Mesenchymal stromal cell-derived extracellular vesicles protect the fetal brain after hypoxia-ischemia

Daan R.M.G. Ophelders, Tim G.A.M. Wolfs, Reint K. Jellema, Alex Zwanenburg, Peter Andriessen, Tammo Delhaas, Anna Kristin Ludwig, Stefan Radtke, Vera Peters, Leon Janssen, Bernd Giebel, Boris W. Kramer

    Research output: Contribution to journalArticleAcademicpeer-review

    120 Citations (Scopus)

    Abstract

    Preterm neonates are susceptible to perinatal hypoxic-ischemic brain injury, for which no treatment is available. Ina preclinical animal model of hypoxic-ischemic brain injury in ovine fetuses, we have demonstrated the neuroprotective potential of systemically administered mesenchymal stromal cells (MSCs). The mechanism of MSC treatment is unclear but suggested to be paracrine, through secretion of extracellular vesicles (EVs). Therefore, we investigated in this study the protective effects of mes-enchymal stromal cell-derived extracellular vesicles (MSC-EVs) in a preclinical model of preterm hypoxic-ischemic brain injury. Ovine fetuses were subjected to global hypoxia-ischemia by transient umbilical cord occlusion, followed by in utero intravenous administration of MSC-EVs. The therapeutic effects of MSC-EV administration were assessed by analysis of electrophysiological parameters and histology of the brain. Systemic administration of MSC-EVs improved brain function by reducing the total number and duration of seizures, and by preserving baroreceptor reflex sensitivity. These functional protections were accompanied by a tendency to prevent hypomyelination. Cerebral inflammation remained unaffected by the MSC-EV treatment. Our data demonstrate that MSC-EV treatment might provide a novel strategy to reduce the neurological sequelae following hypoxic-ischemic injury of the preterm brain. Our study results suggest that a cell-free preparation comprising neuroprotec-tive MSC-EVs could substitute MSCs in the treatment of preterm neonates with hypoxic-ischemic brain injury, thereby circumventing the potential risks of systemic administration of living cells.

    Original languageEnglish
    Pages (from-to)754-763
    Number of pages10
    JournalStem Cells Translational Medicine
    Volume5
    Issue number6
    DOIs
    Publication statusPublished - 1 Jun 2016

    Keywords

    • Animals
    • Brain/physiopathology
    • Brain Injuries/physiopathology
    • Cell Proliferation
    • Cell- and Tissue-Based Therapy
    • Disease Models, Animal
    • Extracellular Vesicles/metabolism
    • Fetus
    • Humans
    • Hypoxia-Ischemia, Brain/physiopathology
    • Inflammation/physiopathology
    • Mesenchymal Stem Cells/cytology
    • Sheep

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