Tiam Mana Saffari

165 STEM CELLS, VASCULARITY, AND NERVE 8 Stem cells and nerve regeneration The importance of stem cells in peripheral nerve regeneration relies on their ability to enhance neurotrophic factors, promote myelin formation, and their capacity to be influenced by the microenvironment to differentiate into Schwann-like cells 12 . Schwann cells are essential within the context of peripheral nerve regeneration after trauma and are crucial during Wallerian degeneration, however, difficult to transplant 4,43 . The acquisition of autologous Schwann cells requires the harvest of large segments of healthy nerve tissue, resulting in donor site morbidities. Additionally, proliferation of Schwann cells in vitro is associated with an extensive culturing and expansion time period. As a result of these limitations, research has been directed towards the use of MSCs, which are easily accessible, and can be differentiated into Schwann-like cells 4 . Schwann-like cells are found to express neurotrophic factors and to interact through multiple pathways to support the repair of injured nerves 17,44 . These factors and pathways include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and myelin related growth factors. BDNF is upregulated in motor neurons and increases myelin thickness in regenerating nerves while promoting remyelination and axonal sprouting 4,45 . In myelin sheath formation, a number of myelin proteins are induced such as myelin basic protein (MBP), peripheral myelin protein-22 (PMP22), and pleiotrophin (PTN). PTN is involved inmyelinated axon regeneration specifically and is increasingly expressed in differentiated MSCs in comparison to undifferentiated MSCs 46,47 . The level of growth factors in the microenvironment influences the sequential growth factor production by the transplanted stem cells, emphasizing their paracrine feedback properties. Only 5% of all types of stem cells can spontaneously differentiate into Schwann cells, however, pre-differentiation towards the desired phenotype in vitro via chemical induction or transfection with growth factors has been shown to be a more effective method to increase the number of Schwann-like cells. 12,48,49 . Drawbacks of pre- differentiation include the need for additional preparation time and higher costs, making this process less favorable for clinical translation 17 . More investigation is needed to confirm the optimal dosage of transplanted stem cells, delivery methods, in vivo survivability, and interaction mechanisms with their environment prior to conducting clinical studies.