The CSF-1 receptor fashions the intestinal stem cell niche

Gastrointestinal (GI) homeostasis requires the action of multiple pathways. There is some controversy regarding whether small intestine (SI) Paneth cells (PCs) play a central role in orchestrating crypt architecture and their relationship with Lgr5+ve stem cells. Nevertheless, we previously showed t...

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Bibliographic Details
Published in:Stem cell research 2013-03, Vol.10 (2), p.203-212
Main Authors: Akcora, Dilara, Huynh, Duy, Lightowler, Sally, Germann, Markus, Robine, Sylvie, de May, Jan R., Pollard, Jeffrey W., Stanley, E. Richard, Malaterre, Jordane, Ramsay, Robert G.
Format: Article
Language:English
Subjects:
Animals
Biochemistry, Molecular Biology
CD24 Antigen - metabolism
Cell Differentiation - genetics
Cell Proliferation
Cellular Biology
Epithelial cells
Gene Deletion
Gene Expression Profiling
Gene Expression Regulation
Intestine, Small - cytology
Life Sciences
Mice
Mice, Inbred C57BL
Mice, Knockout
Organ Specificity - genetics
Organoids - cytology
Organoids - metabolism
Paneth Cells - cytology
Paneth Cells - metabolism
Receptor, Macrophage Colony-Stimulating Factor - deficiency
Receptor, Macrophage Colony-Stimulating Factor - genetics
Receptor, Macrophage Colony-Stimulating Factor - metabolism
Receptors, Notch - metabolism
Stem Cell Niche - genetics
Stem Cells - cytology
Stem Cells - metabolism
Wnt Proteins - metabolism
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Summary:Gastrointestinal (GI) homeostasis requires the action of multiple pathways. There is some controversy regarding whether small intestine (SI) Paneth cells (PCs) play a central role in orchestrating crypt architecture and their relationship with Lgr5+ve stem cells. Nevertheless, we previously showed that germline CSF-1 receptor (Csf1r) knock out (KO) or Csf1 mutation is associated with an absence of mature PC, reduced crypt proliferation and lowered stem cell gene, Lgr5 expression. Here we show the additional loss of CD24, Bmi1 and Olfm4 expression in the KO crypts and a high resolution 3D localization of CSF-1R mainly to PC. The induction of GI-specific Csf1r deletion in young adult mice also led to PC loss over a period of weeks, in accord with the anticipated long life span of PC, changed distribution of proliferating cells and this was with a commensurate loss of Lgr5 and other stem cell marker gene expression. By culturing SI organoids, we further show that the Csf1r−/− defect in PC production is intrinsic to epithelial cells as well as definitively affecting stem cell activity. These results show that CSF-1R directly supports PC maturation and that in turn PCs fashion the intestinal stem cell niche. CSF-1 receptor signaling is required for Paneth cells which in turn support intermingled intestinal stem cells (ISCs) marked by Lgr5 and Olfm4. Pericytes provide local CSF-1 that engages CSF-1 R on PC. PCs produce factors key to the ISC including Wnts. [Display omitted] ► CSF-1R KO eliminates stem and Paneth Cell marker CD24 in the stem cell niche. ► The KO defect is cell intrinsic as shown by organoid cultures. ► Intestinal-specific CSF-1R KO leads to a progressive elimination of Paneth cells. ► This PC loss impacts intestinal stem cell gene expression. ► CSF-1R signaling pathway defects may underpin GI disorders.
ISSN:1873-5061
1876-7753
1876-7753
DOI:10.1016/j.scr.2012.12.001