Down-regulation of Dicer1 promotes cellular senescence and decreases the differentiation and stem cell-supporting capacities of mesenchymal stromal cells in patients with myelodysplastic syndrome
Down-regulation of Dicer1 promotes cellular senescence and decreases the differentiation and stem cell-supporting capacities of mesenchymal stromal cells in patients with myelodysplastic syndrome
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Dicer1的下调促进骨髓增生异常综合征患者的细胞衰老并降低间充质基质细胞的分化和干细胞支持能力
DOI：
10.3324/haematol.2014.109769
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发表时间：
2015-02-01
期刊：
影响因子：
10.1
通讯作者：
Chang, Chunkang
中科院分区：
文献类型：
--
作者：
Zhao, Youshan;Wu, Dong;Chang, Chunkang
尽管已有研究表明骨髓间充质干细胞不能为骨髓增生异常综合征提供足够的造血支持，但其机制尚不清楚。在这项研究中，我们发现骨髓增生异常综合征患者的间充质基质细胞显示出明显的衰老增加，表现为增殖能力降低，形态扁平化以及SA-β-gal和p21表达增加。来自患者的衰老间充质基质细胞分化潜能降低，干细胞支持能力降低。Dicer 1基因敲除可诱导衰老，Dicer 1在患者间充质基质细胞中表达下调。Dicer 1基因敲低可显著抑制分化和干细胞支持能力。Dicer 1在患者间充质基质细胞中的过表达逆转了细胞衰老并增强了干细胞特性。此外，我们确定microRNA-17家族（miR-17- 5 p、miR-20 a/B、miR-106 a/B和miR-93）的表达减少是导致Dicer 1敲低细胞中p21表达增加的潜在因素，p21是一种关键的衰老介质。此外，我们发现miR-93和miR-20 a的表达水平在患者的间充质基质细胞中显著降低，并且miR-93/miR-20 a功能的获得导致细胞衰老的减少。总的来说，我们的研究结果表明，骨髓增生异常综合征患者的间充质基质细胞容易衰老，Dicer 1下调促进细胞衰老，降低间充质基质细胞的分化和干细胞支持能力。Dicer 1下调似乎导致骨髓增生异常综合征患者间充质基质细胞造血支持能力不足。
Although it has been reported that mesenchymal stromal cells are unable to provide sufficient hematopoietic support in myelodysplastic syndrome, the underlying mechanisms remain elusive. In this study, we found that mesenchymal stromal cells from patients with myelodysplastic syndrome displayed a significant increase in senescence, as evidenced by their decreased proliferative capacity, flattened morphology and increased expression of SA-β-gal and p21. Senescent mesenchymal stromal cells from patients had decreased differentiation potential and decreased stem cell support capacity. Gene knockdown of Dicer1, which was down-regulated in mesenchymal stromal cells from patients, induced senescence. The differentiation and stem cell-supporting capacities were significantly inhibited by Dicer1 knockdown. Overexpression of Dicer1 in mesenchymal stromal cells from patients reversed cellular senescence and enhanced stem cell properties. Furthermore, we identified reduced expression in the microRNA-17 family (miR-17-5p, miR-20a/b, miR-106a/b and miR-93) as a potential factor responsible for increased p21 expression, a key senescence mediator, in Dicer1 knockdown cells. Moreover, we found that miR-93 and miR-20a expression levels were significantly reduced in mesenchymal stromal cells from patients and miR-93/miR-20a gain of function resulted in a decrease of cellular senescence. Collectively, the results of our study show that mesenchymal stromal cells from patients with myelodysplastic syndrome are prone to senescence and that Dicer1 down-regulation promotes cellular senescence and decreases the differentiation and stem cell-supporting capacities of mesenchymal stromal cells. Dicer1 down-regulation seems to contribute to the insufficient hematopoietic support capacities of mesenchymal stromal cells from patients with myelodysplastic syndrome.