Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Extracellular purines promote the differentiation capacity of human bone marrow-derived mesenchymal stem cells

ABSTRACT: Extracellular nucleotides are potent signaling molecules mediating cell-specific biological functions. We previously demonstrated that adenosine 5'-triphosphate (ATP) inhibits the proliferation while stimulating the migration, in vitro and in vivo, of human bone marrow-derived mesenchymal stem cells (BM-hMSC). Here, we investigated the effects of ATP on BM-hMSC differentiation capacity. Molecular analysis showed that ATP treatment modulated the expression of several genes (e.g. wnt-pathway-related genes) governing osteoblastic and adipogenic differentiation of MSCs. Functional studies demonstrated that ATP, under specific culture conditions, stimulated adipogenic and osteogenic differentiation by significantly increasing the lipid accumulation and the expression levels of the adipogenic master gene PPARγ (peroxisome proliferator activated receptor-gamma) and by promoting the mineralization and the expression of the osteoblast-related gene RUNX2 (Runt-related transcription factor 2), respectively. BM-hMSCs cells were transiently exposed to ATP 1mM for 24 hours (ATP pre-treatment) before starting differentiation induction. Then, BM-hMSCs were cultured under adipogenic/osteogenic conditions. Gene Expression Profile was performed on differentiate cells after 3 weeks of induction culture.

ORGANISM(S): Homo sapiens

SUBMITTER: Rossella Manfredini

PROVIDER: E-GEOD-37237 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Nucleotides triphosphates are extracellular messengers binding to specific plasma membrane receptors (P2Rs) that modulate responses as different as proliferation, differentiation, migration or cell death on several cell types including hematopoietic stem cells. Little and controversial information is available on the role of extracellular nucleotides in human mesenchimal stem cells (hMSCs). In this study, we assessed whether P2Rs are expressed and functional in bone marrow-derived hMSCs. Our results demonstrated, at the mRNA and protein level, the expression of all P2X and P2Y receptor subtypes identified so far. P2R activation by their natural ligands adenosine triphosphate (ATP) and uridine triphosphate (UTP) induced in hMSCs, intracellular Ca2+ concentration changes, plasma membrane depolarization and permeabilization. hMSCs were resistant to the cytotoxic effects of high dose ATP despite the expression of permeabilizing P2Rs as demonstrated by the lack of morphological changes, significant release of intracellular markers of cell death or modification of the mitochondrial network. Gene expression profiling revealed the down-regulation of cell proliferation genes whereas genes involved in cell migration and cytokine production were strongly up-regulated by ATP. Functional studies confirmed the inhibitory activity of ATP on proliferation of hMSCs and clonogenic progenitors. Moreover, ATP exerted a chemotactic effect on hMSCs and increased their migration in response to the chemokine CXCL12. Finally, whereas ATP did not affect T-cell inhibitory activity of hMSCs, the nucleotide increased the production of pro-inflammatory cytokines by hMSCs. Thus, our data show that purinergic signaling modulates hMSC functions and point to a role for extracellular nucleotides on hMSCs biology. hMSCs from 6 healthy donors were seeded at a density of 2.5 x 103 cells/cm2 for 24 hours with or without 1mM ATP. We then assessed the transcriptome profile of ATPM-bM-^@M-^Streated and untreated cells using Affymetrix HG-U133 Plus 2 GeneChip array.

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Extracellular purines promote the differentiation capacity of human bone marrow-derived mesenchymal stem cells

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