Back to Search
Start Over
Cyclic ADP ribose is a novel regulator of intracellular Ca2+ oscillations in human bone marrow mesenchymal stem cells.
- Source :
-
Journal of cellular and molecular medicine [J Cell Mol Med] 2011 Dec; Vol. 15 (12), pp. 2684-96. - Publication Year :
- 2011
-
Abstract
- Bone marrow mesenchymal stem cells (MSCs) are a promising cell source for regenerative medicine. However, the cellular biology of these cells is not fully understood. The present study characterizes the cyclic ADP-ribose (cADPR)-mediated Ca(2+) signals in human MSCs and finds that externally applied cADPR can increase the frequency of spontaneous intracellular Ca(2+) (Ca(2+) (i) ) oscillations. The increase was abrogated by a specific cADPR antagonist or an inositol trisphosphate receptor (IP3R) inhibitor, but not by ryanodine. In addition, the cADPR-induced increase of Ca(2+) (i) oscillation frequency was prevented by inhibitors of nucleoside transporter or by inhibitors of the transient receptor potential cation melastatin-2 (TRPM2) channel. RT-PCR revealed mRNAs for the nucleoside transporters, concentrative nucleoside transporters 1/2 and equilibrative nucleoside transporters 1/3, IP3R1/2/3 and the TRPM2 channel, but not those for ryanodine receptors and CD38 in human MSCs. Knockdown of the TRPM2 channel by specific short interference RNA abolished the effect of cADPR on the Ca(2+) (i) oscillation frequency, and prevented the stimulation of proliferation by cADPR. Moreover, cADPR remarkably increased phosphorylated extracellular-signal-regulated kinases 1/2 (ERK1/2), but not Akt or p38 mitogen-activated protein kinase (MAPK). However, cADPR had no effect on adipogenesis or osteogenesis in human MSCs. Our results indicate that cADPR is a novel regulator of Ca(2+) (i) oscillations in human MSCs. It permeates the cell membrane through the nucleoside transporters and increases Ca(2+) oscillation via activation of the TRPM2 channel, resulting in enhanced phosphorylation of ERK1/2 and, thereby, stimulation of human MSC proliferation. This study delineates an alternate signalling pathway of cADPR that is distinct from its well-established role of serving as a Ca(2+) messenger for mobilizing the internal Ca(2+) stores. Whether cADPR can be used clinically for stimulating marrow function in patients with marrow disorders remains to be further studied.<br /> (© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)
- Subjects :
- Adipogenesis drug effects
Blotting, Western
Cell Membrane metabolism
Cell Proliferation drug effects
Humans
Inositol 1,4,5-Trisphosphate Receptors metabolism
Osteogenesis drug effects
RNA, Messenger genetics
Real-Time Polymerase Chain Reaction
Signal Transduction drug effects
TRPM Cation Channels genetics
TRPM Cation Channels metabolism
Bone Marrow Cells drug effects
Bone Marrow Cells metabolism
Calcium metabolism
Cyclic ADP-Ribose pharmacology
Mesenchymal Stem Cells drug effects
Mesenchymal Stem Cells metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1582-4934
- Volume :
- 15
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of cellular and molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 21251217
- Full Text :
- https://doi.org/10.1111/j.1582-4934.2011.01263.x