Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors
Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors
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DOI：
10.1073/pnas.0707210104
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发表时间：
2007-09-25
影响因子：
11.1
通讯作者：
Chen, Xin
中科院分区：
文献类型：
--
作者：
Kosinski, Cynthia;Li, Vivian S. W.;Chen, Xin
人类结肠上皮细胞的更新、增殖和分化受到多种调控途径的严格控制。为了确定人类结肠上皮细胞在体内分化的遗传程序以及定义结肠上皮干/祖细胞和干细胞生态位的候选标记基因，我们通过使用具有30，000个基因的表达微阵列对正常人类结肠顶部和基底隐窝进行基因表达分析。发现969个cDNA克隆在人类结肠隐窝和顶部之间差异表达。通路分析揭示了参与细胞周期维持和凋亡的基因的差异表达，以及骨形态发生蛋白（BMP）、Notch、Wnt、EPH和MYC信号通路中的基因。发现BIMP拮抗剂gremlin 1、gremlin 2和chordin样1由结肠隐窝表达。原位杂交和RT-PCR证实，这些BMP拮抗剂表达的肠隐窝肌成纤维细胞和平滑肌细胞在结肠隐窝。体外分析表明，gremlin 1部分抑制Caco-2细胞的分化融合和激活Writ信号在正常大鼠肠上皮细胞。总的来说，表达数据集提供了人结肠上皮细胞分化的全面情况。我们的研究还表明，BMP拮抗剂是组成肠上皮干细胞小生境的候选信号成分。
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. BIMP 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 Writ 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.