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Expression profiling in exosomal miRNAs of human bone marrow stromal cells derived from myelodysplastic syndrome patients

ABSTRACT: Myelodysplastic syndromes (MDS) constitute a heterogeneous group of clonal hematological disorders characterized by the presence of peripheral cytopenias and an increased risk of transformation into acute myeloblastic leukemia (AML). These hematological disorders are complex and their origin in a clonal hematopoietic stem cell disorder is accepted. In the last few years, the importance of the bone marrow (BM) microenvironment has been highlighted. Bone marrow stromal cells (BMSCs) are a non-hematopoietic BM cell population considered to be the osteoblastic progenitors and a key component of the hematopoietic microenvironment. As usual, it was considered that intercellular communication could be achieved by direct cell-to-cell contact or the exchange of soluble factors and intercellular adhesion molecule. Recently, a new mechanism of intercellular communication based on the secretion of extracellular esicles (EVs) has been described. Such a mechanism modifies the functional properties of recipient cells by the transfer of bioactive molecules such as mRNA, proteins and micro-RNAs, among others. BMSCs play an important role in bone marrow environment. Recent evidences suggest that EVs act as a mediator of cell-cell interaction in hematologic neoplasms. To clarify the possible association between the cargo of BMSC-EVs and disease severity, we performed miRNA profiling in BMSC-EVs derived from MDS patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE133276 | GEO | 2019/06/26

REPOSITORIES: GEO

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Project description:Dyskeratosis congenita (DC) is an inherited multi-system disorder, characterized by oral leukoplakia, nail dystrophy, and abnormal skin pigmentation, as well as high rates of bone marrow failure, solid tumors, and other medical problems such as osteopenia. DC and telomere biology disorders (collectively referred to as TBD here) are caused by germline mutations in telomere biology genes leading to very short telomeres and limited proliferative potential of hematopoietic stem cells. We found that skeletal stem cells (SSCs) within the bone marrow stromal cell population (BMSCs, also known as bone marrow-derived mesenchymal stem cells), may contribute to the hematological phenotype. TBD-BMSCs exhibited reduced clonogenicity, reduced telomerase activity, spontaneous differentiation into adipocytes and fibrotic cells, and increased senescence in vitro. Upon in vivo transplantation into mice, TBD-BMSCs failed to form bone or support hematopoiesis, unlike normal BMSCs. TERC reduction (a TBD-associated gene) in normal BMSCs by siTERC-RNA recapitulated the TBD-BMSC phenotype by reducing proliferation and secondary colony forming efficiency, and by accelerating senescence in vitro. Microarray profiles of control and siTERC-BMSCs showed decreased hematopoietic factors at the mRNA level, and decreased secretion of factors at the protein level. These findings are consistent with defects in SSCs/BMSCs contributing to bone marrow failure in TBD. RNA (5 mg) isolated from N-BMSCs, siNC-BMSCs and siTERC-BMSCs 72hrs after transfection using an RNeasy Mini kit (Qiagen), was reverse transcribed and hybridized to an Affymetrix GeneChip Human Genome U133 Plus 2.0 array (LMT, NCI-Frederick). Three independent replicates for each experimental condition were carried out to control for intra-sample variation. Genes that were under/over-represented by >2-fold were analyzed using GeneSpring software. Signal intensity values were normalized using RMA (Robust Multi-array Analysis) summarization and baseline transformation to median of all samples was performed. Entities were filtered based on their signal intensity values. Hierarchical clustering was performed on filtered signal intensity (>20.0), non-averaged, fold change >2. A fold change analysis (>10-fold) was performed to generate a list of top genes under/over represented between the groups.

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Expression profiling in exosomal miRNAs of human bone marrow stromal cells derived from myelodysplastic syndrome patients

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