Martinez J Andres, Williams Christopher S, Amann Joseph M, Ellis Tiffany C, Moreno-Miralles Isabel, Washington M Kay, Gregoli Paul, Hiebert Scott W
Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Gastroenterology. 2006 Aug;131(2):579-88. doi: 10.1053/j.gastro.2006.06.009.
BACKGROUND & AIMS: The disruption of homeostasis between proliferation and apoptosis in the colonic epithelium contributes to the pathogenesis of human ulcerative colitis. Mice lacking the transcriptional corepressor myeloid translocation gene related-1 (Mtgr1) display impaired secretory cell lineage development in the small intestine and an increase in proliferation in the crypts of both the small and large intestines. Despite the increase in proliferating cells, the colons of Mtgr1-null mice have a normal cell lineage distribution and normal architecture. To uncover colonic phenotypes in Mtgr1(-/-) mice, we stressed the colonic epithelium with low-molecular-weight dextran sodium sulfate (DSS), which is a well-studied model of murine ulcerative colitis.
Mtgr1-null mice were given 3% DSS in their drinking water for 4 days and the colons examined at various times thereafter for ulceration and for changes in proliferation and apoptosis.
Treatment with DSS resulted in severe colitis in Mtgr1(-/-) mice, at least partially due to increased epithelial apoptosis rates. Transplantation of wild-type and Mtgr1-null bone marrow into irradiated wild-type mice demonstrated that the severe DSS-induced ulceration seen in Mtgr1-null mice was due to a colonic, rather than a hematologic, defect. Importantly, the epithelium of DSS-treated Mtgr1-null mice failed to completely regenerate, showing changes consistent with chronic colitis, even 10 weeks after a single DSS treatment.
These findings suggest that Mtgr1 has an important role in crypt survival and regeneration after colonic epithelial ulceration.
结肠上皮细胞增殖与凋亡之间的稳态失衡是人类溃疡性结肠炎发病机制的一部分。缺乏转录共抑制因子髓系易位基因相关-1（Mtgr1）的小鼠在小肠中分泌细胞谱系发育受损，在小肠和大肠隐窝中的增殖增加。尽管增殖细胞增多，但Mtgr1基因敲除小鼠的结肠具有正常的细胞谱系分布和正常结构。为了揭示Mtgr1基因敲除小鼠的结肠表型，我们用低分子量葡聚糖硫酸钠（DSS）刺激结肠上皮，DSS是一种经过充分研究的小鼠溃疡性结肠炎模型。
给Mtgr1基因敲除小鼠饮用含3% DSS的水4天，此后在不同时间检查结肠的溃疡情况以及增殖和凋亡的变化。
用DSS处理导致Mtgr1基因敲除小鼠发生严重结肠炎，至少部分原因是上皮细胞凋亡率增加。将野生型和Mtgr1基因敲除小鼠的骨髓移植到经照射的野生型小鼠体内，结果表明，Mtgr1基因敲除小鼠中所见的严重DSS诱导的溃疡是由于结肠缺陷，而非血液学缺陷。重要的是，即使在单次DSS处理10周后，经DSS处理的Mtgr1基因敲除小鼠的上皮也未能完全再生，表现出与慢性结肠炎一致的变化。
这些发现表明，Mtgr1在结肠上皮溃疡后的隐窝存活和再生中起重要作用。
