Clonal Evolution of Stem Cells in the Gastrointestinal Tract
The field of gastrointestinal epithelial stem cells is a rapidly developing area of adult stem cell research. The discovery of Lgr5+ intestinal stem cells has enabled us to study many hidden aspects of the biology of gastrointestinal adult stem cells. Mar
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Clonal Evolution of Stem Cells in the Gastrointestinal Tract Juergen Fink and Bon-Kyoung Koo
The intestine is one of the fastest renewing tissues in our body. Its epithelial layer renews every 3–5 days in the adult. This rapid turnover is sustained by a small number of tissue-specific stem cells. Previous studies aimed to identify a rare population of long-lived cells by conventional means such as electron microscopy, DNA label retention, and staining with several rare cell markers [1–5]. Nevertheless, these studies were not sufficient to definitively identify the true potential of these adult stem cells in tissue homeostasis and regeneration. In 2007, Barker et al. reidentified crypt base columnar (CBC) cells as the stem cell of the intestine using elegant lineage tracing of Lgr5+ cells [6]. These Lgr5+ cells proliferate every day to produce a sufficient number of progenitors to fill up the pocket-like structures known as crypts (Fig. 2.1). Proliferating progenitors migrate upward while differentiating into nutrient-absorbing enterocytes as well as secretory cells that produce mucins (goblet cells) or hormones (enteroendocrine cells). These three cell types comprise the epithelium of the villus, a digit-like protrusion toward the gut lumen. Paneth cells migrate downward and stay together with CBC cells. They play a key role in the secretion of antibacterial compounds and in stem cell maintenance by providing growth factor signals (e.g., Egf, Notch, and Wnt ligands) [7]. Lineage tracing experiments have become the gold standard for investigating the longevity and differentiation potential of adult stem cells in vivo. Currently, lineage tracing experiments mostly rely on the tamoxifen-inducible Cre-Recombinase enzyme and transgenic reporter mice (e.g., Rosa26-reporter) [8–18]. In this system the Cre DNA recombinase is linked to a fragment of the estrogen receptor (ER), generating a fusion protein called CreER [19]. The Cre activity of this artificial
J. Fink • B.-K. Koo (*) Department of Genetics, Wellcome Trust—Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK e-mail: [email protected] © Springer International Publishing Switzerland 2016 M. Jansen, N.A. Wright (eds.), Stem Cells, Pre-neoplasia, and Early Cancer of the Upper Gastrointestinal Tract, Advances in Experimental Medicine and Biology 908, DOI 10.1007/978-3-319-41388-4_2
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J. Fink and B.-K. Koo
Fig. 2.1 Epithelial layer of the small intestine (adapted from Koo et al. [51]). The epithelial barrier of the small intestine is comprised of a single cell layer that forms protrusions, called villi, and invaginations, called crypts. Crypt base columnar (CBC) cells can be found in the crypt base intermingled with Paneth cells. Stem cell proliferation drives cell migration upward to replace the functional cell types within the intestinal epithelium. CBC cells mainly generate transit amplifying cells that are located just above the crypt base. During their upward migration these cells proliferate and differentiate to nutrient absor
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