Wnt signaling regulates the invasion capacity of human mesenchymal stem cells.
Human mesenchymal stem cells (hMSCs) 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 hMSCs through human extracellular matrix (ECM). Stimulation of hMSCs with recombinant Wnt3a or LiCl resulted in the accumulation of the transcriptional activator beta-catenin, its translocation into the nucleus, and the upregulation of typical Wnt target genes such as cyclin D1 and membrane-type matrix metalloproteinase-1 (MT1-MMP). Moreover, both stimuli significantly enhanced hMSC proliferation up to 40%. In addition, an increase of more than twofold in the ability of hMSCs to transmigrate through Transwell filters coated with human ECM was observed. In a reverse approach, Wnt signaling in hMSCs was inhibited by knocking down the expression of either beta-catenin or low-density lipoprotein receptor-related protein 5 using RNA interference technology. These inhibition strategies resulted in downregulation of the Wnt target genes cyclin D1 and MT1-MMP, in a reduced proliferation rate, and 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 hMSCs, representing essential stem cell features indispensable during tissue regeneration processes.
Neth
Peter
P
Department of Surgery, Division of Clinical Chemistry and Clinical Biochemistry, Ludwig-Maximilians-University, Munich, Germany. Peter.Neth@med.uni-muenchen.de
Ciccarella
Marisa
M
Egea
Virginia
V
Hoelters
Juergen
J
Jochum
Marianne
M
Ries
Christian
C
D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D056741:Cyclin D; D016213:Cyclins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018021:Lithium Chloride / Q000737:chemistry / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D053511:Matrix Metalloproteinase 14 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D008969:Molecular Sequence Data; D034622:RNA Interference; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D056741:Cyclin D; D016213:Cyclins; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D011994:Recombinant Proteins; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin; D053511:Matrix Metalloproteinase 14; D018021:Lithium Chloride