progenitor of several more frequently dividing 'proximate' stem cells. An assumption of our model is that each deep stem cell exists in a growth inhibitory niche. We have used information from the literature to develop a model for a quiescent intestinal stem cell niche. This niche is postulated to be primarily defined by an enteroendocrine cell type that maintains stem cell quiescence by secretion of growth inhibitory peptides such as somatostatin and guanylin/uroguanylin. Consistent with this model, there is evidence that the proteins postulated as defining a growth-inhibitory stem cell niche can act as intestinal tumour suppressors. Confirmation that a growth-inhibitory niche does exist would have important implications for our understanding of intestinal homeostasis and tumorigenesis.

Identification of a Novel Putative Gastrointestinal Stem Cell and Adenoma Stem Cell Marker, Doublecortin and CaM Kinase-Like-1, Following Radiation Injury and in Adenomatous Polyposis Coli/Multiple Intestinal Neoplasia Mice

“…Upon closer observation, the unique morphologic appearance of the DCAMKL‐1‐expressing cell resembles that of neural processes observed on gastric D cells [23] (Fig. 7A–7D).…”

Intestinal crypt properties fit a model that incorporates replicative ageing and deep and proximate stem cells

“…A model for a quiescent intestinal crypt stem cell niche is presented in the accompanying paper (Radford & Lobachevsky 2006).…”

“…A model for a quiescent intestinal crypt stem cell niche is presented in the accompanying paper (Radford & Lobachevsky 2006). Assumption 3: Proximate stem cells normally undergo asymmetric divisions that result in selfrenewal and the production of a transit-amplifying cell; however, in certain circumstances they can divide symmetrically, resulting in the production of two proximate stem cells .…”

Somatostatin signaling via SSTR1 contributes to the quiescence of colon cancer stem cells

“…Specific types of neuroendocrine cells (NECs), such as somatostatin receptor 1 cells (SSTR1), have been shown to reside in close proximity to colonic SCs in the niche at the bottom of the normal human colonic crypt (see Additional file 1: Figure S1). NECs are known to function in inhibition and/or enhancement of cell proliferation either by paracrine or autocrine signaling [5–8]. Nonetheless, the mechanisms through which SCs and specific NECs interact with each other in the normal colon have not been extensively studied.…”

“…Thus, the niche likely provides the cues underlying slow-cycling dynamics of the SC population and asymmetric SC division that maintains the hierarchical nature of differentiated cell lineages in the colonic crypt [2]. Of note, colonic NECs do not appear to follow the classical hierarchical model of SC differentiation and are thought to arise by direct differentiation of a colonic SC, again supporting the close interactions between the two cell types [8]. Consequently, it seems feasible that the communication between NECs and colonic SCs is crucial to normal crypt homeostasis and maintenance of the quiescent nature of colonic SCs, and that dysregulation of the interactions and communication between the cell types could lead to colonic SC overpopulation during CRC progression.…”