title: Replacement of Lost Lgr5-Positive Stem Cells through Plasticity of Their Enterocyte-Lineage Daughters.
abstract: 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.
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Tetteh
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Onur
authors.initials: O
authors.lastname: Basak
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Henner F
authors.initials: HF
authors.lastname: Farin
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Kay
authors.initials: K
authors.lastname: Wiebrands
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Kai
authors.initials: K
authors.lastname: Kretzschmar
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: Begthel
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: van den Born
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Korving
authors.affiliation: Molecular Oncology Department, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Frederic
authors.initials: F
authors.lastname: de Sauvage
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Johan H
authors.initials: JH
authors.lastname: van Es
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: van Oudenaarden
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands. Electronic address: h.clevers@hubrecht.eu.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D054337:Cell Dedifferentiation; D002460:Cell Line; D019070:Cell Lineage; D049109:Cell Proliferation; D020895:Enterocytes / Q000378:metabolism* / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D009940:Organoids; D019879:Paneth Cells / Q000378:metabolism / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012038:Regeneration / Q000235:genetics; D059010:Single-Cell Analysis; D013234:Stem Cells / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D015415:Biomarkers; C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; C045073:Cre recombinase; D019426:Integrases; D000469:Alkaline Phosphatase; D001616:beta-Galactosidase