Tiam Mana Saffari

169 STEM CELLS, VASCULARITY, AND NERVE 8 and BDNF leading to a long-lasting therapeutic effect promoting nerve regeneration and protection, which outlasts the life span of ADSC 53,69,70 . Interestingly, ADSCs are reported to support angiogenesis by direct differentiation into vascular endothelium, as well as by associated paracrine effects 71,72 . Difficulties include the unfavorable differentiation potential towards adipocytes 73 . Nonetheless, ADSCs are currently the most practical source of stem cells to obtain and have been and continue to be translated to clinical use 53 . Other types of MSCs including fetal derived stem cells, skin-derived precursors, muscle-derived stem/progenitor cells, hair follicle stem cells and dental pulp stem cells, as well as induced pluripotential stem cells are detailed in Table 1 12,53 . Currently, inherent disadvantages associated with MSC-based therapy still exist: instability of the cellular phenotype, high cost, ethical issues, and difficulties of cellular origin 74 . These difficulties may be overcome by the application of exosomes. Exosomes Recent research has proven that the therapeutic effect of MSCs is highly likely to be accredited to the indirect regeneration of endogenous Schwann cells through cellular paracrine mechanisms, which are partially thought to be mediated by MSC exosomes 75 . MSC exosomes are a subtype of extracellular vesicles released from all cell types, but particularly from stem cells. MSC exosomes located in nearly all biological body fluids including blood, urine, breast milk, ascites, and saliva 76 . These particles maintain cell-to-cell communication by delivering proteins, lipids, DNA, mRNA, and micro ribonucleic acids miRNAs (miRNA), and other subtypes of RNA, which regulate cell biological behavior and can be used to mediate intercellular communication 77-80 . MSC exosomes are found to increase axonal regeneration and promote local angiogenesis by transmitting a number of genetic materials, neurotrophic factors and proteins to axons and thereby restoring the homeostasis of the microenvironment 74 . Furthermore, MSC exosomes have been proven to promote the proliferation of Schwann cells and reduce their apoptosis rate by upregulating the pro-apoptotic Bax mRNA expression resulting in increased regeneration 81 . It is postulated that MSC exosomes are mediators of communication with vascular endothelial cells resulting in enhancement of the plasticity of blood vessels following PNI 82 . MSC exosome-based therapy provides many benefits including the decrease of associated risks with transplantation as exosomes