Femke Mathot

Chapter 10 176 FUTURE PERSPECTIVES The presented thesis demonstrates cautious potential of MSC seeding in the repair of peripheral nerve injuries. As with all forms of basic science research, small research steps will have to follow to confirm this potential. MSC optimization MSC-function and viability has been described to significantly variate between donors. 57, 58 For example, proliferation capacities decreases with increasing donor age 59 , female MSCs have more anti-inflammatory capacities than male MSCs 60 and auto-immune diseases reduce the immunosuppressive capacities of MSCs. 61 Efforts to select ideal MSC donors, either in light of allogenous MSC transplantation or in light of patient selection that are more prone to benefit from autologous MSC therapy, might extend the described enhancing effect of MSCs. A big hurdle in translating MSC-seeding to a clinical trial, are safety concerns and with that FDA approval. However, with sufficient data from animal studies and extensive descriptions of the deriving, culture and implementation steps, usage of adipose derived MSCs might be allowed to be studied under an investigational new drug application (IND). As this allowance will be easier obtained for usage of autologous MSCs than for allogenous MSCs, this thesis focused on autologous MSC application. Contrary to MSCs, stromal vascular fraction (SVF) does not need to be manipulated or cultured prior to use, which limits the risk of contamination, making it safer and subject to lesser regulatory criteria. Stromal vascular fraction is a heterogeneous collection of cells, including MSCs, macrophages and pericytes and has demonstrated regenerative capabilities in multiple clinical settings like neurodegenerative disorders 62 , alopecia areata 63 and perianal fistulizing Crohn’s disease. 64 SVF can be easily and quickly derived from autologous adipose tissue, contains high concentrations of stromal cells and can be directly used after its acquisition. 65 SVF has demonstrated comparable effects as MSCs in other fields of research, but they have not been thoroughly compared in peripheral nerve repair yet. 66, 67 It would therefore be interesting to test if and at what efficiency SVF can be dynamically seeded onto nerve substitutes, to be able to fairly compare its effect on peripheral nerve regeneration to that of MSCs. In vivo gene expression and growth factor production The in vivo gene expression and the release of trophic factors of MSCs when seeded on nerve grafts should be studied to get a complete mechanistic insight in the effect of MSCs. This is preferably done at multiple time points, particularly short term, in an in vivo model to get the most reliable outcomes. Unfortunately this does require the use of many animals since qPCR analysis and trophic factor release analysis is preferably performed on five replicates per group per time point. To bypass the need for extra animals, one could consider another in vitro study, in which the micro-regenerative environment is simulated by presence of an unprocessed cut nerve segment in the same culture dish as the MSC-seeded decellularized nerve grafts. Although suboptimal, presence of a nerve segment in an in vitro culture, might simulate an in vivo setting while exposing the MSCs to trophic signals of the cut nerve segment.