Distinct expression patterns of Notch ligands, Dll1 and Dll4, in normal and inflamed mice intestine.
Distinct expression patterns of Notch ligands, Dll1 and Dll4, in normal and inflamed mice intestine.
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作者：
Shimizu H;Okamoto R;Ito G;Fujii S;Nakata T;Suzuki K;Murano T;Mizutani T;Tsuchiya K;Nakamura T;Hozumi K;Watanabe M
有报道表明，两种Notch配体Dll 1和Dll 4对于维持肠上皮的稳态是必不可少的。然而，在肠上皮内，在蛋白质水平上表达这些配体的细胞的精确分布在很大程度上仍然未知。在这里，我们展示了一系列免疫组织化学分析，通过这些分析，我们成功地鉴定了内源性表达Dll 1或Dll 4的小鼠肠上皮细胞（IEC）。结果表明，Dll 1阳性（Dll 1 +ve）的肠上皮细胞只存在于隐窝内，而Dll 4阳性（Dll 4 +ve）的肠上皮细胞可以定位在隐窝和小肠绒毛。同样在结肠中，Dll 1 +ve IEC位于隐窝的下部，而Dll 4 +ve IEC位于隐窝的上部和下部，包括表面上皮。Dll 1 +ve和Dll 4 +ve IEC均为ATOH 1阳性细胞，而Hes 1阴性细胞，并且位于隐窝内邻近Hes 1阳性细胞。Dll 1 +ve和Dll 4 +ve IEC的亚群似乎共表达Muc 2，但很少共表达其他分泌谱系标志物。然而，与Dll 1 +ve IEC相比，Dll 4 +ve IEC包括更多数量的Muc 2阳性IEC，表明Dll 4更优先由杯状细胞表达。此外，我们发现Dll 4在小肠的潘氏细胞中表达，而Dll 1和Dll 4在结肠的c-kit阳性IEC中表达，表明Dll 1 +ve和Dll 4 +ve IEC可能有助于构成肠干细胞生态位。与正常结肠相比，DSS-结肠炎的分析显示，在发炎的结肠粘膜的伸长的隐窝中，Dll 1 +ve IEC的数量显著减少。与此形成鲜明对比的是，Dll 4 +ve IEC的数量在这些隐窝中显示出显著增加，这伴随着Hes 1阳性IEC数量的增加。这些Dll 4 +ve IEC大多与Hes 1阳性IEC相邻，表明Dll 4可能在发炎的结肠粘膜的隐窝中充当主要Notch配体。我们的研究结果说明了不同的表达模式的Dll 1和Dll 4在肠上皮细胞，并建议这两个配体可能有不同的作用，在正常和发炎的粘膜。
Reports have suggested that the two Notch ligands, Dll1 and Dll4, are indispensable to maintain the homeostasis of the intestinal epithelium. However, within the intestinal epithelium, the precise distribution of the cells that express those ligands at the protein level remains largely unknown. Here, we show a series of immunohistochemical analysis through which we successfully identified mice intestinal epithelial cells (IECs) that endogenously express Dll1 or Dll4. Results showed that Dll1-positive (Dll1+ve) IECs reside exclusively within the crypt, whereas Dll4-positive (Dll4+ve) IECs can locate both in the crypt and in the villus of the small intestine. Also in the colon, Dll1+ve IECs resided at the lower part of the crypt, whereas Dll4+ve IECs resided at both upper and lower part of the crypt, including the surface epithelium. Both Dll1+ve and Dll4+ve IECs were ATOH1-positive, but Hes1-negative cells, and located adjacent to Hes1-positive cells within the crypts. A sub-population of both Dll1+ve and Dll4+ve IECs appeared to co-express Muc2, but rarely co-expressed other secretory lineage markers. However, as compared to Dll1+ve IECs, Dll4+ve IECs included larger number of Muc2-postive IECs, suggesting that Dll4 is more preferentially expressed by goblet cells. Also, we identified that Dll4 is expressed in the Paneth cells of the small intestine, whereas Dll1 and Dll4 is expressed in the c-kit-positive IECs of the colon, indicating that Dll1+ve and Dll4+ve IECs may contribute to constitute the intestinal stem cell niche. Compared to the normal colon, analysis of DSS-colitis showed that number of Dll1+ve IECs significantly decrease in the elongated crypts of the inflamed colonic mucosa. In sharp contrast, number of Dll4+ve IECs showed a significant increase in those crypts, which was accompanied by the increase in number of Hes1-positive IECs. Those Dll4+ve IECs were mostly found adjacent to the Hes1-positive IECs, suggesting that Dll4 may act as a major Notch ligand in the crypts of the inflamed colonic mucosa. Our results illustrate distinct expression patterns of Dll1 and Dll4 within the intestinal epithelium, and suggest that these two ligands may have different roles in normal and inflamed mucosa.
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