Tiam Mana Saffari

242 CHAPTER 11 PART II: THE CONTRIBUTION OF ANGIOGENESIS AND STEM CELLS IN NERVE REGENERATION Neural stem cell (NSC) research is not novel. The discovery of adult NSCs and neurogenesis occurred in the 1960s and since then a great amount of research has been focusing on increasing our understanding of NSCs 47-49 . Despite advancements, stem cell transplantation still remains in pre-clinical stages and has to make significant headways into clinical practice. Stem cell-based therapy may offer a suitable treatment with several regenerative benefits to restore neuronal function, including supporting remyelination and revascularization of the affected organ 50 . Specifically, stem cells that have been differentiated into Schwann cell-like cells, mimicking the function of the original facilitators of axonal regeneration, may enhance neuron survival to improve motor outcomes 51,52 . Growth factors secreted by stem cells may enhance angiogenesis, the sprouting of new capillaries from preexisting ones, to promote revascularization 53-56 . On the other hand, vasculature serves as a niche for stem cells that are mostly quiescent and are activated in response to injury 57,58 . The interaction of stem cells with vascularity and its contribution to nerve regeneration remains complex, however, it is postulated to be interconnected and interdependent. To understand the mechanisms of action, studies have been designed to investigate interactions per causal order. Previous studies have shown that seeding of adipose-derived mesenchymal stem cells (MSC) onto decellularized nerve allografts results in an elevation of neurotrophic and angiogenic factors 40,41 . Using our established techniques to objectively measure angiogenesis, revascularization was found to be increased in nerve allografts that were seeded with MSCs compared to unseeded nerve allografts 59 . These MSCs were dynamically seeded onto nerve allografts, leading to evenly distributed cells on the outer surface of nerve grafts. This technique does not damage the nerve infrastructure nor is harmful to cell viability 60,61 . While many researchers have questioned how the presence of MSCs on the outer surface may elicit therapeutic potential for nerve regeneration, I hypothesize that the stem cell secretome, i.e. the paracrine factors secreted by stem cells and utilized for inter-cell communication, plays a more important role in this process than the location of the MSCs 62 . The stimulated stem cell secretome and the circular coverage of the nerve graft with MSCs have contributed to the centripetal pattern of increased revascularization 59 , together leading to enhanced motor outcomes of nerve allografts seeded with undifferentiated and differentiated