title: ATP autocrine/paracrine signaling induces calcium oscillations and NFAT activation in human mesenchymal stem cells.
abstract: 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+)](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 [Ca(2+)](i) oscillations in hMSCs and found that IP(3)-induced Ca(2+) release is essential for spontaneous [Ca(2+)](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 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+)](i) oscillations. Furthermore, we found that [Ca(2+)](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 [Ca(2+)](i) oscillations. As the hMSCs differentiated to adipocytes, the [Ca(2+)](i) oscillations disappeared and the translocation of NFAT ceased. These results provide new insight into the molecular and physiological mechanism of [Ca(2+)](i) oscillations in undifferentiated hMSCs.
authors.affiliation: Department of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Japan. seiko.card@mri.tmd.ac.jp
authors.forename: Seiko
authors.initials: S
authors.lastname: Kawano
authors.forename: Keishi
authors.initials: K
authors.lastname: Otsu
authors.forename: Akinori
authors.initials: A
authors.lastname: Kuruma
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shoji
authors.forename: Eri
authors.initials: E
authors.lastname: Yanagida
authors.forename: Yuko
authors.initials: Y
authors.lastname: Muto
authors.forename: Fumio
authors.initials: F
authors.lastname: Yoshikawa
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Hirayama
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
authors.forename: Teiichi
authors.initials: T
authors.lastname: Furuichi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism / Q000502:physiology*; D050156:Adipogenesis / Q000502:physiology; D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D017629:Gap Junctions / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000378:metabolism*; D019899:Paracrine Communication / Q000502:physiology*; D011983:Receptors, Purinergic / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
chemical_list: D050778:NFATC Transcription Factors; D011983:Receptors, Purinergic; D014157:Transcription Factors; D000255:Adenosine Triphosphate