Colony Stimulating Factor-1 Dependence of Paneth Cell Development in the Mouse Small Intestine

Background & Aims

Paneth cells (PCs) secrete defensins and antimicrobial enzymes that contribute to innate immunity against pathogen infections within the mucosa of the small intestine. We examined the role of colony stimulating factor-1 (CSF-1) in PC development.

Methods

CSF-1–deficient and CSF-1 receptor (CSF-1R)–deficient mice and administration of neutralizing anti–CSF-1R antibody were used to study the requirement of CSF-1 for the development of epithelial cells of the small intestine. CSF-1 transgenic reporter mice and mice that express only the membrane-spanning, cell-surface CSF-1 isoform were used to investigate regulation by systemic versus local CSF-1.

Results

Mice deficient in CSF-1 or CSF-1R had greatly reduced numbers of mature PCs. PCs express the CSF-1R, and administration of anti–CSF-1R antibody to neonatal mice significantly reduced the number of PCs. Analysis of transgenic CSF-1 reporter mice showed that CSF-1–expressing cells are in close proximity to PCs. CSF-1/CSF-1R–deficient mice also had reduced numbers of the proliferating epithelial cell progenitors and lamina propria macrophages. Expression of the membrane-spanning, cell-surface CSF-1 isoform in CSF-1–deficient mice completely rescued the deficiencies of PCs, proliferating progenitors, and lamina propria macrophages.

Conclusions

These results indicate local regulation by CSF-1 of PC development, either directly, in a juxtacrine/paracrine manner, or indirectly, by lamina propria macrophages. Therefore, CSF-1R hyperstimulation could be involved in hyperproliferative disorders of the small intestine, such as Crohn's disease and ulcerative colitis.

Abbreviations used in this paper: β-gal, β-galactosidase, AB, alcian blue, Apc, adenomatous polyposis coli gene, csCSF-1, cell surface isoform of CSF-1, CSF-1, colony-stimulating factor, CSF-1R, colony-stimulating factor receptor, Lgr5, leucine-rich G-coupled receptor gene, PAS, periodic acid Schiff, PBS, phosphate-buffered saline, PC, Paneth cell, PCNA, proliferating cell nuclear antigen, PFA, paraformaldehyde, PLPG, periodate-lysine-2% paraformaldehyde-0.05% glutaraldehyde, RT-PCR, reverse transcription–polymerase chain reaction, SI, small intestine, WT, wild-type