ArticleGastroenterology2021
Bone Morphogenetic Protein Pathway Antagonism by Grem1 Regulates Epithelial Cell Fate in Intestinal Regeneration.
Article in Gastroenterology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 57 citations in OpenAlex.
- BMP4 cocktail promotes utricular progenitor reprogramming and vestibular functional recovery in adult mice.Journal of advanced research · 2026Article
- Comparable expression of stem markers and damage-responsive proteins in untreated and chemoradiation-treated rectal cancer.Histology and histopathology · 2026Article
- Polygonatum cyrtonema Hua fructan ameliorates ulcerative colitis via gut microbiota modulation and follistatin targeting.NPJ science of food · 2026Article
- A paracrine-to-autocrine shunt of GREM1 fuels colorectal cancer metastasis via ACVR1C.Molecular cancer · 2026Article
- Intestinal epithelial cells in health and disease.Tissue barriers · 2026Review
- Multiorgan and gut microbial alterations in ovariectomized mice: a multiomics analysis.Frontiers in immunology · 2026Article
- Arsenic exposure affects Pdgfrα stromal cells in the ileum of the small intestine.Toxicology and applied pharmacology · 2025Article
- Defining the mucosal ecosystem: epithelial-mesenchymal interdependence in gastrointestinal health and disease.Nature reviews. Gastroenterology & hepatology · 2025Review
- BMP antagonist CHRDL2 enhances the cancer stem-cell phenotype and increases chemotherapy resistance in colorectal cancer.Molecular oncology · 2025Article
- BMP signalling in colorectal cancer: losing the yin to WNTs yang.The Journal of pathology · 2025Review
- Expression of bone morphogenetic protein signaling pathway players in the jejunum and colon of adult rats.European journal of histochemistry : EJH · 2025Article
- Epithelial GREMLIN1 disrupts intestinal epithelial-mesenchymal crosstalk to induce a wnt-dependent ectopic stem cell niche through stromal remodelling.Nature communications · 2025Article
- miR-181a-5p mediates the effects of BMP4 on intestinal cell proliferation and differentiation.Cell death & disease · 2025Article
- Extrusion of BMP2+ surface colonocytes promotes stromal remodeling and tissue regeneration.Nature communications · 2025Article
- A Gremlin 1-expressing splenic niche cell population restrains chronic myeloid leukemia by antagonizing the BMP pathway.Nature cancer · 2025Article
- An integrated machine learning framework for developing and validating diagnostic models and drug predictions based on ulcerative colitis genes.Frontiers in medicine · 2025Article
- Targeted delivery of Grem1 and IL-10 separately by mesenchymal stem cells effectively mitigates SETD2-deficient inflammatory bowel disease.Theranostics · 2025Article
- Alteration of skin fibroblast steady state contributes to healing outcomes.bioRxiv : the preprint server for biology · 2024Article
- BMP suppresses Wnt signaling via the Bcl11b-regulated NuRD complex to maintain intestinal stem cells.The EMBO journal · 2024Article
- Gremlin1: a BMP antagonist with therapeutic potential in Oncology.Investigational new drugs · 2024Review
Corrections and comments
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Authors and funding
17 authors at 6 institutions in 3 countries.
Funding
Abstract
BACKGROUND &
aimsIn homeostasis, intestinal cell fate is controlled by balanced gradients of morphogen signaling. The bone morphogenetic protein (BMP) pathway has a physiological, prodifferentiation role, predominantly inferred through previous experimental pathway inactivation. Intestinal regeneration is underpinned by dedifferentiation and cell plasticity, but the signaling pathways that regulate this adaptive reprogramming are not well understood. We assessed the BMP signaling landscape and investigated the impact and therapeutic potential of pathway manipulation in homeostasis and regeneration.
methodsA novel mouse model was generated to assess the effect of the autocrine Bmp4 ligand on individual secretory cell fate. We spatiotemporally mapped BMP signaling in mouse and human regenerating intestine. Transgenic models were used to explore the functional impact of pathway manipulation on stem cell fate and intestinal regeneration.
resultsIn homeostasis, ligand exposure reduced proliferation, expedited terminal differentiation, abrogated secretory cell survival, and prevented dedifferentiation. After ulceration, physiological attenuation of BMP signaling arose through upregulation of the secreted antagonist Grem1 from topographically distinct populations of fibroblasts. Concomitant expression supported functional compensation after Grem1 deletion from tissue-resident cells. BMP pathway manipulation showed that antagonist-mediated BMP attenuation was obligatory but functionally submaximal, because regeneration was impaired or enhanced by epithelial overexpression of Bmp4 or Grem1, respectively. Mechanistically, Bmp4 abrogated regenerative stem cell reprogramming despite a convergent impact of YAP/TAZ on cell fate in remodeled wounds.
conclusionsBMP signaling prevents epithelial dedifferentiation, and pathway attenuation through stromal Grem1 upregulation was required for adaptive reprogramming in intestinal regeneration. This intercompartmental antagonism was functionally submaximal, raising the possibility of therapeutic pathway manipulation in inflammatory bowel disease.
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