Wnt Signaling Mediates the Aging-Induced Differentiation Impairment of Intestinal Stem Cells
Wnt Signaling Mediates the Aging-Induced Differentiation Impairment of Intestinal Stem Cells
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Wnt 信号介导衰老诱导的肠干细胞分化损伤
DOI：
10.1007/s12015-019-09880-9
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发表时间：
2019-06-01
影响因子：
4.8
通讯作者：
Tao, Si
中科院分区：
文献类型：
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作者：
Cui, Hui;Tang, Duozhuang;Tao, Si
干细胞老化是衰老相关疾病的基础，如肿瘤发病率急剧增加和应激时再生能力受损。然而，肠道干细胞是否以及如何衰老在很大程度上仍然未知。本研究表明，来自24月龄小鼠的肠道干细胞很难形成具有隐窝绒毛结构的典型类器官，而主要形成没有分化细胞类型的大而圆的囊肿，这模仿了apc -小鼠系的杂合apc缺陷细胞的培养。进一步分析表明，老年小鼠培养的隐窝分化基因表达水平降低，Wnt靶基因表达水平升高。降低培养系统中R-spondin-1的浓度可显著减少圆形囊肿的形成，并伴有来自老年小鼠的隐窝类器官的形成增加。我们是第一个发现来自老年小鼠的肠道干细胞具有显著的分化缺陷，可以通过减少R-spondin-1暴露来部分挽救。这可能与肠道肿瘤的发展和在老年人群中观察到的再生潜力降低高度相关。我们的研究首次提供了实验证据，证明衰老肠道干细胞对Wnt/ β -catenin信号的过度反应介导了衰老诱导的分化缺陷，并可能作为改善衰老相关肠道病变的潜在靶点。
Stem cell aging underlies aging-associated disorders, such as steeply increased incidences of tumors and impaired regeneration capacity upon stress. However, whether and how the intestinal stem cells age remains largely unknown. Here we show that intestinal stem cells derived from 24-month-old mice hardly form typical organoids with crypt-villus structures, but rather mainly form big, rounded cysts devoid of differentiated cell types, which mimics the culturing of heterozygous APC-deficient cells from theAPCminmouse line. Further analysis showed that cultured crypts derived from aged mice exhibited reduced expression levels of differentiation genes and higher expression of Wnt target genes. Lowering the concentration of R-spondin-1 in the culture system significantly reduced formation of rounded cysts, accompanied by an increased formation of organoids from crypts derived from old mice. We are the first to uncover that intestinal stem cells derived from old mice harbor significant deficiency in differentiation that can be partially rescued through a reduction in R-spondin-1 exposure. This could be highly relevant to intestinal tumor development and the reduced regeneration potential observed in the aged population. Our study provides the first experimental evidence that an over-responsiveness to Wnt/beta-catenin signaling of aged intestinal stem cells mediates the aging-induced deficiency in differentiation, and could serve as a potential target to ameliorate aging-associated intestinal pathologies.