Downregulation of Dicer1 Promotes Cellular Senescence and Decreases the Differentiation and Stem Cell-Supporting Capacities of MSCs in Patients with Myelodysplastic Syndrome

Abstract

Myelodysplastic syndrome (MDS) is characterized by decreased blood counts caused by ineffective hematopoiesis. Although the insufficient hematopoietic support capabilities of mesenchymal stromal cells (MSCs) have been reported in patients with MDS, the underlying mechanisms remain elusive. In this study, we found that MSCs from patients with MDS 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 MDS-MSCs exhibited decreased osteoblastic and adipogenic differentiation potential and decreased stem cell support capacity. Next, we found that Dicer1 expression was downregulated in MSCs from patients with lower-risk (LR)-MDS and higher-risk (HR)-MDS. Gene knockdown of Dicer1 induced senescence in the MSCs. The differentiation of MSCs into osteoblasts and adipocytes was significantly inhibited by Dicer1 knockdown (Dicer1-KD). Moreover, Dicer1-KD MSCs exhibited less vascular endothelial growth factor (VEGF) and granulocyte colony-stimulating factor (G-CSF) expression than normal MSCs. Long-term culture assays showed that layers of MSCs with the Dicer1 gene knocked down are inefficient at supporting hematopoiesis. Further, we observed that the key senescence mediators, p21,but not p16, was elevated in Dicer1-KD MSCs. We also identified reduced expression in the miR-17 family (miR-17-5p, miR-20a/b, miR-106a/b and miR-93) as a potential factor responsible for increased p21 expression in Dicer1-KD MSCs. A verification experiment showed that miR-93 and miR-20a expression levels were significantly reduced in MSCs from patients with MDS. Taken together, our study shows that MSCs from MDS patients are prone to senescence and that Dicer1downregulation promotes cellular senescence and decreases the differentiation and stem cell-supporting capacities of MSCs in MDS patients. Dicer1 downregulation seems to contribute to the insufficient hematopoietic support capacities of MSCs in patients with MDS. DisclosuresNo relevant conflicts of interest to declare.