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

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.

Macrophages and CSF-1

“…82 The two major cell populations regulated by CSF-1 via expression of the CSF-1R are cells of the trophoblast lineage and hemopoietic cells of the mononuclear phagocyte system, 83 with distinct promoters specific to each lineage in humans. 84 Expression beyond these lineages is also reported in settings including Paneth cells of the small intestine, 85,86 neural stem cells 87 and kidney tubular epithelium in a setting of acute injury. 88 CSF-1 is essential in regulating trophic macrophages during development.…”

Regulation of Embryonic and Postnatal Development by the CSF-1 Receptor

“…Basolateral immunohistochemical expression of CSF-1R has been reported by immunohistochemical methods on epithelial cells of both mouse and human colonic crypts (Huynh et al, 2013; Ramsay et al, 2004). Both Csf op/op and Csf1r −/− mice were found to have abnormal colon organization, with altered enterocyte and enteroendocrine cell fates, excessive goblet cell staining, reduced cell proliferation and stem cell marker (Lgr5) expression (Huynh et al, 2013).…”

“…Both Csf op/op and Csf1r −/− mice were found to have abnormal colon organization, with altered enterocyte and enteroendocrine cell fates, excessive goblet cell staining, reduced cell proliferation and stem cell marker (Lgr5) expression (Huynh et al, 2013). However, neither CSF-1R ligand elicited significant in vitro proliferative responses from immortalized mouse colonic epithelial cells, indicating that the CSF-1R does not directly regulate colonocyte proliferation in vivo.…”

“…Apart from its expression on cells of hematopoietic origin (macrophages, osteoclasts, dendritic cells, and their precursors), the CSF-1R is also expressed on nonhematopoietic cells (reviewed in Chitu, Caescu, et al, 2015; Chitu, Gokhan, Nandi, Mehler, & Stanley, 2016; Chitu & Stanley, 2006), including Paneth cells (PC) (Huynh et al, 2009), epithelial intestinal cells of the colon (Huynh et al, 2013), renal proximal tubule epithelial cells (Menke et al, 2009), neural progenitor cells (NPCs; Nandi et al, 2012), and several subpopulations of neurons (Luo et al, 2013; Nandi et al, 2012; Wang, Berezovska, & Fedoroff, 1999), oocytes, preimplantation embryos, decidual, and trophoblastic cells (Arceci, Pampfer, & Pollard, 1992; Arceci, Shanahan, Stanley, & Pollard, 1989; Pampfer, Arceci, & Pollard, 1991; Regenstreif & Rossant, 1989; Sasmono et al, 2003). In man, two separate CSF1R promoters drive expression in myeloid cells and cells of the trophoblast (Visvader & Verma, 1989).…”

Plasma citrulline level as a biomarker for cancer therapy-induced small bowel mucosal damage.

“…The control of cell-cell adhesion during cell migration, division and morphogenesis is crucial for its maintenance in health, disease and regeneration (Solanas & Batlle, 2011). The homeostasis of these remarkable stem cell driven multicellular proliferative units (Potten & Loeffler, 1987) requires the regulation of gene networks, signaling pathways, and many dynamic processes (Huynh et al, 2013;Vanuytsel et al, 2013). The mucous membrane cells of the small intestine are one of hierarchical tissues (HTs).…”