Tiam Mana Saffari

162 CHAPTER 8 The exact interaction between stem cell and vascularity remains unexplored and is postulated to be part of a complex pathway that enhances peripheral nerve regeneration. This review will provide an in-depth perspective of currently available stem cell-based therapy applications in PNIs and discusses the interaction between stem cells and vascularity in peripheral nerve regeneration. Furthermore, sources of stem cells, methods of delivery to the injury site, relevant pre-clinical studies and clinical trials, and future applications will be reviewed. Search strategy and selection criteria Literature research was performed using PubMed, Web of Science, MEDLINE and Google Scholar databases, using the following search terms: angiogenesis, vascularity, nerve regeneration, nerve transplantation, nerve graft, neural stem cells, mesenchymal stem cells, exosomes and various combinations of the above terms. Available English studies discussing stem cells and vascularity in peripheral nerve injuries in both animals and humans were included until July 2020. Interaction of stem cells, vascularity and nerve regeneration The interaction of stem cells, vascularity, and axon regeneration is complex (Figure 1). The paracrine property of stem cells is much broader than previously was appreciated. When stimulated by surrounding tissues, stem cells have the ability to affect vascularity via cell-to-cell communication, differentiation, and release of angiogenic factors, such as vascular endothelial growth factor (VEGF) 18-20 . On the other hand, stem cells demonstrate the capacity to stimulate the upregulation of neurotrophic factors to enhance nerve regeneration as a response to nerve injury 17,19,21,22 . After nerve injury, angiogenesis is stimulated by hypoxia, usually mediated by VEGF, resulting in the growth of pre-existing vessels into new areas. It is postulated that these newly modeled vessel tracks precede the repair of damaged nerves 14,16,23,24 . The therapeutic potency of stem cells in nerve regeneration and vascularity is inf luenced by its microenvironment. The interaction of the environment, stem cells, and vascularity with respect to peripheral nerve regeneration will be discussed per causal order below.