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Cyclic ADP ribose is a novel regulator of intracellular Ca2+ oscillations in human bone marrow mesenchymal stem cells.

Tao R, Sun HY, Lau CP, Tse HF, Lee HC, Li GR - J. Cell. Mol. Med. (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.

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Nucleoside transporters and cADPR transportation. (A) RT-PCR detected significant gene expression for CNT1, CNT3, ENT1, ENT2, BST-1 and Cx43. No significant CD38 gene expression was detected in human MSCs. CNT: concentrative nucleoside transporter; ENT: equilibrative nucleoside transporter; BST-1: bone marrow stroma antigen-1; Cx43: connexin 43. (B) Spontaneous Ca2+i oscillations in a representative cell. (C) cADPR had no significant effect on Ca2+i oscillations in the cell pre-treated with 10 nM NBMPR (nitrobenzylthioinosine). Similar results were obtained in a total of 10 cells. (D) The nucleoside transporter inhibitor dypyridamole (100 nM) prevented cADPR effect. (E) Mean values for the effects of 50 μM cADPR (n = 36), 10 nM NBMPR plus 50 μM cADPR (n = 10) and 100 nM dipyridamole plus 50 μM cADPR (n = 11) on the frequencies of Ca2+i oscillations. *P < 0.05 versus before cADPR.
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fig03: Nucleoside transporters and cADPR transportation. (A) RT-PCR detected significant gene expression for CNT1, CNT3, ENT1, ENT2, BST-1 and Cx43. No significant CD38 gene expression was detected in human MSCs. CNT: concentrative nucleoside transporter; ENT: equilibrative nucleoside transporter; BST-1: bone marrow stroma antigen-1; Cx43: connexin 43. (B) Spontaneous Ca2+i oscillations in a representative cell. (C) cADPR had no significant effect on Ca2+i oscillations in the cell pre-treated with 10 nM NBMPR (nitrobenzylthioinosine). Similar results were obtained in a total of 10 cells. (D) The nucleoside transporter inhibitor dypyridamole (100 nM) prevented cADPR effect. (E) Mean values for the effects of 50 μM cADPR (n = 36), 10 nM NBMPR plus 50 μM cADPR (n = 10) and 100 nM dipyridamole plus 50 μM cADPR (n = 11) on the frequencies of Ca2+i oscillations. *P < 0.05 versus before cADPR.

Mentions: Previous studies have demonstrated that concentrative nucleoside transporters (CNTs) and equilibrative nucleoside transporters (ENTs) are responsible for the transport of external cADPR into human haematopoietic progenitors [24] and human promyelocytic leukemia (HL)-60 cells [36]. To determine whether these nucleoside transporters are present in human MSCs, the related mRNAs were examined by RT-PCR, which showed significant expression of ENT1/ENT2 and CNT1/CNT3 in the cells (Fig. 3A). Two other components of the cADPR-pathway were also present in human MSCs, the hexameric hemichannel connexin 43 (Cx43) and the bone marrow stromal cell antigen-1 (BST-1). Cx43 has been demonstrated to mediate the nicotinamide adenine dinucleotide (NAD+) transport and it is known to be functionally interacting with the multifunctional ecto-enzymes, CD38 and/or BST-1 (also called CD157) in the plasma membrane, both catalyse the synthesis and hydrolysis of cADPR [37]. Indeed, BST-1 (CD157) [38, 39], but not CD38, was strongly expressed in human MSCs (Fig. 3A).


Cyclic ADP ribose is a novel regulator of intracellular Ca2+ oscillations in human bone marrow mesenchymal stem cells.

Tao R, Sun HY, Lau CP, Tse HF, Lee HC, Li GR - J. Cell. Mol. Med. (2011)

Nucleoside transporters and cADPR transportation. (A) RT-PCR detected significant gene expression for CNT1, CNT3, ENT1, ENT2, BST-1 and Cx43. No significant CD38 gene expression was detected in human MSCs. CNT: concentrative nucleoside transporter; ENT: equilibrative nucleoside transporter; BST-1: bone marrow stroma antigen-1; Cx43: connexin 43. (B) Spontaneous Ca2+i oscillations in a representative cell. (C) cADPR had no significant effect on Ca2+i oscillations in the cell pre-treated with 10 nM NBMPR (nitrobenzylthioinosine). Similar results were obtained in a total of 10 cells. (D) The nucleoside transporter inhibitor dypyridamole (100 nM) prevented cADPR effect. (E) Mean values for the effects of 50 μM cADPR (n = 36), 10 nM NBMPR plus 50 μM cADPR (n = 10) and 100 nM dipyridamole plus 50 μM cADPR (n = 11) on the frequencies of Ca2+i oscillations. *P < 0.05 versus before cADPR.
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Related In: Results  -  Collection

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fig03: Nucleoside transporters and cADPR transportation. (A) RT-PCR detected significant gene expression for CNT1, CNT3, ENT1, ENT2, BST-1 and Cx43. No significant CD38 gene expression was detected in human MSCs. CNT: concentrative nucleoside transporter; ENT: equilibrative nucleoside transporter; BST-1: bone marrow stroma antigen-1; Cx43: connexin 43. (B) Spontaneous Ca2+i oscillations in a representative cell. (C) cADPR had no significant effect on Ca2+i oscillations in the cell pre-treated with 10 nM NBMPR (nitrobenzylthioinosine). Similar results were obtained in a total of 10 cells. (D) The nucleoside transporter inhibitor dypyridamole (100 nM) prevented cADPR effect. (E) Mean values for the effects of 50 μM cADPR (n = 36), 10 nM NBMPR plus 50 μM cADPR (n = 10) and 100 nM dipyridamole plus 50 μM cADPR (n = 11) on the frequencies of Ca2+i oscillations. *P < 0.05 versus before cADPR.
Mentions: Previous studies have demonstrated that concentrative nucleoside transporters (CNTs) and equilibrative nucleoside transporters (ENTs) are responsible for the transport of external cADPR into human haematopoietic progenitors [24] and human promyelocytic leukemia (HL)-60 cells [36]. To determine whether these nucleoside transporters are present in human MSCs, the related mRNAs were examined by RT-PCR, which showed significant expression of ENT1/ENT2 and CNT1/CNT3 in the cells (Fig. 3A). Two other components of the cADPR-pathway were also present in human MSCs, the hexameric hemichannel connexin 43 (Cx43) and the bone marrow stromal cell antigen-1 (BST-1). Cx43 has been demonstrated to mediate the nicotinamide adenine dinucleotide (NAD+) transport and it is known to be functionally interacting with the multifunctional ecto-enzymes, CD38 and/or BST-1 (also called CD157) in the plasma membrane, both catalyse the synthesis and hydrolysis of cADPR [37]. Indeed, BST-1 (CD157) [38, 39], but not CD38, was strongly expressed in human MSCs (Fig. 3A).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.

Show MeSH