Epigenome analysis of normal and myelodysplastic sundrome (MDS) bone marrow derived mesenchymal stromal cells (MSCs)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE119617 | GEO | 2019/09/06
REPOSITORIES: GEO
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Project description:Altered bone marrow hematopoiesis and immune suppression is a hallmark of myelodysplastic syndrome (MDS). While the bone marrow microenvironment influences malignant hematopoiesis, the mechanism leading to MDS-associated immune suppression is unknown. We tested whether mesenchymal stromal cells (MSCs) contribute to this process. Here, we developed a model to study cultured MSCs from MDS patients compared to similar aged matched normal controls for regulation of immune function. MSCs from MDS patients (MDS-MSC) and healthy donor MSC (HD-MSC) exhibited a similar in vitro phenotype and neither had a direct effect on NK cell function. However, when MDS and HD-MSCs were cultured with monocytes, only the MDS-MSCs acquired phenotypic and metabolic properties of myeloid-derived suppressor cells (MDSCs), with resulting suppression of NK cell function, along with T cell proliferation. A unique MSC transcriptome was observed in MDS-MSCs compared to HD-MSCs, including increased expression of the reactive oxygen species (ROS) regulator, ENC1. High ENC1 expression in MDS-MSC induced suppressive monocytes with increased INHBA, a gene that encodes for a member of the TGF? superfamily of proteins. These monocytes also had reduced expression of the TGF? transcriptional repressor MAB21L2, further adding to their immune suppressive function. Silencing ENC1 or inhibiting ROS production in MDS-MSCs abrogated the suppressive function of MDS-MSC conditioned monocytes. In addition, silencing MAB21L2 in healthy MSC conditioned monocytes mimicked the MDS-MSC suppressive transformation of monocytes. Our data demonstrate that MDS-MSCs are responsible for inducing an immune suppressive microenvironment in MDS through an indirect mechanism involving monocytes.
2020-02-11 | GSE140101 | GEO
Project description:Genome wide DNA methylation profiling of normal and pathologic mesenchymal stromal cells (MSCs). The Illumina Infinium 850k Human DNA methylation Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpGs total DNA from in vitro-amplified MSCs. Samples included 11 normal MSCs, 11 MSCs from MDS patients, and 10 MSCs from AML patients.
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Project description:To characterize the dysregulated MSCs in the murine MDS models, we performed a single-cell RNA sequence (scRNA-seq) analysis of FACS-sorted MSCs. The proportions of subclusters comprising MSCs were discrete between controls and MDS, and Osteolineage population was reduced in MDS compared with the control. In addition, Lepr+ mesenchymal population in MDS mice exhibited the remarkable reduction of skeletal stem marker Grem1 and MSC marker genes. This transcriptome analysis suggested that the osteolineage differentiation of MSCs is suppressed in vivo in the presence of MDS cells.
2022-10-01 | GSE199665 | GEO
Project description:Ineffective hematopoiesis is a hallmark of myelodysplastic syndromes (MDS). Hematopoietic alterations in MDS patients strictly correlate with microenvironment dysfunctions, eventually affecting also the mesenchymal stromal cells (MSCs) compartment. Stromal cells are indeed epigenetically reprogrammed to cooperate with leukemic cells and propagate the disease as "tumor unit"; therefore, changes on MSCs epigenetic profile might contribute to the hematopoietic perturbations typical of MDS. Here, we unveil that the histone variant macroH2A1 (mH2A1) regulates the crosstalk between epigenetics and inflammation in MDS-MSCs, potentially affecting their hematopoietic support ability. We show that the mH2A1 splicing isoform mH2A1.1 accumulates in MDS-MSCs, correlating with the expression of the Toll-like receptor 4 (TLR4), an important pro-tumor activator of MSC phenotype associated to a pro-inflammatory behavior. MH2A1.1-TLR4 axis was further investigated in HS-5 stromal cells after ectopic mH2A1.1 overexpression (mH2A1.1-OE). Proteomic data confirmed the activation of a pro-inflammatory signature associated to TLR4 and nuclear factor kappa B (NFkB) activation. Moreover, mH2A1.1-OE proteomic profile identified several upregulated proteins associated to DNA and histones hypermethylation, including S-adenosylhomocysteine hydrolase, a strong inhibitor of DNA methyltransferase and of the methyl donor S-adenosyl-methionine (SAM). HPLC analysis confirmed higher SAM/SAH ratio along with a metabolic reprogramming. Interestingly, an increased LDHA nuclear localization was detected both in mH2A1.1-OE cells and MDS-MSCs, probably depending on MSC inflammatory phenotype. Finally, coculturing healthy mH2A1-OE MSCs with CD34+ cells, we found a significant reduction in the number of CD34+ cells, which was reflected in a decreased number of colony forming units (CFU -Cs). These results suggest a key role of mH2A1.1 in driving the crosstalk between epigenetic signaling, inflammation and cell metabolism networks in MDS-MSCs.
