Tian H, Biehs B, Warming S et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 2011; 478: 255-259

Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Nature (Impact Factor: 41.46). 09/2011; 478(7368):255-9. DOI: 10.1038/nature10408
Source: PubMed


The small intestine epithelium renews every 2 to 5 days, making it one of the most regenerative mammalian tissues. Genetic inducible fate mapping studies have identified two principal epithelial stem cell pools in this tissue. One pool consists of columnar Lgr5-expressing cells that cycle rapidly and are present predominantly at the crypt base. The other pool consists of Bmi1-expressing cells that largely reside above the crypt base. However, the relative functions of these two pools and their interrelationship are not understood. Here we specifically ablated Lgr5-expressing cells in mice using a human diphtheria toxin receptor (DTR) gene knocked into the Lgr5 locus. We found that complete loss of the Lgr5-expressing cells did not perturb homeostasis of the epithelium, indicating that other cell types can compensate for the elimination of this population. After ablation of Lgr5-expressing cells, progeny production by Bmi1-expressing cells increased, indicating that Bmi1-expressing stem cells compensate for the loss of Lgr5-expressing cells. Indeed, lineage tracing showed that Bmi1-expressing cells gave rise to Lgr5-expressing cells, pointing to a hierarchy of stem cells in the intestinal epithelium. Our results demonstrate that Lgr5-expressing cells are dispensable for normal intestinal homeostasis, and that in the absence of these cells, Bmi1-expressing cells can serve as an alternative stem cell pool. These data provide the first experimental evidence for the interrelationship between these populations. The Bmi1-expressing stem cells may represent both a reserve stem cell pool in case of injury to the small intestine epithelium and a source for replenishment of the Lgr5-expressing cells under non-pathological conditions.

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Available from: Søren Warming, Aug 03, 2015
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    • "CBC ISCs play a dominant role during daily intestinal maintenance and are sensitive to intestinal stress and injury (Barker et al., 2007;Carlone and Breault, 2012;Metcalfe et al., 2014;Ritsma et al., 2014). In contrast, d-ISCs, located in the ''+4'' supra-Paneth position, are resistant to stress and are activated upon injury to restore homeostasis (Metcalfe et al., 2014;Montgomery et al., 2011;Powell et al., 2012;Ritsma et al., 2014;Sangiorgi and Capecchi, 2008;Takeda et al., 2011;Tian et al., 2011). Adding additional complexity, recent data suggest a level of cellular plasticity within the ISC population , thereby allowing for inter-conversion between compartments (Goodell et al., 2015;Muñ oz et al., 2012;Ritsma et al., 2014;Takeda et al., 2011). "
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    • "toxin, as previously described (Tian et al., 2011). First, we confirmed at 24 hr following tamoxifen induction that Krt19-Tomato + cells were located above the crypt base and were almost entirely distinct from Lgr5-GFP + CBCs (Figures 3A and 3B). "
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    ABSTRACT: Epithelium of the colon and intestine are renewed every 3 days. In the intestine there are at least two principal stem cell pools. The first contains rapid cycling crypt-based columnar (CBC) Lgr5(+) cells, and the second is composed of slower cycling Bmi1-expressing cells at the +4 position above the crypt base. In the colon, however, the identification of Lgr5(-) stem cell pools has proven more challenging. Here, we demonstrate that the intermediate filament keratin-19 (Krt19) marks long-lived, radiation-resistant cells above the crypt base that generate Lgr5(+) CBCs in the colon and intestine. In colorectal cancer models, Krt19(+) cancer-initiating cells are also radioresistant, while Lgr5(+) stem cells are radiosensitive. Moreover, Lgr5(+) stem cells are dispensable in both the normal and neoplastic colonic epithelium, as ablation of Lgr5(+) stem cells results in their regeneration from Krt19-expressing cells. Thus, Krt19(+) stem cells are a discrete target relevant for cancer therapy. Copyright © 2015 Elsevier Inc. All rights reserved.
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