Enhanced Chondrogenic Capacity of Mesenchymal Stem Cells After TNFα Pre-treatment

Mesenchymal stem cells (MSCs) are promising cells to treat cartilage defects due to their chondrogenic differentiation potential. However, an inflammatory environment during differentiation, such as the presence of the cytokine TNFα, inhibits chondrogenesis and limits the clinical use of MSCs. On the other hand, it has been reported that exposure to TNFα during in vitro expansion can increase proliferation, migration, and the osteogenic capacity of MSCs and therefore can be beneficial for tissue regeneration. This indicates that the role of TNFα on MSCs may be dependent on the differentiation stage. To improve the chondrogenic capacity of MSCs in the presence of an inflamed environment, we aimed to determine the effect of TNFα on the chondrogenic differentiation capacity of MSCs. Here, we report that TNFα exposure during MSC expansion increased the chondrogenic differentiation capacity regardless of the presence of TNFα during chondrogenesis and that this effect of TNFα during expansion was reversed upon TNFα withdrawal. Interestingly, pre-treatment with another pro-inflammatory cytokine, IL-1β, did not increase the chondrogenic capacity of MSCs indicating that the pro-chondrogenic effect is specific for TNFα. Finally, we show that TNFα pre-treatment increased the levels of SOX11 and active β-catenin suggesting that these intracellular effectors may be useful targets to improve MSC-based cartilage repair. Overall, these results suggest that TNFα pre-treatment, by modulating SOX11 levels and WNT/β-catenin signaling, could be used as a strategy to improve MSC-based cartilage repair

New Era of Cell-Based Orthopedic Therapies

There has long been a described relationship between mesenchymal stem cells (MSCs) and blood vessels in aspects of bone and other skeletal tissues with regard to their embryonic formation and their adult repair and regeneration dynamics. The use of exogenously added MSCs to supplement the naturally available progenitor cell stock has been a standard practice in several orthopedic surgeries by adding bone marrow to the repair constructs. This, coupled with the well-established need for vasculature to orient and drive bone formation, firmly established the functional relationship between MSCs, osteoprogenitors, and blood vessels. It is now apparent that MSCs are pericytes (cells that surround blood vessels) throughout the body. In addition, MSCs can function to secrete bioactive factors that are immunomodulatory, thus allowing allogeneic MSCs to be infused into patients requiring clinically relevant treatments. Such infused MSCs trophically establish microenvironments that support the regeneration of the injured tissue. These new functions usher in a new era of cell-based therapies

Effect of dual growth factor delivery on chondrogenic differentiation of rabbit marrow mesenchymal stem cells encapsulated in injectable hydrogel composites.

Contains fulltext : 80847.pdf (publisher's version ) (Open Access)An injectable hydrogel composite consisting of oligo(poly(ethylene glycol)fumarate) (OPF) and gelatin microparticles has been developed as a novel carrier system for cells and growth factors. Rabbit marrow mesenchymal stem cells (MSCs) and gelatin microparticles (MPs) loaded with insulin-like growth factor-1 (IGF-1), transforming growth factor-beta1 (TGF-beta1), or a combination of both growth factors were mixed with OPF, a poly(ethylene glycol)-diacrylate crosslinker and the radical initiators ammonium persulfate and N,N,N',N'-tetramethylethylenediamine, and then crosslinked at 37 degrees C for 8 min to form hydrogel composites. Hydrogel composites encapsulating rabbit marrow MSCs and blank MPs served as controls. At day 14, confocal fluorescent images of OPF hydrogels showed a strong aggregation of rabbit marrow MSCs when encapsulated with IGF-1-loaded MPs with or without TGF-beta1-loaded MPs. Quantitative RT-PCR results showed that rabbit marrow MSCs encapsulated with MPs loaded with TGF-beta1 or both TGF-beta1 and IGF-1 had a significant increase in the expression of chondrocyte-specific genes such as collagen type II and aggrecan at day 14 as compared with the control group. Specifically, samples with both TGF-beta1-loaded MPs and IGF-1-loaded MPs exhibited a 121 +/- 20-fold increase of type II collagen gene expression and a 71 +/- 24-fold increase of aggrecan gene expression after 14 days of in vitro culture as compared with controls at day 0. These results suggest that hydrogel composites based on OPF and gelatin microparticles have great potential as carriers for MSCs and multiple growth factors for cartilage tissue engineering applications

Bone formation: The rules for fabricating a composite ceramic

Bone, teeth and shells are complex composite ceramics which are fabricated at low temperature by living organisms. The detailed understanding of this fabrication process is required if we are to attempt to mimic this low temperature assembly process. The guiding principles and major components are outlined with the intent of establishing non-vital fabrication schemes to form a complex composite ceramic consisting of an organix matrix inorganic crystalline phase. 19 refs