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Loss of bone morphogenetic protein signaling in fibroblasts results in CXCL12-driven serrated polyp development
Ist Teil von
Journal of gastroenterology, 2023-01, Vol.58 (1), p.25-43
Ort / Verlag
Singapore: Springer Nature Singapore
Erscheinungsjahr
2023
Quelle
SpringerLink
Beschreibungen/Notizen
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.