Mesenchymal Stem Cell–Derived Exosomes Improve Functional Recovery in Rats After Traumatic Brain Injury: A Dose-Response and Therapeutic Window Study

作者：Yanlu Zhang, Yi Zhang, Michael Chopp, Zheng Gang Zhang, Asim Khalid Mahmood, Ye Xiong · 发表于：Neurorehabilitation and neural repair · 年份：2020 · DOI：10.1177/1545968320926164 · 被引用次数：127 · 研究领域：Extracellular vesicles in disease、Traumatic Brain Injury Research、Traumatic Brain Injury and Neurovascular Disturbances

Background. Mesenchymal stem cell (MSC)-derived exosomes play a critical role in regenerative medicine. Objective. To determine the dose- and time-dependent efficacy of exosomes for treatment of traumatic brain injury (TBI). Methods. Male rats were subjected to a unilateral moderate cortical contusion. In the dose-response study, animals received a single intravenous injection of exosomes (50, 100, 200 µg per rat) or vehicle, with treatment initiated at 1 day after injury. In the therapeutic window study, animals received a single intravenous injection of 100 µg exosomes or vehicle starting at 1, 4, or 7 days after injury. Neurological functional tests were performed weekly after TBI for 5 weeks. Spatial learning was measured on days 31 to 35 after TBI using the Morris water maze test. Results. Compared with the vehicle, regardless of the dose and delay in treatment, exosome treatment significantly improved sensorimotor and cognitive function, reduced hippocampal neuronal cell loss, promoted angiogenesis and neurogenesis, and reduced neuroinflammation. Exosome treatment at 100 µg per rat exhibited a significant therapeutic effect compared with the 50- or 200-µg exosome groups. The time-dependent exosome treatment data demonstrated that exosome treatment starting at 1 day post-TBI provided a significantly greater improvement in functional and histological outcomes than exosome treatments at the other 2 delayed treatments. Conclusions. These results indicate that exosomes have ...