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

• Published in: International journal of molecular sciences 2022-09, Vol.23 (17), p.9532
• Main Authors: Yoon, Eun-Jung, Choi, Yunseo, Kim, Tae Myoung, Choi, Ehn-Kyoung, Kim, Yun-Bae, Park, Dongsun
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Biosynthesis; Brain; Brain damage; Brain injury; Cerebral blood flow; Cerebral infarction; Cytokines; Deoxyribonucleic acid; Deprivation; DNA; DNA damage; Enzymes; Exosomes; Gene expression; Glial fibrillary acidic protein; Hypoxia; Inflammation; Ischemia; L-Lactate dehydrogenase; Lactate dehydrogenase; Lactic acid; Membrane filters; Neural stem cells; Neuronal-glial interactions; Neuroprotection; Neurotrophic factors; Patients; Proteins; Recovery of function; Reperfusion; Stem cell transplantation; Stem cells; Stroke; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23179532

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.