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Intestinal Foxl1+ cell-derived CXCL12 maintains epithelial homeostasis by modulating cellular metabolism
Mayu Yagita-Sakamaki1,2, Takayoshi Ito1, Taiki Sakaguchi1
1Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
International Immunology
|January 8, 2025
Summary
Mesenchymal cells secrete CXCL12, which regulates intestinal epithelial cell metabolism. This process inhibits tumor progression in ApcMin/+ mice by modulating the mevalonate-cholesterol pathway.
Area of Science:
- Gastroenterology
- Cell Biology
- Cancer Research
Background:
- Mesenchymal cells regulate intestinal stem cells (ISCs), but non-ISC niche factors' roles are unclear.
- Host and microbial metabolites influence sub-epithelial mesenchymal cells.
Purpose of the Study:
- Investigate how mesenchymal cell-derived signaling mediators impact epithelial homeostasis.
- Determine the role of CXCL12 in intestinal epithelial cell cycle arrest and tumor suppression.
Main Methods:
- Analyzed metabolite effects on PDGFRαhigh Foxl1high mesenchymal cells.
- Utilized Foxl1-cre; Cxcl12f/f mice to assess CXCL12's function.
- Examined the mevalonate-cholesterol synthesis pathway and AMPK/SREBP signaling in epithelial cells.
- Assessed tumor development in ApcMin/+ mice with Cxcl12 deficiency.
Main Results:
- Metabolites like taurine and GABA regulate mesenchymal cell transcription.
- CXCL12 from Foxl1high mesenchymal cells induces epithelial cell cycle arrest via the mevalonate-cholesterol pathway.
- CXCL12-induced AMPK phosphorylation inhibits SREBP maturation, suppressing mevalonate pathway activation.
- Cxcl12 deficiency in mesenchymal cells promotes tumor development in ApcMin/+ mice.
Conclusions:
- CXCL12 secreted by Foxl1high mesenchymal cells is crucial for intestinal epithelial homeostasis.
- CXCL12 manipulates epithelial cell metabolism, linking to tumor progression prevention in ApcMin/+ mice.
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