Regulation and plasticity of intestinal stem cells during homeostasis and regeneration

Abstract

The intestinal epithelium is the fastest renewing tissue in mammals and has a large flexibility to adapt to different types of damage. Lgr5 + crypt base columnar (CBC) cells act as stem cells during homeostasis and are essential during regeneration. Upon perturbation, the activity of CBCs is dynamically regulated to maintain homeostasis and multiple dedicated progenitor cell populations can reverse to the stem cell state upon damage, adding another layer of compensatory mechanisms to facilitate regeneration. Here, we review our current understanding of how intestinal stem and progenitor cells contribute to homeostasis and regeneration, and the different signaling pathways that regulate their behavior. Nutritional state and inflammation have been recently identified as upstream regulators of stem cell activity in the mammalian intestine, and we explore how these systemic signals can influence homeostasis and regeneration.

Ap4 is rate limiting for intestinal tumor formation by controlling the homeostasis of intestinal stem cells

“…10Model summarizing the results of this study. The results are explained in the context of the previously described biology of the intestinal crypt: The homeostasis of the intestinal epithelium is regulated by the Wnt/β-catenin and Notch pathways, which control stem cell maintenance and differentiation 16,17 . In the small intestine, the crypt base harbors 4–6 intestinal stem cells (ISCs), which are surrounded by supporting Paneth cells.…”

“…These signatures also showed preferential enrichment among the mRNAs downregulated after deletion of Ap4 . Moreover, mRNAs encoding for proteins involved in Wnt/β-catenin and Notch signaling, which control the homeostasis of ISCs 16,17 , were also preferentially downregulated in Ap4 -deficient adenomas (Fig. 4a, b, Supplementary Fig.…”

Skin and Its Regenerative Powers: An Alliance between Stem Cells and Their Niche

“…Thus, for example, both scale and interscale tail skin progenitors participate in re-epithelialization following a punch wound, but only the EpdSCs in the compartment closest to the wound site appear to contribute long term (Mascre et al, 2012; Sada et al, 2016) (Figure 5). Examples of such wound-induced plasticity in epithelial progenitors now abound, being described not only for the skin epidermis but also the sweat gland (Lu et al, 2012) and intestinal epithelium (reviewed by Beumer and Clevers, 2016). By essentially making an emergency “911” call to all nearby progenitors in the vicinity of the wound, optimal restoration of epithelial barriers is ensured.…”

Epithelial WNT Ligands Are Essential Drivers of Intestinal Stem Cell Activation

“…Intestinal stem cells (ISCs) in the crypts maintain and repair the epithelial surface by giving rise to differentiated cells on the villi. Differentiation of ISCs in the crypts produces daughter cells that migrate up in a “conveyer belt” fashion to the villi, where they mature into both absorptive and secretory cells that play a major role in nutrient absorption and other intestinal functions (Potten, 1997; van der Flier and Clevers, 2009; Mezoff and Shroyer, 2015; Henning and von Furstenberg, 2016; Beumer and Clevers, 2016). One exception to this migratory pathway is the mature Paneth cells, which remain in the crypts instead of migrating upward, interact closely with the ISCs, and secrete stem cell maintenance factors, including WNT (Henning and von Furstenberg, 2016; Mezoff and Shroyer, 2015; Beumer and Clevers, 2016).…”

“…The crypts are thought to contain two types of ISCs (Henning and von Furstenberg, 2016; Mezoff and Shroyer, 2015; Beumer and Clevers, 2016). The best studied is the crypt-based columnar cells (CBCs) located at the base of the crypt.…”