title: Short-term BMP-2 expression is sufficient for in vivo osteochondral differentiation of mesenchymal stem cells.
abstract: Currently available murine models to evaluate mesenchymal stem cell (MSC) differentiation are based on cell injection at ectopic sites such as muscle or skin. Due to the importance of environmental factors on the differentiation capacities of stem cells in vivo, we investigated whether the peculiar synovial/cartilaginous environment may influence the lineage specificity of bone morphogenetic protein (BMP)-2-engineered MSCs. To this aim, we used the C3H10T1/2-derived C9 MSCs that express BMP-2 under control of the doxycycline (Dox)-repressible promoter, Tet-Off, and showed in vitro, using the micropellet culture system that C9 MSCs kept their potential to differentiate toward chondrocytes. Implantation of C9 cells, either into the tibialis anterior muscles or into the joints of CB17-severe combined immunodeficient bg mice led to the formation of cartilage and bone filled with bone marrow as soon as day 10. However, no differentiation was observed after injection of naïve MSCs or C9 cells that were repressed to secrete BMP-2 by Dox addition. The BMP-2-induced differentiation of adult MSCs is thus independent of soluble factors present in the local environment of the synovial/cartilaginous tissues. Importantly, we demonstrated that a short-term expression of the BMP-2 growth factor is necessary and sufficient to irreversibly induce bone formation, suggesting that a stable genetic modification of MSCs is not required for stem cell-based bone/cartilage engineering.
authors.affiliation: Inserm U475, Montpellier, France. noel@montp.inserm.fr
authors.forename: Danièle
authors.initials: D
authors.lastname: Noël
authors.forename: Dan
authors.initials: D
authors.lastname: Gazit
authors.forename: Celine
authors.initials: C
authors.lastname: Bouquet
authors.forename: Florence
authors.initials: F
authors.lastname: Apparailly
authors.forename: Claire
authors.initials: C
authors.lastname: Bony
authors.forename: Pascale
authors.initials: P
authors.lastname: Plence
authors.forename: Virginie
authors.initials: V
authors.lastname: Millet
authors.forename: Gadi
authors.initials: G
authors.lastname: Turgeman
authors.forename: Michel
authors.initials: M
authors.lastname: Perricaudet
authors.forename: Jacques
authors.initials: J
authors.lastname: Sany
authors.forename: Christian
authors.initials: C
authors.lastname: Jorgensen
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis* / Q000235:genetics; D001842:Bone and Bones / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D002356:Cartilage / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D019070:Cell Lineage / Q000235:genetics; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D045604:Extracellular Fluid / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006133:Growth Substances / Q000378:metabolism; D007596:Joints / Q000166:cytology / Q000254:growth & development / Q000601:surgery; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D018482:Muscle, Skeletal / Q000166:cytology / Q000254:growth & development / Q000601:surgery; D041681:NIH 3T3 Cells; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D033581:Stem Cell Transplantation; D016212:Transforming Growth Factor beta
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D006133:Growth Substances; D016212:Transforming Growth Factor beta