Abstract
Mesenchymal Stromal Cells (MSC) are multipotent cells characterized by self-renewal, multilineage differentiation, and immunomodulatory properties. To obtain a gene regulatory profile of human MSCs, we generated a compendium of more than two hundred cell samples with genome-wide expression data, including a homogeneous set of 93 samples of five related primary cell types: bone marrow mesenchymal stem cells (BM-MSC), hematopoietic stem cells (HSC), lymphocytes (LYM), fibroblasts (FIB), and osteoblasts (OSTB). All these samples were integrated to generate a regulatory gene network using the algorithm ARACNe (Algorithm for the Reconstruction of Accurate Cellular Networks; based on mutual information), that finds regulons (groups of target genes regulated by transcription factors) and regulators (i.e., transcription factors, TFs). Furtherly, the algorithm VIPER (Algorithm for Virtual Inference of Protein-activity by Enriched Regulon analysis) was used to inference protein activity and to identify the most significant TF regulators, which control the expression profile of the studied cells. Applying these algorithms, a footprint of candidate master regulators of BM-MSCs was defined, including the genes EPAS1, NFE2L1, SNAI2, STAB2, TEAD1, and TULP3, that presented consistent upregulation and hypomethylation in BM-MSCs. These TFs regulate the activation of the genes in the bone marrow MSC lineage and are involved in development, morphogenesis, cell differentiation, regulation of cell adhesion, and cell structure.
Highlights
Mesenchymal Stromal Cells (MSCs) are multipotent cells located in the stroma of multiple human tissues
To gain insight into the transcriptomic characterization of MSCs, genome-wide expression profiles were generated for these mesenchymal cells isolated from bone marrow and several related human primary cells: hematopoietic stem cells (HSCs) and lymphocytes (LYMs) as cells of the hematopoietic lineage; fibroblasts (FIBs) as cells of the stromal lineage; primary osteoblasts isolated from bone (OSTBs); several cell types derived by differentiation from MSCs; and MSCs stimulated with TGFβ
The list of the 188 genes selected is provided in Supplementary Table S3, that includes the statistical parameters corresponding to the differential expression analysis of MSCs versus HSCs
Summary
Mesenchymal Stromal Cells (MSCs) are multipotent cells located in the stroma of multiple human tissues They are present in the bone marrow (BM) hematopoietic niche, coexisting and regulating the maintenance of hematopoietic stem cells (HSCs). This BM niche includes osteolineage cells (i.e., osteoblasts and osteoclasts), perivascular cells, endothelial cells, adipocytes, and macrophages. FIBs share immunomodulatory proprieties with MSCs, such as the modulation of macrophages and the suppression of T cell proliferation [3] Despite these similarities in phenotype, their transcriptomic signatures show significant differences between them, associating FIBs with a clear enrichment in genes related to the organization and function of the extracellular matrix and BM-MSCs in bone development tasks [4]
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