The Neuroprotective Effects of Exosomes Derived from TSG101-Overexpressing Human Neural Stem Cells in a Stroke Model

Abstract

Although tissue-type plasminogen activator was approved by the FDA for early reperfusion of occluded vessels, there is a need for an effective neuroprotective drug for stroke patients. In this study, we established tumor susceptibility gene (TSG)101-overexpressing human neural stem cells (F3.TSG) and investigated whether they showed enhanced secretion of exosomes and whether treatment with exosomes during reperfusion alleviated ischemia-reperfusion-mediated brain damage. F3.TSG cells secreted higher amounts of exosomes than the parental F3 cells. In N2A cells subjected to oxygen–glucose deprivation (OGD), treatment with exosomes or coculture with F3.TSG cells significantly attenuated lactate dehydrogenase release, the mRNA expression of proinflammatory factors, and the protein expression of DNA-damage-related proteins. In a middle cerebral artery occlusion (MCAO) rat model, treatment with exosomes, F3 cells, or F3.TSG cells after 2 h of occlusion followed by reperfusion reduced the infarction volume and suppressed inflammatory cytokines, DNA-damage-related proteins, and glial fibrillary acidic protein, and upregulated several neurotrophic factors. Thus, TSG101-overexpressing neural stem cells showed enhanced exosome secretion; exosome treatment protected against MCAO-induced brain damage via anti-inflammatory activities, DNA damage pathway inhibition, and growth/trophic factor induction. Therefore, exosomes and F3.TSG cells can affect neuroprotection and functional recovery in acute stroke patients.

Preventive Effects of Exosome-Rich Conditioned Medium From Amniotic Membrane-Derived Mesenchymal Stem Cells for Diabetic Retinopathy in Rats

“…ERCM was harvested according to a previous protocol. 18 , 19 ERCM contained 4 × 10 8 exosomes/µL. The characteristics of ERCM are described in previously published paper and U.S. Patent No.…”

Cardiomyocyte-targeting exosomes from sulforaphane-treated fibroblasts affords cardioprotection in infarcted rats

“…TSG101, a component of the endosomal sorting complex necessary for transport machinery that is highly conserved in mice and humans, was shown to be substantially expressed in SFN-F-EXOs and protects ischemic cardiomyocytes from oxidative stress [ 63 ]. Furthermore, TSG101-rich exosomes have neuroprotective properties [ 64 ]. Hsp70, a molecular chaperone physiologically secreted by exosomes that protects hypoxic cardiomyocytes from apoptosis [ 21 , 37 ], enriches SFN-F-EXOs.…”

“…So far, we have ruled out the possibility that alterations in exosome release after chronic SFN 3 µM treatment are due to increasing levels of histone acetylation and Nrf2 expression in viable murine fibroblasts, as opposed to treatment with higher concentrations of SFN [ 48 ]. However, TSG101 overexpression may be required for SFN-induced increased exosome secretion [ 64 ]. More research into the processes behind SFN-mediated impacts on the biogenesis of fibroblast-derived exosomes is needed.…”

An Exosome-Rich Conditioned Medium from Human Amniotic Membrane Stem Cells Facilitates Wound Healing via Increased Reepithelization, Collagen Synthesis, and Angiogenesis

“…Purified exosomes were adjusted to 10 8 particles/mL (in accordance with the manufacturer's recommendations) in PBS. The camera level was adjusted until the particle signal saturation did not exceed 20% and all particles were clearly visible, 5 images were captured in 60 s, the size and particle concentration were analyzed [23,24].…”