Mesenchymal stem cells stimulate intestinal stem cells to repair radiation-induced intestinal injury.
Mesenchymal stem cells stimulate intestinal stem cells to repair radiation-induced intestinal injury.
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间充质干细胞刺激肠道干细胞修复辐射引起的肠道损伤。
DOI：
10.1038/cddis.2016.276
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发表时间：
2016-09-29
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
位于肠隐窝底部的干细胞丢失在放射性肠损伤中起着关键作用。特别是，Lgr5+肠道干细胞(ISCs)对于辐射后的肠道再生是不可或缺的。在辐射损伤的小鼠模型中，间充质干细胞(MSCs)已经被证明可以改善肠上皮修复，因此，假设这种保护作用与Lgr5+ISCs有关。在本研究中，研究发现，在接受辐射后，移植MSCs可以提高小鼠的存活率，改善肠道损伤，并增加再生隐窝的数量。此外，经MSCs处理后，Lgr5+ISCs及其子代细胞显著增加，包括Ki67+瞬时扩增细胞、Vil1+肠上皮细胞和溶菌酶+Paneth细胞。与PBS组相比，经MSCs处理的小鼠的隐窝形成了更多数量和更大的肠样体。骨髓间充质干细胞移植还可减少照射后6h小肠内的凋亡细胞数。有趣的是，骨髓间充质干细胞处理的小鼠的小肠中WNT3a和活性β-连环素蛋白水平增加。此外，辐射后静脉注射重组小鼠WNT3a减少了小肠的损伤，并具有放射防护作用，尽管程度不如MSC治疗。我们的结果表明，MSCs支持内源性Lgr5+ISCs的生长，从而促进辐射后小肠的修复。这种作用的分子机制被发现与Wnt/β-连环蛋白信号通路的激活有关。
The loss of stem cells residing in the base of the intestinal crypt has a key role in radiation-induced intestinal injury. In particular, Lgr5+ intestinal stem cells (ISCs) are indispensable for intestinal regeneration following exposure to radiation. Mesenchymal stem cells (MSCs) have previously been shown to improve intestinal epithelial repair in a mouse model of radiation injury, and, therefore, it was hypothesized that this protective effect is related to Lgr5+ ISCs. In this study, it was found that, following exposure to radiation, transplantation of MSCs improved the survival of the mice, ameliorated intestinal injury and increased the number of regenerating crypts. Furthermore, there was a significant increase in Lgr5+ ISCs and their daughter cells, including Ki67+ transient amplifying cells, Vil1+ enterocytes and lysozyme+ Paneth cells, in response to treatment with MSCs. Crypts isolated from mice treated with MSCs formed a higher number of and larger enteroids than those from the PBS group. MSC transplantation also reduced the number of apoptotic cells within the small intestine at 6 h post-radiation. Interestingly, Wnt3a and active β-catenin protein levels were increased in the small intestines of MSC-treated mice. In addition, intravenous delivery of recombinant mouse Wnt3a after radiation reduced damage in the small intestine and was radioprotective, although not to the same degree as MSC treatment. Our results show that MSCs support the growth of endogenous Lgr5+ ISCs, thus promoting repair of the small intestine following exposure to radiation. The molecular mechanism of action mediating this was found to be related to increased activation of the Wnt/β-catenin signaling pathway.
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