2024-01-26 | PXD039866 | Pride
Project description:RNA-seq analysis of HD and MDS MSCs and MSC-conditioned monocytes
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Project description:Mesenchymal stromal cells (MSC) are crucial components of the bone marrow (BM) microenvironment essential for regulating self-renewal, survival and differentiation of hematopoietic stem/progenitor cells (HSPC) in the stem cell niche. MSC are functionally and phenotypically altered in myelodysplastic syndromes (MDS), contributing to disease progression. MDS MSC do not harbor recurrent genetic alterations but have been shown to exhibit an altered methylome compared to MSC from healthy controls. We examined growth, differentiation and HSPC-supporting capacity of ex vivo expanded MSC from MDS patients in comparison to age-matched healthy controls after direct treatment in vitro with the hypomethylating agent azacitidine (AZA). We show that AZA exerts a direct effect on MSC by modulating their differentiation potential. Osteogenesis was significantly boosted in healthy MSC while adipogenesis was inhibited in both healthy and MDS MSC. In co-culture experiments, both AZA treated MDS MSC and healthy MSC exhibited enhanced support of non-clonal HSPC which was associated with increased cell cycle induction. Conversely, clonal MDS HSPC were inhibited by contact with AZA treated MSC. RNA-sequencing analyses of stromal cells revealed changes in pathways essential for HSPC support as well as in immune regulatory pathways. In sum, our data demonstrate that AZA treatment of stromal cells leads to upregulation of HSPC-supportive genes and cell cycle induction in co-cultured healthy HSPC, resulting in a proliferative advantage over clonal HSPC. Thus, restoration of functional hematopoiesis by AZA may be driven by activated stromal support factors in MSC providing cell cycle cues to healthy HSPC.
2018-12-19 | GSE112461 | GEO
Project description:Epigenome analysis of normal and myelodysplastic sundrome (MDS) bone marrow derived mesenchymal stromal cells (MSCs)
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Project description:To identify the mechanism by which miRNAs in EVs derived from MDS cells suppressed the osteolineage differentiation of MSCs and disrupted normal hematopoiesis, we comprehensively explored the miRNAs encapsulated in EVs by miRNA-array. Consistent with the heterogeneous nature of MDS, the hypoplastic Abcg2-MDS/AML model and the hyperplastic NHD13Tg model share few elevated miRNAs. However, it is noteworthy that the pathways targeted by each upregulated miRNA are mutually shared, such as the pathways associated with MSC differentiation and survival, including axon guidance and MAPK signaling. These results suggest that miRNAs play an essential role in the MSC impairment observed in MDS.
2022-10-01 | GSE199997 | GEO
Project description:Myelodysplastic syndrome (MDS) is a group of heterogeneous clonal stem cell disorders. We hypothesize that gene expression changes in the bone marrow (BM) microenvironment might play a fundamental role in the development and progression of MDS. The goal of the present study is to investigate the differences in gene expression profiles of BM mesenchymal stromal cells (MSCs) between MDS patients and normal individuals, as well as between MDS subtypes. To this end, we applied global gene expression profiling on BM MSCs from adult de novo MDS patients and from controls. The results suggest that gene expression of the MDS BM microenvironment is difference from control BM. In particular, interferon signaling pathway was shown to be up-regulated in MDS BM. The results also showed altered expression according to disease progression. The present study provides evidence supporting MDS as an immune disease and suggests that BM MSCs are a possible therapeutic target in MDS.
2015-03-25 | GSE61853 | GEO
Project description:Myelodysplastic syndromes (MDS) are a group of clonal disorders of hematopoietic stem cells. Mesenchymal stem cells (MSC) are the progenitors of the Bone Marrow (BM) stroma and have been involved in the physiopathology of MDS. The presence of cytogenetic aberrations on MSC from MDS patients is controversial. The aim of the study is to characterize BM derived MSC from patients with MDS using: kinetic studies, immunophenotyping, fluorescent in situ hybridisation (FISH) analysis and genetic changes by array based comparative genomic hybridization (array-CGH). 32 cases of untreated MDS were included in the study. MSC from MDS achieved confluence at a slower rate than donor-MSC, and the antigenic expression of CD105 and CD104 was also lower. Array-CGH studies showed DNA genomic changes that were proved not to be somatic, and gains were more frequent than looses. The results of array-CGH were confirmed by FISH. When an unsupervised hierarchical cluster analysis was performed two clusters were identified: one of them included the 5q- syndrome patients, while the other incorporated the rest of the MDS patients. Our results shows, for the first time, that MSC from MDS display genomic aberrations, assessed by array-CGH and FISH, some of them specially linked to particular MDS subtypes. Keywords: Genomic comparison between mesenchymal cells
2008-08-01 | GSE10822 | GEO