Wnt Signaling Regulates the Invasion Capacity of Human Mesenchymal Stem Cells

¹ Division of Clinical Chemistry and Clinical Biochemistry in the Surgical Department of the Ludwig-Maximilians-University of Munich, Germany

^* To whom correspondence should be addressed. E-mail: Peter.Neth{at}med.uni-muenchen.de.

	Abstract

Human mesenchymal stem cells (hMSC) exhibit the potential to contribute to a wide variety of endogenous organ tissue repair. However, the signals governing hMSC mobilization out of the bone marrow, release into the bloodstream, and migration/invasion into the target tissue are largely unknown. Since canonical Wnt signaling regulates not only tumor but also various stem cell attributes, we hypothesized that this signal transduction pathway might also be involved in governing the transmigration of hMSC through human extracellular matrix (ECM). Stimulation of hMSC with recombinant Wnt3a or LiCl resulted in the accumulation of the transcriptional activator -catenin, its translocation into the nucleus, and in the upregulation of typical Wnt target genes such as Cyclin D1 and the matrix metalloproteinase MT1-MMP. Moreover, both stimuli significantly enhanced hMSC proliferation up to 40%. In addition, a more than 2-fold increase in the ability of hMSC to transmigrate through Transwell® filters coated with human ECM was observed. In a reverse approach, Wnt signaling in hMSC was inhibited by knocking down either the expression of -catenin or lowdensity lipoprotein receptor-related protein 5 (LRP5) using RNA interference technology. These inhibition strategies resulted in down-regulation of the Wnt target genes Cyclin D1 and MT1-MMP, in a reduced proliferation rate as well as in a strikingly diminished invasion capacity (64% and 52%). Taken together, this study provides for the first time decisive evidence that canonical Wnt signaling is critically involved in the regulation of the proliferation as well as of the migration/invasion capacity of hMSC, representing essential stem cell features indispensable during tissue regeneration processes.

Key Words. Mesenchymal stem cells, migration, invasion, Wnt signaling, -catenin, LRP5, RNA interference, small interfering RNA

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