Kawano Seiko, Otsu Keishi, Kuruma Akinori, Shoji Satoshi, Yanagida Eri, Muto Yuko, Yoshikawa Fumio, Hirayama Yoshiyuki, Mikoshiba Katsuhiko, Furuichi Teiichi
Department of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Japan.
Cell Calcium. 2006 Apr;39(4):313-24. doi: 10.1016/j.ceca.2005.11.008. Epub 2006 Jan 30.
Human bone marrow-derived mesenchymal stem cells (hMSCs) have the potential to differentiate into several types of cells. Calcium ions (Ca(2+)) play an important role in the differentiation and proliferation of hMSCs. We have demonstrated that spontaneous Ca(2+) 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 Ca(2+) oscillations in hMSCs and found that IP(3)-induced Ca(2+) release is essential for spontaneous Ca(2+) 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 P(2)Y(1) receptors, resulting in the activation of PLC-beta to produce IP(3). We were able to pharmacologically block this pathway, and thereby to completely halt the Ca(2+) oscillations. Furthermore, we found that Ca(2+) 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 Ca(2+) oscillations. As the hMSCs differentiated to adipocytes, the Ca(2+) oscillations disappeared and the translocation of NFAT ceased. These results provide new insight into the molecular and physiological mechanism of Ca(2+) oscillations in undifferentiated hMSCs.
人骨髓间充质干细胞（hMSCs）具有分化为多种细胞类型的潜力。钙离子（Ca(2+)）在hMSCs的分化和增殖中起重要作用。我们已经证明，在hMSCs中，无激动剂刺激时会发生自发的[Ca(2+)]i振荡。然而，其产生的确切机制仍不清楚。在本研究中，我们研究了hMSCs中自发[Ca(2+)]i振荡的机制和作用，发现IP(3)诱导的Ca(2+)释放对于自发[Ca(2+)]i振荡至关重要。我们还发现ATP自分泌/旁分泌信号通路参与了这些振荡。在该通路中，ATP通过半缝隙连接通道分泌；它刺激P(2)Y(1)受体，导致PLC-β激活以产生IP(3)。我们能够通过药理学方法阻断该通路，从而完全停止[Ca(2+)]i振荡。此外，我们发现[Ca(2+)]i振荡与未分化hMSCs中NFAT转位到细胞核有关。一旦ATP自分泌/旁分泌信号通路被阻断，就无法检测到NFAT的核转位，这表明NFAT的激活与[Ca(2+)]i振荡密切相关。随着hMSCs分化为脂肪细胞，[Ca(2+)]i振荡消失，NFAT的转位停止。这些结果为未分化hMSCs中[Ca(2+)]i振荡的分子和生理机制提供了新的见解。
