Short-term BMP-2 expression is sufficient for in vivo osteochondral differentiation of mesenchymal stem cells.
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.
Noël
Danièle
D
Inserm U475, Montpellier, France. noel@montp.inserm.fr
Gazit
Dan
D
Bouquet
Celine
C
Apparailly
Florence
F
Bony
Claire
C
Plence
Pascale
P
Millet
Virginie
V
Turgeman
Gadi
G
Perricaudet
Michel
M
Sany
Jacques
J
Jorgensen
Christian
C
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
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D006133:Growth Substances; D016212:Transforming Growth Factor beta