Sphingosylphosphorylcholine induces proliferation of human adipose tissue-derived mesenchymal stem cells via activation of JNK.
Sphingosylphosphorylcholine (SPC) has been implicated in a variety of cellular responses, including proliferation and differentiation. In this study, we demonstrate that d-erythro-SPC, but not l-threo-SPC, stereoselectively stimulated the proliferation of human adipose tissue-derived mesenchymal stem cells (hADSCs), with a maximal increase at 5 microM, and increased the intracellular concentration of Ca(2+) ([Ca(2+)](i)) in hADSCs, which do not express known SPC receptors (i.e., OGR1, GPR4, G2A, and GPR12). The SPC-induced proliferation and increase in [Ca(2+)](i) were sensitive to pertussis toxin (PTX) and the phospholipase C (PLC) inhibitor U73122, suggesting that PTX-sensitive G proteins, Gi or Go, and PLC are involved in SPC-induced proliferation. In addition, SPC treatment induced the phosphorylation of c-Jun and extracellular signal-regulated kinase, and SPC-induced proliferation was completely prevented by pretreatment with the c-Jun N-terminal kinase (JNK)-specific inhibitor SP600125 but not with the MEK-specific inhibitor U0126. Furthermore, the SPC-induced proliferation and JNK activation were completely attenuated by overexpression of a dominant negative mutant of JNK2, and the SPC-induced activation of JNK was inhibited by pretreatment with PTX or U73122. Treatment of hADSCs with lysophosphatidic acid (LPA) receptor antagonist, Ki16425, had no impact on the SPC-induced increase in [Ca(2+)](i). However, SPC-induced proliferation was partially, but significantly, attenuated by pretreatment of the cells with Ki16425.These results indicate that SPC stimulates the proliferation of hADSCs through the Gi/Go-PLC-JNK pathway and that LPA receptors may be responsible in part for the SPC-induced proliferation.
Jeon
Eun Su
ES
Research Center for Ischemic Tissue Regeneration, Pusan National University, Busan 602-739, Republic of Korea.
Song
Hae Young
HY
Kim
Mi Ra
MR
Moon
Hyun Jung
HJ
Bae
Yong Chan
YC
Jung
Jin Sup
JS
Kim
Jae Ho
JH
D000273:Adipose Tissue / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006801:Humans; D008244:Lysophosphatidylcholines / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D037342:Pertussis Toxin / Q000378:metabolism / Q000494:pharmacology; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism
D008244:Lysophosphatidylcholines; D049368:Receptors, Lysophosphatidic Acid; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D037342:Pertussis Toxin; D048056:Mitogen-Activated Protein Kinase 9; D048670:MAP Kinase Kinase 4; D010738:Type C Phospholipases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D013110:Sphingosine; D002118:Calcium