Exosomes and Nano-SDF Scaffold as a Cell-Free-Based Treatment Strategy Improve Traumatic Brain Injury Mechanisms by Decreasing Oxidative Stress, Neuroinflammation, and Increasing Neurogenesis

Traumatic brain injury (TBI) causes a variety of complex pathological changes in brain parenchymal tissue by increasing neuroinflammatory and apoptosis responses. Currently, there is no treatment to resolve the consequences related to TBI. Recently, an extensive literature has grown up around the theme of bystander effects of stem cells, a mechanism of stem cells without the need for cell transplantation, which is called cell-free therapy. The purpose of this investigation was to determine the efficacy of a cell-free-based therapy strategy using exosomes derived from human neural stem cells (hNSCs) and a novel nano-scaffold in rats subjected to TBI. In this study, a series of in vitro and in vivo experiments from behavior tests to gene expression was performed to define the effect of exosomes in combination with a three-dimensional (3D) nano-scaffold containing a bio-motif of SDF1 alpha (Nano-SDF). Application of exosomes with Nano-SDF significantly decreased oxidative stress in serum and brain samples. Moreover, treatment with exosomes and Nano-SDF significantly reduced the expression of Toll-like receptor 4 and its downstream signaling pathway, including NF-k beta and interleukin-1 beta. We also found that the cell-free-based therapy strategy could decrease reactive gliosis at the injury site. Interestingly, we showed that exosomes with Nano-SDF increased neurogenesis in the sub-ventricular zone of the lateral ventricle, indicating a bio-bridge mechanism. To sum up, the most obvious finding to emerge from this study is that a cell-free-based therapy strategy can be an effective option for future practice in the course of TBI.