title: 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.
abstract: 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.
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Youshan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Chengming
authors.initials: C
authors.lastname: Fei
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Shuncheng
authors.initials: S
authors.lastname: Gu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China changchunkang7010@aliyun.com.
authors.forename: Chunkang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D015153:Blotting, Western; D016022:Case-Control Studies; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D005260:Female; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: D012333:RNA, Messenger