Replacement of Lost Lgr5-Positive Stem Cells through Plasticity of Their Enterocyte-Lineage Daughters

• Enterocytes in intestinal crypts can dedifferentiate to replace lost Lgr5+ stem cells
• Dedifferentiating enterocytes generate proliferative stem cells and Paneth-like cells
• Enterocytes with Apc/Kras mutations do not form tumors in vivo
• “Stemness” in intestinal crypts is not “hard-wired”

SummaryIntestinal crypts display robust regeneration upon injury. The relatively rare secretory precursors can replace lost stem cells, but it is unknown if the abundant enterocyte progenitors that express the Alkaline phosphate intestinal (Alpi) gene also have this capacity. We created an Alpi-IRES-CreERT2 (AlpiCreER) knockin allele for lineage tracing. Marked clones consist entirely of enterocytes and are all lost from villus tips within days. Genetic fate-mapping of Alpi+ cells before or during targeted ablation of Lgr5-expressing stem cells generated numerous long-lived crypt-villus “ribbons,” indicative of dedifferentiation of enterocyte precursors into Lgr5+ stems. By single-cell analysis of dedifferentiating enterocytes, we observed the generation of Paneth-like cells and proliferative stem cells. We conclude that the highly proliferative, short-lived enterocyte precursors serve as a large reservoir of potential stem cells during crypt regeneration.

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