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. Stem Cells 2004;22:74-85 STEM CELLS 2004;22:74-85 www.StemCells.com Correspondence: Danièle Noël, Ph.D., Inserm U475,

The chondrogenic differentiation of mesenchymal stem cells on an extracellular matrix scaffold derived from porcine chondrocytes

“…The adverse events of matrix calcification and hypertrophic changes were also much delayed and less significant in the ECM group. The defect area of the cartilage might not be the same as subcutaneous environment but is still under harsh conditions that are not favorable for chondrogenic differentiation and cartilage tissue formation of stem cells [36,37]. Therefore, we speculate that our ECM scaffold could also be a promising scaffold that can both support well chondrogenic differentiation of MSCs and reduce degenerative changes of engineered tissue in cartilage defect.…”

Significance of soluble growth factors in the chondrogenic response of human umbilical cord matrix stem cells in a porous three dimensional scaffold

“…Hence, in the present study, instead of ITS in chondrogenic medium supplemented with IGF, only transferrin and selenium were used. Combined with the knowledge that BMP signalling is required for the formation of precartilagenous condensation and differentiation of chondroprecursors and, in adult articular cartilage homeostasis, by enhancing proteoglycan and type II collagen synthesis (Zhang et al, 2002;Schmitt et al, 2003;Noel et al, 2004), the extent of hUCMSC chondrogenesis by these growth factors, when administered singly or in combination with BMP2, is evaluated after 28 d culture with the respective growth factors.…”

Cartilage tissue engineering for degenerative joint disease☆

“…In a rat model implantation of MSC expressing BMP-2 or IGF-1 efficiently filled cartilage defect. Recently, in a murine model, only MSC expressing BMP-2 were shown to produce cartilage [152]. Unfortunately, none of the studies could demonstrate long lasting tissue formation suggesting that more investigation is needed before MSCs can be used in cartilage regeneration.…”