Phenotype of mesenchymal stem cells from patients with myelodyplastic syndrome maybe partly modulated by decitabine

Abstract

Mesenchymal stem cells (MSCs) derived from myelodysplastic syndromes (MDSs) have been demonstrated to accelerate the progression of MDS. However, whether the phenotype of MSCs derived from MDS (MDS-MSCs) may be reversed and serve as a potential target for the treatment of MDS remains unclear. The present study investigated the functional alternations of MDS-MSCs following in vitro decitabine-treatment. Primary MSCs were cultured from the bone marrow aspirates of 28 patients with MDS. The impact on the growth of MDS-MSCs treated with decitabine was analyzed using the MTT assay. Changes in the gene expression levels of runt related transcription factor 2 (RUNX2), Sp7 transcription factor (SP7), cyclin dependent kinase inhibitor 1A (CDKN1A) and CD274 in MDS-MSCs following treatment with decitabine were analyzed by reverse transcription-quantitative polymerase chain reaction. The effects of decitabine on apoptosis and the cell cycle were examined using flow cytometry. The effect of decitabine on the immune regulation of MDS-MSCs was tested by the co-culture of MSCs with activated T cells in vitro. The results revealed that proliferation, apoptosis and the mRNA expression levels of RUNX2 and SP7 in MDS-MSCs did not significantly change following treatment with decitabine compared with control MDS-MSCs. However, treatment with decitabine resulted in a smaller population of cells in the G1 phase and an increase in the number of cells in the G2/M phase compared with control MDS-MSCs. This change was associated with decreased expression of CDKN1A in cells treated with decitabine compared with control cells. Notably, the ability of MDS-MSCs treated with decitabine to induce the differentiation of T cells into regulatory T cells was significantly reduced compared with control MDS-MSCs. This was associated with a decreased expression of CD274 in MDS-MSCs treated with decitabine compared with control MDS-MSCs. In conclusion, the phenotype of MSCs derived from patients with MDS was partially reversed by treatment with decitabine, presenting a potential therapeutic intervention.

Small Molecule Treatments Improve Differentiation Potential of Human Amniotic Fluid Stem Cells

“…When cells were treated with small molecules individually, stable or upregulated cell viability was observed. Many papers report tendencies that agree with our results with decitabine ( Pang et al, 2019 ), TSA ( Han et al, 2013 ), NaBut ( Panta et al, 2019 ), RA ( Pourjafar et al, 2017 ), vitC ( Markmee et al, 2019 ). Decitabine is a well-known hypomethylating agent which incorporates itself into host DNA, but is used as a drug to treat myelodisplastic syndrome and acute myeloid leukemia.…”

Targeting the Microenvironment in MDS: The Final Frontier

“…Finally, treatment with decitabine ex vivo can reset the immunosuppressive phenotype of MDS-MSCs, resulting in decreased expression of PDL1 and optimization of the immune milieu in the BM of patients with MDS (Pang et al, 2019). To this end, decitabine decreases T cell differentiation towards Tregs, a population known to be expanded in high risk MDS (Kordasti et al, 2007;Zhao et al, 2012).…”

The mesenchymal compartment in myelodysplastic syndrome: Its role in the pathogenesis of the disorder and its therapeutic targeting

“…Incubation of culture expanded BM-MSCs from MDS patients in the presence of Decitabine resulted in a significant decrease in the proportion of cells in the G0/G1 phases as compared to MDS-derived BM-MSCs incubated in the absence of the drug (control group). This effect was associated with a reduced gene expression of cyclin dependent kinase inhibitor 1A (CDKN1A) ( 74 ). Moreover the ability of BM-MSCs from MDS patients incubated in the presence of decitabine to induce the differentiation of T cells into Tregs was significantly reduced compared with control BM-MSCs and this was linked to decreased gene expression of programmed death-ligand 1 ( PDL1 ) ( 74 ).…”

“…This effect was associated with a reduced gene expression of cyclin dependent kinase inhibitor 1A (CDKN1A) (74). Moreover the ability of BM-MSCs from MDS patients incubated in the presence of decitabine to induce the differentiation of T cells into Tregs was significantly reduced compared with control BM-MSCs and this was linked to decreased gene expression of programmed death-ligand 1 (PDL1) (74). Taken together these findings suggest that decitabine may improve, at least to a certain extent, the impaired properties of MDS-derived BM-MSCs Lenalidomide is an immunomodulatory agent showing efficacy in lower risk MDS (80,81).…”