A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable
By H. Tian, B. Biehs, S. Warming, K. Leong, Linda Rangell, O. Klein, Frederic J. de Sauvage. Nature, 2011
1,122 citations recorded by the source corpus.
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.
Subfields: Genetics, Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/0e62c38783a63ade575fd149c2584c5a4a88c8b9
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Citations in the corpus
- An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control (2014, background): “Yet, slowly cycling “reserve” +4 stem cells can be recalled to Lgr5 status (40) and vice versa (35).”
- Sox2+ adult stem/progenitor cells are important for tissue regeneration and survival of mice (2011, neutral): “The notion of distinct stomach stem cells is reminiscent of recently identified stem cell markers in the small intestine that seem to label different cell populations (Barker et al., 2007; Montgomery et al., 2011; Sangiorgi and Capecchi, 2008; Tian et al., 2011).”
- The intestinal crypt, a prototype stem cell compartment. (2013, background): “De Sauvage and colleagues applied an elegant strategy to inducibly kill Lgr5+ cells, i.e., through transgenic expression of the receptor for diphtheria toxin from the Lgr5 locus (Tian et al., 2011).”
- Cancer stem cells: an evolving concept (2012, background): “, although a more quiescent, reserve population may also exis”
- The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations (2011, background): “It has been suggested that Bmi1 and Lgr5 mark an overlapping and possibly identical or redundant population of ISCs (5, 7, 9); however, no direct exploration of their functional similarities and differences has been performed.”
- Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. (2013, background): “Recently, it was demonstrated that Lgr5+ cells comprise the tumor-initiating cell population (Barker et al., 2009), whereas they can be repopulated by Bmi1+ cells after tissue damage (Tian et al., 2011).”