Notch regulation of gastrointestinal stem cells

Abstract

The gastrointestinal (GI) tract epithelium is continuously replenished by actively cycling stem and progenitor cells. These cell compartments are regulated to balance proliferation and stem cell renewal with differentiation into the various mature cell types to maintain tissue homeostasis. In this topical review we focus on the role of the Notch signalling pathway to regulate GI stem cell function in adult small intestine and stomach. We first present the current view of stem and progenitor cell populations in these tissues and then summarize the studies that have established the Notch pathway as a key regulator of gastric and intestinal stem cell function. Notch signalling has been shown to be a niche factor required for maintenance of GI stem cells in both tissues. In addition, Notch has been described to regulate epithelial cell differentiation. Recent studies have revealed key similarities and differences in how Notch regulates stem cell function in the stomach compared to intestine. We summarize the literature regarding Notch regulation of GI stem cell proliferation and differentiation, highlighting tissue‐specific functions to compare and contrast Notch in the stomach and intestine.

Role of ADAM10 in intestinal crypt homeostasis and tumorigenesis

“…A layer of columnar epithelium lining the lumen of the adult gastrointestinal tract is organized into proliferative crypts that undergo constant renewal to replenish differentiated cells along the crypt-villus axis. Intestinal stem and progenitor cells located in the crypts continuously divide and differentiate to maintain intestinal homeostasis and tissue integrity throughout the lifespan of the organism [9–12]. In the small intestine, at least 6 distinct post-mitotic epithelial cell types are formed.…”

“…Underlying the epithelial layer, mesenchymal components (pericryptal myofibroblasts, muscle layers etc), immune cells, enteric neurons and vasculature all play critical and complex roles in maintaining intestinal homeostasis (Figure 1). Excellent reviews have been published on intestinal development, cell fate specification and stem cell homeostasis[9–12, 16]. In the following sections, I provide a brief summary about specific aspects of intestinal development, cell lineage specification and intestinal stem cell niche dynamics pertinent to the role of ADAM10 in regulating intestinal homeostasis in vivo .…”

“…Interestingly, the appearance of morphologically distinct Paneth cells within the crypt base only occurs after post-natal day 7 and their numbers continue to increase until weaning. However, the intestine only achieves full maturation and functionality after weaning[11, 12, 16, 17, 20, 21]. …”

Notch as a Driver of Gastric Epithelial Cell Proliferation

“…Notch components are expressed broadly to regulate many homeostatic processes in adult tissues, including the GI tract 14 . The Notch signaling pathway, present in all metazoans, is highly conserved.…”

“…Distinct pools of actively cycling stem cells in each region fuel epithelial cell turnover throughout life. These active stem cells generate proliferating progenitors that differentiate into the various mature epithelial cell lineages of the stomach 14 . In the corpus, adult stem cells thought to be located in the midregion of each gland generate progeny that migrate bidirectionally to form the differentiated cell types, including short-lived surface mucous cells, and longer-lived acid-secreting parietal cells, endocrine cells, and zymogenic lineage cells.…”