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(Circulation Research. 2008;103:635.)
© 2008 American Heart Association, Inc.

Cellular Biology

A Rho Kinase/Myocardin-Related Transcription Factor-A–Dependent Mechanism Underlies the Sphingosylphosphorylcholine-Induced Differentiation of Mesenchymal Stem Cells Into Contractile Smooth Muscle Cells

Eun Su Jeon^*, Won Sun Park^*, Mi Jeong Lee, Young Mi Kim, Jin Han^#, Jae Ho Kim^#

From the Medical Research Center for Ischemic Tissue Regeneration (E.S.J., M.J.L., Y.M.K., J.H.K.), the Medical Research Institute, Department of Physiology, College of Medicine, Pusan National University; and National Research Laboratory for Mitochondrial Signaling (W.S.P., J.H.), FIRST Mitochondria Research Group, Department of Physiology and Biophysics, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Republic of Korea.

Correspondence to Jae Ho Kim, PhD, Pusan National University College of Medicine, Department of Physiology, 1-Ga, Ami-Dong, Suh-Gu, Busan 602-739, Republic of Korea. E-mail jhkimst{at}pusan.ac.kr

Sphingosylphosphorylcholine (SPC) induces differentiation of human adipose tissue–derived mesenchymal stem cells (hADSCs) to smooth muscle cells (SMCs). In the present study, we characterized contractile and ion channel properties of SMCs differentiated from hADSCs (hADSC-SMCs) as a result of SPC treatment, and we investigated the molecular mechanisms involved in the SPC-induced differentiation. Using in vitro collagen gel lattice contraction and whole cell patch clamp, we showed that the hADSC-SMCs expressed functional L-type voltage-gated Ca²⁺ channels and contractile activities in response to KCl, carbachol, and the L-type Ca²⁺ channel opener Bay K8644, whereas the L-type Ca²⁺ channel blocker nifedipine abrogated the contractility of hADSC-SMCs. Furthermore, hADSC-SMCs expressed functional big conductance Ca²⁺-activated K⁺ (BK_Ca) channels, and the BK_Ca channel blocker iberiotoxin potentiated the Bay K8644-stimulated contractility of the hADSC-SMCs, indicating that these cells exhibited SMC-like contractile characteristics. SPC activated RhoA in hADSCs and pretreatment with the Rho kinase inhibitor Y27632 or by overexpression of dominant-negative mutants of RhoA or Rho kinase completely abrogated the SPC-induced differentiation of hADSCs into SMCs. SPC also increased the expression levels of myocardin-related transcription factor (MRTF)-A, a transcription factor involved in smooth muscle differentiation, in hADSCs. Small interference RNA–mediated depletion of endogenous MRTF-A abolished the SPC-induced differentiation of hADSCs into SMCs. Furthermore, SPC promoted nuclear translocation of MRTF-A, and pharmacological inhibition of Rho kinase blocked this effect. These results suggest that SPC induced differentiation of hADSCs into contractile SMCs through a mechanism involving RhoA/Rho kinase–dependent nuclear translocation of MRTF-A.

Key Words: sphingosylphosphorylcholine • mesenchymal stem cells • smooth muscle • differentiation • Rho kinase

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