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Lgr5 Stem Cells in self-renewal and cancer

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Joint lecture with CRI and MRC LMB

The intestinal epithelium is the most rapidly self-renewing mammalian tissue. Lgr5 is a gene transcribed in cycling, crypt base columnar cells at the crypt base. Using lineage tracing experiments the Lgr5+ve cells were identified as the stem cells of the intestinal epithelium. Furthermore, Lgr5+ve stem cells can initiate ever-expanding organoids in vitro. The Lgr5+ve stem cell hierarchy of differentiation is maintained in these organoids. Thus, intestinal crypt-villus units can be built from a single stem cell in the absence of a non-epithelial cellular niche.

Although, Lgr5 stem cells persist life-long, crypts drift toward clonality quickly. The cellular dynamics are consistent with a model in which the stem cells divide symmetrically, and stochastically adopt stem or transient amplifying cell fates after cell division.

Lgr5 stem cells are interspersed between differentiated Paneth cells, which produce all essential signals for stem-cell maintenance. Co-culturing of sorted stem cells with Paneth cells dramatically improves organoid formation. Genetic removal of Paneth cells in vivo results in the concomitant loss of Lgr5 stem cells.

Intestinal cancer is initiated by Wnt pathway-activating mutations in genes such as APC . Deletion of APC in stem cells, but not in other crypt cells results in neoplasia, identifying the stem cell as the cell-of-origin of adenomas. Moreover, a stem cell/progenitor cell hierarchy is maintained in stem cell-derived adenomas, lending support to the “cancer stem cell”-concept.

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