title: Inhibition of hedgehog signaling decreases proliferation and clonogenicity of human mesenchymal stem cells.
abstract: Human mesenchymal stem cells (hMSC) have the ability to differentiate into osteoblasts, adipocytes and chondrocytes. We have previously shown that hMSC were endowed with a basal level of Hedgehog signaling that decreased after differentiation of these cells. Since hMSC differentiation is associated with growth-arrest we investigated the function of Hh signaling on cell proliferation. Here, we show that inhibition of Hh signaling, using the classical inhibitor cyclopamine, or a siRNA directed against Gli-2, leads to a decrease in hMSC proliferation. This phenomenon is not linked to apoptosis but to a block of the cells in the G0/G1 phases of the cell cycle. At the molecular level, it is associated with an increase in the active form of pRB, and a decrease in cyclin A expression and MAP kinase phosphorylation. Inhibition of Hh signaling is also associated with a decrease in the ability of the cells to form clones. By contrast, inhibition of Hh signaling during hMSC proliferation does not affect their ability to differentiate. This study demonstrates that hMSC are endowed with a basal Hedgehog signaling activity that is necessary for efficient proliferation and clonogenicity of hMSC. This observation unravels an unexpected new function for Hedgehog signaling in the regulation of human mesenchymal stem cells and highlights the critical function of this morphogen in hMSC biology.
authors.affiliation: CNRS UMR6543, Institute of Biology, Development and Cancer, Faculté de Médecine, Nice, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Plaisant
authors.forename: Sophie
authors.initials: S
authors.lastname: Giorgetti-Peraldi
authors.forename: Marike
authors.initials: M
authors.lastname: Gabrielson
authors.forename: Agnes
authors.initials: A
authors.lastname: Loubat
authors.forename: Christian
authors.initials: C
authors.lastname: Dani
authors.forename: Pascal
authors.initials: P
authors.lastname: Peraldi
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002999:Clone Cells; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013723:Teratogens / Q000494:pharmacology; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000075746:Zinc Finger Protein Gli2
chemical_list: C082593:GLI2 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D013723:Teratogens; D014704:Veratrum Alkaloids; D000075746:Zinc Finger Protein Gli2; C000541:cyclopamine