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Article: Cyclic ADP ribose is a novel regulator of intracellular Ca 2+ oscillations in human bone marrow mesenchymal stem cells

TitleCyclic ADP ribose is a novel regulator of intracellular Ca 2+ oscillations in human bone marrow mesenchymal stem cells
Authors
KeywordsCalcium signalling
Cyclic ADP ribose
Human bone marrow
Mesenchymal stem cells
TRPM2
Issue Date2011
PublisherWiley-Blackwell Publishing Ltd.. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=1582-1838
Citation
Journal Of Cellular And Molecular Medicine, 2011, v. 15 n. 12, p. 2684-2696 How to Cite?
AbstractBone 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+ oscillationviaactivation 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. © 2011 The Authors © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
Persistent Identifierhttp://hdl.handle.net/10722/142379
ISSN
2012 Impact Factor: 4.753
2015 SCImago Journal Rankings: 1.941
ISI Accession Number ID
Funding AgencyGrant Number
Research Grant Council of Hong Kong734703M
769107M
768408
769309
8CRF09
University of Hong Kong
NCRR of the NIHP40RR017447
Funding Information:

This study was supported by Grants from the Research Grant Council of Hong Kong (734703M to GRL, 769107M, 768408 and 769309 to HCL, and the group grant 8CRF09 to H. F. T. and G. R. L.). Dr. R. T. was supported by a postgraduate studentship from the University of Hong Kong. We thank Dr. Darwin J. Prockop at Texas A&M Health Science Center College of Medicine Institute for Regenerative Medicine at Scott & White (through a grant from NCRR of the NIH, Grant #P40RR017447) for providing the human MSCs.

References

 

DC FieldValueLanguage
dc.contributor.authorTao, Ren_HK
dc.contributor.authorSun, HYen_HK
dc.contributor.authorLau, CPen_HK
dc.contributor.authorTse, HFen_HK
dc.contributor.authorLee, HCen_HK
dc.contributor.authorLi, GRen_HK
dc.date.accessioned2011-10-28T02:44:40Z-
dc.date.available2011-10-28T02:44:40Z-
dc.date.issued2011en_HK
dc.identifier.citationJournal Of Cellular And Molecular Medicine, 2011, v. 15 n. 12, p. 2684-2696en_HK
dc.identifier.issn1582-1838en_HK
dc.identifier.urihttp://hdl.handle.net/10722/142379-
dc.description.abstractBone 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+ oscillationviaactivation 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. © 2011 The Authors © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.en_HK
dc.languageengen_US
dc.publisherWiley-Blackwell Publishing Ltd.. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=1582-1838en_HK
dc.relation.ispartofJournal of Cellular and Molecular Medicineen_HK
dc.rightsThe definitive version is available at www3.interscience.wiley.comen_US
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subjectCalcium signallingen_HK
dc.subjectCyclic ADP riboseen_HK
dc.subjectHuman bone marrowen_HK
dc.subjectMesenchymal stem cellsen_HK
dc.subjectTRPM2en_HK
dc.subject.meshBone Marrow Cells - drug effects - metabolism-
dc.subject.meshCalcium - metabolism-
dc.subject.meshCell Membrane - metabolism-
dc.subject.meshCyclic ADP-Ribose - pharmacology-
dc.subject.meshMesenchymal Stem Cells - drug effects - metabolism-
dc.titleCyclic ADP ribose is a novel regulator of intracellular Ca 2+ oscillations in human bone marrow mesenchymal stem cellsen_HK
dc.typeArticleen_HK
dc.identifier.emailTse, HF:hftse@hkucc.hku.hken_HK
dc.identifier.emailLi, GR:grli@hkucc.hku.hken_HK
dc.identifier.authorityTse, HF=rp00428en_HK
dc.identifier.authorityLi, GR=rp00476en_HK
dc.description.naturepostprint-
dc.identifier.doi10.1111/j.1582-4934.2011.01263.xen_HK
dc.identifier.pmid21251217-
dc.identifier.scopuseid_2-s2.0-79960640911en_HK
dc.identifier.hkuros184242en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79960640911&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume15en_HK
dc.identifier.issue12en_HK
dc.identifier.spage2684en_HK
dc.identifier.epage2696en_HK
dc.identifier.isiWOS:000297855700014-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridTao, R=7102857104en_HK
dc.identifier.scopusauthoridSun, HY=53265070800en_HK
dc.identifier.scopusauthoridLau, CP=7401968501en_HK
dc.identifier.scopusauthoridTse, HF=7006070805en_HK
dc.identifier.scopusauthoridLee, HC=54412699000en_HK
dc.identifier.scopusauthoridLi, GR=7408462932en_HK

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