Loss of bone morphogenetic protein signaling in fibroblasts results in CXCL12-driven serrated polyp development

Sarah Ouahoud, Barbara Florien Westendorp, Philip Willen Voorneveld, Subinuer Abudukelimu, Pim Johan Koelink, Elena Pascual Garcia, Jessica Flora Isabella Buuren, Tom Jacob Harryvan, Kristiaan Jan Lenos, Tom van Wezel, Johan Arnold Offerhaus, Arantza Fariña-Sarasqueta, Stijn Crobach, Marije Slingerland, James Christopher Henry Hardwick, Lukas Jacobus Antonius Christiaan Hawinkels

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)


Mutations in Bone Morphogenetic Protein (BMP) Receptor (BMPR)1A and SMAD4 are detected in 50% of juvenile polyposis syndrome (JPS) patients, who develop stroma-rich hamartomatous polyps. The established role of stromal cells in regulating BMP activity in the intestine implies a role for stromal cells in polyp development. We used conditional Cre-LoxP mice to investigate how specific loss of BMPR1A in endothelial cells, fibroblasts, or myofibroblasts/smooth muscle cells affects intestinal homeostasis. Selective loss of BMPR1A in fibroblasts causes severe histological changes in the intestines with a significant increase in stromal cell content and epithelial cell hyperproliferation, leading to numerous serrated polyps. This phenotype suggests that crucial changes occur in the fibroblast secretome that influences polyp development. Analyses of publicly available RNA expression databases identified CXCL12 as a potential candidate. RNAscope in situ hybridization showed an evident increase of Cxcl12-expressing fibroblasts. In vitro, stimulation of fibroblasts with BMPs resulted in downregulation of CXCL12, while inhibition of the BMP pathway resulted in gradual upregulation of CXCL12 over time. Moreover, neutralization of CXCL12 in vivo in the fibroblast-specific BMPR1A KO mice resulted in a significant decrease in polyp formation. Finally, in CRC patient specimens, mRNA-expression data showed that patients with high GREMLIN1 and CXCL12 expression had a significantly poorer overall survival. Significantly higher GREMLIN1, NOGGIN, and CXCL12 expression were detected in the Consensus Molecular Subtype 4 (CMS4) colorectal cancers, which are thought to arise from serrated polyps. Taken together, these data imply that fibroblast-specific BMP signaling–CXCL12 interaction could have a role in the etiology of serrated polyp formation.
Original languageEnglish
Pages (from-to)25-43
Number of pages19
JournalJournal of Gastroenterology
Issue number1
Early online date2022
Publication statusPublished - Jan 2023


  • BMPR1A
  • CXCL12
  • Colorectal cancer
  • Consensus molecular subtypes 4
  • Fibroblasts

Cite this