Femke Mathot

2 Stem cell differentiation in peripheral nerve repair 37 Differentiated MSCs versus undifferentiated MSCs in vivo When seeded on a conduit and transplanted in a rat-model, differentiatedMSCs characterized by Kingham and colleagues increased the distance of axon regeneration and enhanced vascularity in nerve conduits compared to undifferentiated MSCs. These findings show that neurotrophic and angiogenic factors produced by differentiated MSCs interact with regenerative mechanisms that support repair of injured nerves by enhancing vascularization and improved nerve regeneration. 17 Ladak and colleagues found in vivo that differentiated MSCs seeded in a nerve conduit resulted in an equal number of regenerating axons across the nerve gap compared to seeded Schwann cells. However, the improved axon regeneration did not translate into improved electrodiagnostic parameters or increased muscle weight. 23 Keilhoff and colleagues compared the outcomes of Schwann cells, undifferentiated MSCs and differentiated MSCs injected in a devitalized muscle. The authors found both Schwann cells and differentiated MSCs contribute to appropriate regeneration while undifferentiated MSCs did not exhibit the ability to improve nerve repair. 47 Kappos showed in a rat sciatic nerve gap model that the addition of differentiated human MSCs to a nerve conduit led to functional outcomes (sciatic functional index and gastrocneumius muscle mass) that exceeded the results of undifferentiated human MSCs and Schwann cells. 54 In contrast, other studies showed low potential of the Schwann-like cells. Fox and colleagues demonstrated in a rat model that primary Schwann cells did not have a beneficial effect on nerve regeneration after 4 weeks when injected into nerve grafts. 55 Orbay and colleagues evaluated the effects of differentiated and undifferentiated MSCs when seeded in silicone tubes and compared the outcomes to empty silicone tubes and nerve grafts. Although the functional outcomes of both MSC-groups were significantly better than those of the other groups, there were no significant differences between differentiated or control MSCs. 24 Watanabe compared undifferentiated MSCs, differentiated MSCs and Schwann cells in a rat facial nerve gap model and came to similar conclusions in that all groups had a comparable amount of nerve regeneration and all cell based strategies gave functional results close to that of autografts. 56 The advantages and disadvantages of differentiated versus undifferentiated MSCs in vitro and in vivo are presented in table 2 . Although the majority of in vitro studies demonstrated a larger trophic potential of differentiated MSCs compared to undifferentiated MSCs, the in vivo outcomes were less unanimous. These conflicting results may be due to the embedded growth agents in the ECM that is generated in cell culture. Differences in differentiation methods, dosing and efficiency of cell delivery methods, and the composition of the nerve substitutes could affect the persistence of differentiation in vivo in the absence of the differentiation medium and could account for different outcomes. Further careful studies are required to confirm differentiated MSCs preserve their described enhanced trophic function in vivo. CONCLUSION Adipose derived MSCs are easy to access, deFfigrive, expand and can be successfully differentiated into Schwann-like cells. Therefore, adipose derived MSCs, and in particular adipose derived MSCs differentiated into Schwann-like cells have been broadly studied in