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Journal of Lipid Research, Vol. 47, 653-664, March 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Sphingosylphosphorylcholine induces proliferation of human adipose tissue-derived mesenchymal stem cells via activation of JNK

Eun Su Jeon^*, Hae Young Song^*, Mi Ra Kim^*, Hyun Jung Moon^*, Yong Chan Bae, Jin Sup Jung^* and Jae Ho Kim^1,*,

^* Research Center for Ischemic Tissue Regeneration, Pusan National University, Busan 602-739, Republic of Korea
Department of Plastic Surgery, College of Medicine, Pusan National University, Busan 602-739, Republic of Korea
Medical Research Institute, Pusan National University, Busan 602-739, Republic of Korea

Published, JLR Papers in Press, December 7, 2005.

¹ To whom correspondence should be addressed. e-mail: jhkimst{at}pusan.ac.kr

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 µM, and increased the intracellular concentration of Ca²⁺ ([Ca²⁺]_i) in hADSCs, which do not express known SPC receptors (i.e., OGR1, GPR4, G2A, and GPR12). The SPC-induced proliferation and increase in [Ca²⁺]_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 [Ca²⁺]_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.

Supplementary key words c-Jun N-terminal kinase • phospholipase C • G proteins

Abbreviations: BAPTA, 1,2-bis(o-aminophenoxy)ethane-N,N,N,N-tetraacetic acid; [Ca²⁺]_i, intracellular concentration of Ca²⁺; DN-JNK2, dominant negative mutant of JNK2; DN-MEK1, dominant negative mutant of MEK1; ERK, extracellular signal-regulated kinase; GFP, green fluorescent protein; GPCR, G protein-coupled receptor; GST, glutathione-S-transferase; HA, hemagglutinin; hADSC, human adipose tissue-derived mesenchymal stem cell; JNK, c-Jun N-terminal kinase; LPA, lysophosphatidic acid; LPC, lysophosphatidylcholine; MAP, mitogen-activated protein; MTT, 3-(4,5-dimethyl-2-thiozol)-2,5-diphenyl-2H-tetrazolium bromide; PTX, pertussis toxin; S1P, sphingosine-1-phosphate; SPC, sphingosylphosphorylcholine

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