Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors

Abstract

Human colonic epithelial cell renewal, proliferation, and differentiation are stringently controlled by numerous regulatory pathways. To identify genetic programs of human colonic epithelial cell differentiation in vivo as well as candidate marker genes that define colonic epithelial stem/progenitor cells and the stem cell niche, we applied gene expression analysis of normal human colon tops and basal crypts by using expression microarrays with 30,000 genes. Nine hundred and sixty-nine cDNA clones were found to be differentially expressed between human colon crypts and tops. Pathway analysis revealed the differential expression of genes involved in cell cycle maintenance and apoptosis, as well as genes in bone morphogenetic protein (BMP), Notch, Wnt, EPH, and MYC signaling pathways. BMP antagonists gremlin 1, gremlin 2, and chordin-like 1 were found to be expressed by colon crypts. In situ hybridization and RT-PCR confirmed that these BMP antagonists are expressed by intestinal cryptal myofibroblasts and smooth muscle cells at the colon crypt. In vitro analysis demonstrated that gremlin 1 partially inhibits Caco-2 cell differentiation upon confluence and activates Wnt signaling in normal rat intestinal epithelial cells. Collectively, the expression data set provides a comprehensive picture of human colonic epithelial cell differentiation. Our study also suggests that BMP antagonists are candidate signaling components that make up the intestinal epithelial stem cell niche.gremlin ͉ expression profiling ͉ microarray ͉ crypt maturation program ͉ myofibroblast

Eph receptor and ephrin function in breast, gut, and skin epithelia

“…88,89 Human intestinal epithelia contain mRNA transcripts for the majority of Eph receptor and ephrin family members and a few of these have been directly implicated in intestinal epithelial homeostasis. 90,91 The general expression pattern of Eph receptors and ephrins is relatively similar in the mucosal epithelium of the small and large intestines. 90 In particular, EphB2 and EphB3 expression is concentrated in the cells that populate the crypt nadirs and decreases toward the top of the villi.…”

Tumour–stroma interactions in colorectal cancer: converging on β-catenin activation and cancer stemness

“…Moving upwards along the crypt-to-villus axis, terminal differentiation coincides with the more restricted membrane-bound b-catenin localisation and its absence in the nucleus and cytosol (Figure 1). Recently, it has been reported that the BMP antagonists, gremlin 1, gremlin 2, and chrodin-like 1, are selectively expressed by crypt-based myofibroblasts and smooth muscle cells (Kosinski et al, 2007). Moreover, Gremlin 1 was shown to activate Wnt/b-catenin signalling in normal rat intestinal epithelial cells, thus indicating that stromal-derived factors regulate Wnt/b-catenin-signalling activity in the intestinal stem cell niche.…”

Loss of EphA2 receptor tyrosine kinase reduces Apcmin/+ tumorigenesis

“…44 EphA2 and its ligand Ephrin A1 (previously referred to as B61 and the primary endogenous ligand for EphA2) also have been reported to act in an autocrine loop to regulate intestinal cell migration and barrier function. 45,46 In intestinal neoplasia, EphA2 has been reported to be up-regulated in human colorectal cancers, and EPHA2 overexpression correlates with colon cancer metastasis and high microvessel count in primary human colorectal cancers.…”