CSF-1 Receptor-Dependent Colon Development, Homeostasis and Inflammatory Stress Response

Chee Kai Chan,Ivan Bertoncello,Duy Huynh,Robert G. Ramsay,Jordane Malaterre,Xu-Ming Dai,Dilara Akçora,E. Richard Stanley

doi:10.1371/journal.pone.0056951

Abstract

The colony stimulating factor-1 (CSF-1) receptor (CSF-1R) directly regulates the development of Paneth cells (PC) and influences proliferation and cell fate in the small intestine (SI). In the present study, we have examined the role of CSF-1 and the CSF-1R in the large intestine, which lacks PC, in the steady state and in response to acute inflammation induced by dextran sulfate sodium (DSS). As previously shown in mouse, immunohistochemical (IHC) analysis of CSF-1R expression showed that the receptor is baso-laterally expressed on epithelial cells of human colonic crypts, indicating that this expression pattern is shared between species. Colons from Csf1r null and Csf1op/op mice were isolated and sectioned for IHC identification of enterocytes, enteroendocrine cells, goblet cells and proliferating cells. Both Csf1r−/− and Csf1op/op mice were found to have colon defects in enterocytes and enteroendocrine cell fate, with excessive goblet cell staining and reduced cell proliferation. In addition, the gene expression profiles of the cell cycle genes, cyclinD1, c-myc, c-fos, and c-myb were suppressed in Csf1r−/− colonic crypt, compared with those of WT mice and the expression of the stem cell marker gene Lgr5 was markedly reduced. However, analysis of the proliferative responses of immortalized mouse colon epithelial cells (lines; Immorto-5 and YAMC) indicated that CSF-1R is not a major regulator of colonocyte proliferation and that its effects on proliferation are indirect. In an examination of the acute inflammatory response, Csf1r +/− male mice were protected from the adverse affects of DSS-induced colitis compared with WT mice, while Csf1r +/− female mice were significantly less protected. These data indicate that CSF-1R signaling plays an important role in colon homeostasis and stem cell gene expression but that the receptor exacerbates the response to inflammatory challenge in male mice.

Highlights

Colonic and small intestinal (SI) crypts share a range of architectural and molecular features and for convenience are often discussed interchangeably
Using approaches pioneered by investigators of the hematopoietic system, we previously showed that colony stimulating factor-1 (CSF-1) supported the colony formation of fetal and new born colonocytes in vitro and that CSF-1R is expressed on the basal lateral surface of mouse colonic crypts [19]
The CSF-1R is Expressed in Human Colonic Crypts We have previously reported the baso-lateral presence of CSF

Summary

Introduction

Colonic and small intestinal (SI) crypts share a range of architectural and molecular features and for convenience are often discussed interchangeably. Each generates the three cell lineages; the enterocytes, which secrete hydrolases and absorb nutrients, [1] mucin-producing goblet cells [2,3] and the less common enteroendocrine cells that secrete a spectrum of mediators including serotonin, secretin and substance P [4,5]. The SI possesses PC, which reside as a cluster of up to 16 cells at the SI crypt base [7] that out live the cells of the other three SI lineages and are absent in the colonic crypt. The SI contain villi, absorptive structures (predominantly enterocytes) supported by approximately 6 crypts, that increase the epithelial surface area of the SI [8]

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Results

Conclusion