Reg4 + deep crypt secretory cells function as epithelial niche for Lgr5 + stem cells in colon
Open accessAbstract
Leucine-rich repeat-containing G-protein coupled receptor 5-positive (Lgr5(+)) stem cells reside at crypt bottoms of the small and large intestine. Small intestinal Paneth cells supply Wnt3, EGF, and Notch signals to neighboring Lgr5(+) stem cells. Whereas the colon lacks Paneth cells, deep crypt secretory (DCS) cells are intermingled with Lgr5(+) stem cells at crypt bottoms. Here, we report regenerating islet-derived family member 4 (Reg4) as a marker of DCS cells. To investigate a niche function, we eliminated DCS cells by using the diphtheria-toxin receptor gene knocked into the murine Reg4 locus. Ablation of DCS cells results in loss of stem cells from colonic crypts and disrupts gut homeostasis and colon organoid growth. In agreement, sorted Reg4(+) DCS cells promote organoid formation of single Lgr5(+) colon stem cells. DCS cells can be massively produced from Lgr5(+) colon stem cells in vitro by combined Notch inhibition and Wnt activation. We conclude that Reg4(+) DCS cells serve as Paneth cell equivalents in the colon crypt niche.
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Residual iKAP tumor cells shared gene expression signatures with intestinal Paneth cells but differed from Paneth-like cells in the colon and Reg4+ deep crypt secretory cells.
“Comparative analysis revealed that residual tumor cells shared gene expression signatures with intestinal Paneth cells but differed from Paneth-like cells in the colon35(Figure S1G), as well as Reg4+ deep crypt secretory cells (Figure S1H), which are functionally analogous to Paneth cells in the murine colon.36,37”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [36]
Cites
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Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts
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Single-cell messenger RNA sequencing reveals rare intestinal cell types
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Self-citationRedundant sources of Wnt regulate intestinal stem cells and promote formation of Paneth cells
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Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer
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“36,37 Evaluation of Paneth cell lineage-specific genes revealed upregulation of multiple defensins (e.g., Defa5 and Defa17) and Lyz1 in tumors treated with MRTX1133 and cetuximab (Figure 1G).”
- Authors
- Sasaki, N., Sachs, N., Wiebrands, K., Ellenbroek, S. I. J., Fumagalli, A., Lyubimova, A., Begthel, H., van den Born, M., van Es, J. H., Karthaus, W. R., Li, V. S. W., López-Iglesias, C., Peters, P. J., van Rheenen, J., van Oudenaarden, A., & Clevers, H.
- Affiliations
- University Medical Center Utrecht (NL)
- Hubrecht Institute for Developmental Biology and Stem Cell Research, 3584 CT, Utrecht, The Netherlands;
- Memorial Sloan Kettering Cancer Center (US)
- The Institute of Nanoscopy, Maastricht University, 6211 LK, Maastricht, The Netherlands
- Maastricht University (NL)
- Corresponding author
- Clevers, Hans
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-08-29
- Volume
- 113
- Issue
- 37
- Pages
- E5399-407
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5027439
- OpenAlex
- W2511082564
- Cited by
- 314
- References
- 6
- Citations by year
- 2026: 19 · 2025: 25 · 2024: 35 · 2023: 22 · 2022: 49 · 2021: 40 · 2020: 35 · 2019: 27 · 2018: 39 · 2017: 22 · 2016: 1
- FWCI
- 15.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion, other-oa)
- The Japanese Biochemical Society
- Funders
- Massachusetts Institute of Technology
- Francis Crick Institute (10105)
- European Commission
- Astellas Pharma
- Astellas Foundation for Research on Metabolic Disorders
- National Institutes of Health
- Genentech
- Japan Society for the Promotion of Science (16H07176)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
- Keywords
- REG4, Lgr5+ stem cells, colon organoids, Notch signaling, Wnt signaling, intestinal homeostasis, intestinal stem cells
- MeSH terms
- Pancreatitis-Associated Proteins, Animals, Colon, Colonic Neoplasms, Epithelial Cells, Intestine, Small, Neoplasm Proteins, Organoids, Stem Cells, Paneth Cells, Receptors, G-Protein-Coupled, Mice, Receptors, Notch, Stem Cell Niche, Wnt Signaling Pathway
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