Cynthia Kosinski1, Vivian Li2, Annie S Y Chan2, Ji Zhang3,4, Coral Ho3, US Khoo2, Tsun Leung Chan2, Randy C. Mifflin5, Don W. Powell5, Siu Tsan Yuen2, Suet Yi Leung2, Xin Chen3
1Department of Biopharmaceutical Sciences, University of California, San Francisco, CA 94143, USA
2Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
3*Department of Biopharmaceutical Sciences, University of California, San Francisco, CA 94143;
4Department of Surgery, Beijing Cancer Hospital, Beijing 100036, China; and
5Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555-0144
Tóm tắt
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.
