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

TY - JOUR

T1 - Replacement of Lost Lgr5-Positive Stem Cells through Plasticity of Their Enterocyte-Lineage Daughters

AU - Tetteh, Paul W

AU - Basak, Onur

AU - Farin, Henner F

AU - Wiebrands, Kay

AU - Kretzschmar, Kai

AU - Begthel, Harry

AU - van den Born, Maaike

AU - Korving, Jeroen

AU - de Sauvage, Frederic

AU - van Es, Johan H

AU - van Oudenaarden, Alexander

AU - Clevers, Hans

N1 - Copyright © 2016 Elsevier Inc. All rights reserved.

PY - 2016/2/4

Y1 - 2016/2/4

N2 - Intestinal 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 (Alpi(CreER)) 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.

AB - Intestinal 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 (Alpi(CreER)) 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.

U2 - 10.1016/j.stem.2016.01.001

DO - 10.1016/j.stem.2016.01.001

M3 - Article

C2 - 26831517

SN - 1934-5909

VL - 18

SP - 203

EP - 213

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 2

ER -