Femke Mathot

Chapter 2 38 the effort to improve the outcomes of peripheral nerve repair/reconstruction. The neural induction of MSCs by chemicals combined with growth factors (PDFG-AA, bFGF/FGF2, Forskolin, neuregulin-1/NRG1) remains the preferred method to obtain Schwann cell- like differentiation and has been validated for human MSCs differentiation. To obtain the putative trophic effect of MSCs, they should be delivered in a timely and non-traumatic method. Dynamic seeding of MSCs on nerve grafts meets these criteria. Despite the wide interest in the use of both differentiated and undifferentiated MSCs in peripheral nerve repair, the optimal delivery and dosing of differentiated MSCs is a rather under-explored research topic. The advantages of using undifferentiated versus differentiated MSCs remain to be further defined. In vitro studies have shown that differentiated MSCs permit enhanced expression of neurotrophic genes and the secretion of neurotrophic proteins, resulting in increased neurite outgrowth when compared to undifferentiated MSCs. The beneficial effect of differentiated MSCs has not yet been convincingly confirmed in in vivo studies. Future studies are needed to determine the ideal method of delivery and optimal dosages of differentiated and undifferentiated MSCs to nerve allografts to ascertain their regenerative potential for peripheral nerve reconstruction. These studies should consider the ultimate goal of clinical applications, as well as be cognizant of the time and cost issues of peripheral nerve reconstruction/repair. Table 2. Overview of the pros and cons of the use of undifferentiated versus differentiated MSCs in vitro and in vivo for peripheral nerve repair. MSCs = mesenchymal stem cells. Cell type In vitro In vivo Pros Cons Pros Cons Undifferentiated MSCs • No extended preparation time • No extra preparation costs • Less expression of neurotrophic genes • Less production of neurotrophic growth factors • No extended preparation time • No extra preparation costs • Functional outcomes comparable to differentiated MSCs • Histologically less axon regeneration Differentiated MSCs • Enhanced expression of neurotrophic genes • Enhanced production of neurotrophic growth factors • Extended number and length of neurites • Suitable for human MSCs • Extended preparation time • Extra preparation costs • Increased axon regeneration distance • Enhanced vascularity • Inconsistency about functional outcomes • Extended preparation time • Extra preparation costs