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Exp Neurol. 2018 Sep;307:99-108. doi: 10.1016/j.expneurol.2018.06.001. Epub 2018 Jun 6.

Endothelial colony-forming cell-derived exosomes restore blood-brain barrier continuity in mice subjected to traumatic brain injury.

Author information

1
Department of Neurology, Tianjin Huanhu Hospital, 6 Jizhao Road, Tianjin, China.
2
Department of Neurosurgery, Tianjin Baodi Hospital, Baodi Clinical College of Tianjin Medical University, Tianjin 301800, PR China.
3
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Tianjin 300052, PR China; Key Laboratory of Post-neurotrauma Neuro-repair and Regeneration in the Central Nervous System, Ministry of Education, Tianjin City 300052, PR China.
4
Department of Neurosurgery, Tianjin Huanhu Hospital, 6 Jizhao Road, Tianjin, PR China. Electronic address: Yinghuang00@aliyun.com.
5
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Tianjin 300052, PR China; Key Laboratory of Post-neurotrauma Neuro-repair and Regeneration in the Central Nervous System, Ministry of Education, Tianjin City 300052, PR China. Electronic address: jianningzhang@hotmail.com.

Abstract

Traumatic brain injury (TBI) tends to cause disruption of the blood-brain barrier (BBB). Previous studies have shown that intravenously or intracerebroventricularly infused human umbilical cord blood-derived endothelial colony-forming cells (ECFCs) can home to injury sites and improve outcomes in mice subjected to experimental TBI. Several reports have demonstrated that these cells did not incorporate directly into newly formed vasculature but instead stimulated the proliferation and migration of tissue-resident endothelial cells (ECs) via paracrine mechanisms. In the present study, exosomes, which range from 30 to 150 nm in diameter, were isolated from ECFC-conditioned medium. The exosomes were labeled with PKH67 ex vivo, and we observed that they were taken up by ECs with high efficiency after 12 h of incubation. Pretreatment with ECFC-derived exosomes promoted the migration of ECs subjected to scratch injury, and incubating ECs exposed to hypoxia with ECFC-derived exosomes decreased PTEN expression, stimulated AKT phosphorylation and increased tight junction (TJ) protein expression in the cells. Furthermore, in vivo delivery of ECFC-derived exosomes into TBI mice also inhibited PTEN expression and increased AKT expression, changes accompanied by reductions in Evans blue (EB) dye extravasation, brain edema and TJ degradation. These data demonstrated that ECFC-derived exosomes have beneficial effects on BBB integrity in mice with TBI.

KEYWORDS:

Endothelial colony-forming cells; Exosomes; Tight junction proteins; Traumatic brain injury

PMID:
29883579
DOI:
10.1016/j.expneurol.2018.06.001
[Indexed for MEDLINE]

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