Replacement of lost Lgr5-positive stem cells through plasticity of their enterocyte-lineage daughters
Open accessAbstract
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.
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Reprogramming of differentiated cells into progenitor-like cells is an important injury-repair paradigm independent of adult stem cells in various epithelial tissues in mammals.
“The reprogramming of differentiated cells into progenitor-like cells has recently been discovered as an important injury-repair paradigm independent of adult stem cells in a variety of epithelial tissues in mammals, 1 such as the lung, 2 intestine, 3 pancreas, 4 and liver.5,6”
From Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers (2023) · cites this paper as [3]
Intestinal progenitors can revert to a stem cell fate.
“In the intestine, progenitors have been shown to be able to revert to a stem cell fate, 101”
From Aging of hematopoietic stem cells (2018) · cites this paper as [101]
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- Authors
- Tetteh, P. W., Basak, O., Farin, H. F., Wiebrands, K., Kretzschmar, K., Begthel, H., van den Born, M., Korving, J., de Sauvage, F., van Es, J. H., van Oudenaarden, A., & Clevers, H.
- Affiliations
- Royal Netherlands Academy of Arts and Sciences (NL)
- Corresponding author
- Clevers, Hans
- Venue
- Cell stem cell
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 18
- Issue
- 2
- Pages
- 203-213
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W2262448048
- Cited by
- 575
- References
- 47
- Citations by year
- 2026: 41 · 2025: 42 · 2024: 49 · 2023: 36 · 2022: 48 · 2021: 59 · 2020: 77 · 2019: 60 · 2018: 76 · 2017: 59 · 2016: 28
- FWCI
- 59.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- stem cell replacement, dedifferentiation, lineage tracing, fate mapping, intestinal injury, intestinal stem cell niche
- MeSH terms
- Alkaline Phosphatase, Animals, beta-Galactosidase, Cell Line, Intestinal Neoplasms, Mutation, Organoids, Regeneration, Stem Cells, Biomarkers, Cell Lineage, Integrases, Paneth Cells, Enterocytes, Receptors, G-Protein-Coupled, Cell Proliferation, Mice, Cell Dedifferentiation, Single-Cell Analysis
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