Purinergic stimulation of human mesenchymal stem cells potentiates their chemotactic response to CXCL12, increases the homing capacity and the production of pro-inflammatory cytokines.

OBJECTIVE: Extracellular ATP is a well recognised mediator of cell-to-cell communication. Here we show ATP effects on bone marrow (BM)-derived human mesenchymal stem cell (hMSCs) functions. MATERIALS AND METHODS: ATP-induced modification of hMSCs gene expression profile was assessed by Affymetrix technology. Clonogenic and migration assays, in vitro, as well as xenotransplant experiments, in vivo, were performed to evaluate the effects of ATP on hMSCs proliferation and BM homing. ELISA assays were used to assess hMSCs cytokines production whereas T-cell cultures demonstrated the immunoregulatory activity of ATP-treated hMSCs. RESULTS: hMSCs were resistant to the cytotoxic effects of ATP, as demonstrated by the lack of morphological and mitochondrial changes or release of intracellular markers of cell death. Gene expression profiling revealed that ATP-stimulated hMSCs underwent a down-regulation of genes involved in cell proliferation, whereas those involved in cell migration were strongly up-regulated. The inhibitory activity of ATP on hMSCs proliferation was confirmed by assessing clonogenic stromal progenitors. ATP potentiated the chemotactic response of hMSCs to the chemokine CXCL12, and increased their spontaneous migration. In vivo, the homing capacity of hMSCs to the BM of immunodeficient mice was significantly increased by pre-treatment with ATP. Moreover, ATP increased the production of the pro-inflammatory cytokines IL-2, IFN-gamma, and IL-12p70, while decreasing the anti-inflammatory cytokine IL-10 and this finding was associated with the reduced ability of MSCs of inhibiting T-cell proliferation. CONCLUSIONS: Our data show that purinergic signaling modulates hMSCs functions and highlight a role for extracellular nucleotides in hMSCs biology.