ATP autocrine/paracrine signaling induces calcium oscillations and NFAT activation in human mesenchymal stem cells

Human bone marrow-derived mesenchymal stem cells (hMSCs) have the potential to differentiate into several types of cells. Calcium ions (Ca2+) play an important role in the differentiation and proliferation of hMSCs. We have demonstrated that spontaneous [Ca2+]i oscillations occur without agonist stimulation in hMSCs. However, the precise mechanism of its generation remains unclear. In this study, we investigated the mechanism and role of spontaneous [Ca2+]i oscillations in hMSCs and found that IP3-induced Ca2+ release is essential for spontaneous [Ca2+]i oscillations. We also found that an ATP autocrine/paracrine signaling pathway is involved in the oscillations. In this pathway, an ATP is secreted via a hemi-gap–junction channel; it stimulates the P2Y1 receptors, resulting in the activation of PLC-β to produce IP3. We were able to pharmacologically block this pathway, and thereby to completely halt the [Ca2+]i oscillations. Furthermore, we found that [Ca2+]i oscillations were associated with NFAT translocation into the nucleus in undifferentiated hMSCs. Once the ATP autocrine/paracrine signaling pathway was blocked, it was not possible to detect the nuclear translocation of NFAT, indicating that the activation of NFAT is closely linked to [Ca2+]i oscillations. As the hMSCs differentiated to adipocytes, the [Ca2+]i oscillations disappeared and the translocation of NFAT ceased. These results provide new insight into the molecular and physiological mechanism of [Ca2+]i oscillations in undifferentiated hMSCs.