Enterocytes originating from gastrointestinal stem cells are basic building blocks of villi and crypts in human intestine. Little is known about intestinal stem cells (ISCs), their interaction with niche, and key pathways in their regulation. In this paper, we have reviewed the characteristics of ISC, its interaction with niche, and the understanding of key signaling pathways like Wnt. A better understanding of all of this will help to better utilize novel therapies like mesenchymal stromal cells (MSCs), R-spondin1, and sulindac in various disorders like colon cancer, graft-versus-host disease, intestinal polyposis, and radiation-related bowel injuries. 1. Introduction The intestinal epithelium is composed of five primary cell types: the common absorptive enterocyte, the enteroendocrine cell, the mucous-secreting goblet cell, the tuft cell, and the Paneth cells [1, 2]. The epithelium of mammalian intestine undergoes rapid turnover to be replenished every 3–5 days [3]. Proliferation occurs near the base of the crypts, with cell maturation occurring as they migrate along the crypt/villus axis. The crypt is the monoclonal proliferative compartment of the intestinal epithelium. The villus represents the differentiated polyclonal compartment, as its cells derive from several crypts. Potten and his colleagues showed in an adult mouse model that every villus has approximately 7000 cells in the duodenum and each villus is surrounded by approx 15 crypts containing 350–400 cells. There are approximately one million crypts in the human small intestine [4]. Enterocytes are the most common epithelial cells and are responsible for absorption of nutrients and water via active and passive transport. Goblet cells secrete mucins and other proteins that are used for lubrication and as a barrier defense against pathogens, and Paneth cells secrete lysozyme to prevent bacterial infection [5, 6]. Driven by the Notch signaling pathway, enteroendocrine cells having ten different subtypes comprise 1% of total epithelium. They are responsible for secreting a variety of hormones that participate in glucose homeostasis [7], satiety (ghrelin), pH balance (secretin), gall bladder contraction (cholecystokinin), gut motility (neurotensin and motilin), and the regulation of pancreatic and pituitary hormone secretion (somatostatin) [8–10]. 2. Intestinal Stem Cells (ISCs) Maintenance of the functional integrity of intestinal epithelium is a challenging task which is done by small numbers of long-lived multipotent cells called intestinal stem cells (ISCs) [11]. The discovery of the ISC
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