title: Mesenchymal Stromal Cell-Derived Extracellular Vesicles Protect the Fetal Brain After Hypoxia-Ischemia.
abstract: Preterm neonates are susceptible to perinatal hypoxic-ischemic brain injury, for which no treatment is available. In a 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 mesenchymal 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 neuroprotective 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.
  
  
  CONCLUSIONS
  Bone marrow-derived mesenchymal stromal cells (MSCs) show promise in treating hypoxic-ischemic injury of the preterm brain. Study results suggest administration of extracellular vesicles, rather than intact MSCs, is sufficient to exert therapeutic effects and avoids potential concerns associated with administration of living cells. The therapeutic efficacy of systemically administered mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) on hypoxia-ischemia-induced injury was assessed in the preterm ovine brain. Impaired function and structural injury of the fetal brain was improved following global hypoxia-ischemia. A cell-free preparation of MSC-EVs could substitute for the cellular counterpart in the treatment of preterm neonates with hypoxic-ischemic brain injury. This may open new clinical applications for "off-the-shelf" interventions with MSC-EVs.
authors.affiliation: School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands Department of Pediatrics, Maastricht University, Maastricht, The Netherlands.
authors.forename: Daan R M G
authors.initials: DR
authors.lastname: Ophelders
authors.affiliation: Department of Pediatrics, Maastricht University, Maastricht, The Netherlands School of Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Tim G A M
authors.initials: TG
authors.lastname: Wolfs
authors.affiliation: School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands Department of Pediatrics, Maastricht University, Maastricht, The Netherlands Department of Pediatrics, Máxima Medical Center, Veldhoven, The Netherlands.
authors.forename: Reint K
authors.initials: RK
authors.lastname: Jellema
authors.affiliation: Department of Pediatrics, Maastricht University, Maastricht, The Netherlands Department of Biomedical Engineering, Maastricht University, Maastricht, The Netherlands.
authors.forename: Alex
authors.initials: A
authors.lastname: Zwanenburg
authors.affiliation: Department of Pediatrics, Maastricht University, Maastricht, The Netherlands Department of Pediatrics, Máxima Medical Center, Veldhoven, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Andriessen
authors.affiliation: Department of Biomedical Engineering, Maastricht University, Maastricht, The Netherlands School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
authors.forename: Tammo
authors.initials: T
authors.lastname: Delhaas
authors.affiliation: Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Anna-Kristin
authors.initials: AK
authors.lastname: Ludwig
authors.affiliation: Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Radtke
authors.affiliation: Department of Pediatrics, Maastricht University, Maastricht, The Netherlands.
authors.forename: Vera
authors.initials: V
authors.lastname: Peters
authors.affiliation: School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands Department of Pediatrics, Maastricht University, Maastricht, The Netherlands.
authors.forename: Leon
authors.initials: L
authors.lastname: Janssen
authors.affiliation: Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany b.kramer@maastrichtuniversity.nl bernd.giebel@uk-essen.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Giebel
authors.affiliation: School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands Department of Pediatrics, Maastricht University, Maastricht, The Netherlands School of Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands b.kramer@maastrichtuniversity.nl bernd.giebel@uk-essen.de.
authors.forename: Boris W
authors.initials: BW
authors.lastname: Kramer
mesh_terms: D000818:Animals; D001921:Brain / Q000503:physiopathology; D001930:Brain Injuries / Q000503:physiopathology / Q000628:therapy; D049109:Cell Proliferation; D064987:Cell- and Tissue-Based Therapy; D004195:Disease Models, Animal; D000067128:Extracellular Vesicles / Q000378:metabolism; D005333:Fetus; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000503:physiopathology / Q000628:therapy*; D007249:Inflammation / Q000503:physiopathology / Q000628:therapy*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D012756:Sheep
keywords: Brain injury; Exosomes; Extracellular vesicles; Hypoxia-ischemia; Mesenchymal stromal cells; Preterm