BMP restricts stemness of intestinal Lgr5(+) stem cells by directly suppressing their signature genes
Open accessAbstract
The intestinal epithelium possesses a remarkable self-renewal ability, which is mediated by actively proliferating Lgr5 + stem cells. Bone morphogenetic protein (BMP) signalling represents one major counterforce that limits the hyperproliferation of intestinal epithelium, but the exact mechanism remains elusive. Here we demonstrate that epithelial BMP signalling plays an indispensable role in restricting Lgr5 + stem cell expansion to maintain intestinal homeostasis and prevent premalignant hyperproliferation on damage. Mechanistically, BMP inhibits stemness of Lgr5 + stem cells through Smad-mediated transcriptional repression of a large number of stem cell signature genes, including Lgr5 , and this effect is independent of Wnt/β-catenin signalling. Smad1/Smad4 recruits histone deacetylase HDAC1 to the promoters to repress transcription, and knockout of Smad4 abolishes the negative effects of BMP on stem cells. Our findings therefore demonstrate that epithelial BMP constrains the Lgr5 + stem cell self-renewal via Smad-mediated repression of stem cell signature genes to ensure proper homeostatic renewal of intestinal epithelium.
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SMAD1 regulates intestinal homeostasis by constraining Lgr5+ stem cell expansion.
“Although SMAD1 has been shown to regulate intestinal homeostasis by constraining Lgr5+ stem cell expansion,52 its role in treatment-induced lineage plasticity remains under-explored.”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [52]
The Abstract (no page specified) says BMP constrains Lgr5+ stem cell expansion to maintain intestinal homeostasis through Smad-mediated repression. The Results section on ISC signature genes shows Smad1 binding at relevant gene regions, but the functional loss-of-function evidence is for Smad4, not Smad1 specifically. The paper therefore supports a role for Smad1 in the pathway without establishing that SMAD1 itself constrains stem cell expansion. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSMAD1 has been reported to repress Lgr5+ stem cell signature genes, thereby limiting stem cell expansion and maintaining intestinal homeostasis.
“As a major receptor-activated SMADs (R-SMADs) downstream of BMP pathway, SMAD1 has been reported to repress Lgr5+ stem cell signature genes, thereby limiting stem cell expansion and maintaining intestinal homeostasis.50–52”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [52]
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- Authors
- Qi, Z., Li, Y., Zhao, B., Xu, C., Liu, Y., Li, H., Zhang, B., Wang, X., Yang, X., Xie, W., Li, B., Han, J.-D. J., & Chen, Y.-G.
- Affiliations
- Center for Life Sciences (CN)
- Chinese Academy of Sciences (CN)
- Tsinghua University (CN)
- State Key Laboratory of Proteomics (CN)
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Chen, Ye-Guang
- ORCID
- Venue
- Nature Communications
- Published
- 2017-01-06
- Volume
- 8
- Issue
- 1
- Pages
- 13824-13824
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5227110
- OpenAlex
- W2567946031
- Cited by
- 320
- References
- 70
- Citations by year
- 2026: 18 · 2025: 35 · 2024: 41 · 2023: 39 · 2022: 41 · 2021: 46 · 2020: 42 · 2019: 24 · 2018: 26 · 2017: 8
- FWCI
- 11.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (973 Program, 31330049, 91519310)
- National Key Research and Development Program of China (31330049, 2013CB933700)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- BMP signaling, Lgr5+ stem cells, intestinal stem cells, stem cell self-renewal, HDAC1, transcriptional repression, intestinal homeostasis, epithelial hyperproliferation, intestinal epithelium
- MeSH terms
- Cell Self Renewal, Animals, Female, Gene Expression Regulation, Histone Deacetylases, Homeostasis, Intestines, Male, Mice, Inbred C57BL, Precancerous Conditions, Promoter Regions, Genetic, Protein Binding, Radiation, Ionizing, Regeneration, Stem Cells, Transcription, Genetic, Bone Morphogenetic Proteins, Gene Expression Profiling, Receptors, G-Protein-Coupled, Cell Proliferation, Wnt Proteins, beta Catenin, Smad Proteins, Cell Cycle Checkpoints, Wnt Signaling Pathway
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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