Dicer1的下调会促进细胞衰老，并降低骨髓增生异常综合征患者间充质基质细胞的分化能力和干细胞支持能力。
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.
作者信息
Zhao Youshan, Wu Dong, Fei Chengming, Guo Juan, Gu Shuncheng, Zhu Yang, Xu Feng, Zhang Zheng, Wu Lingyun, Li Xiao, Chang Chunkang
机构信息
Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
出版信息
Haematologica. 2015 Feb;100(2):194-204. doi: 10.3324/haematol.2014.109769. Epub 2014 Oct 31.
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.
尽管有报道称间充质基质细胞在骨髓增生异常综合征中无法提供足够的造血支持，但其潜在机制仍不清楚。在本研究中，我们发现骨髓增生异常综合征患者的间充质基质细胞衰老显著增加，其增殖能力下降、形态扁平以及衰老相关β-半乳糖苷酶（SA-β-gal）和p21表达增加均证明了这一点。患者来源的衰老间充质基质细胞分化潜能降低，干细胞支持能力下降。Dicer1在患者的间充质基质细胞中表达下调，对其进行基因敲低可诱导衰老。Dicer1敲低显著抑制了分化和干细胞支持能力。在患者的间充质基质细胞中过表达Dicer1可逆转细胞衰老并增强干细胞特性。此外，我们发现微小RNA-17家族（miR-17-5p、miR-20a/b、miR-106a/b和miR-93）表达降低是导致Dicer1敲低细胞中关键衰老介质p21表达增加的潜在因素。此外，我们发现患者的间充质基质细胞中miR-93和miR-20a表达水平显著降低，miR-93/miR-20a功能获得导致细胞衰老减少。总体而言，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易于衰老，Dicer1下调促进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。Dicer1下调似乎导致了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。
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