title: Mesenchymal stem cell-derived extracellular vesicles ameliorate inflammation-induced preterm brain injury.
abstract: OBJECTIVE
  Preterm brain injury is a major cause of disability in later life, and may result in motor, cognitive and behavioural impairment for which no treatment is currently available. The aetiology is considered as multifactorial, and one underlying key player is inflammation leading to white and grey matter injury. Extracellular vesicles secreted by mesenchymal stem/stromal cells (MSC-EVs) have shown therapeutic potential in regenerative medicine. Here, we investigated the effects of MSC-EV treatment on brain microstructure and maturation, inflammatory processes and long-time outcome in a rodent model of inflammation-induced brain injury.
  
  
  METHODS
  3-Day-old Wistar rats (P3) were intraperitoneally injected with 0.25mg/kg lipopolysaccharide or saline and treated with two repetitive doses of 1×108cell equivalents of MSC-EVs per kg bodyweight. Cellular degeneration and reactive gliosis at P5 and myelination at P11 were evaluated by immunohistochemistry and western blot. Long-term cognitive and motor function was assessed by behavioural testing. Diffusion tensor imaging at P125 evaluated long-term microstructural white matter alterations.
  
  
  RESULTS
  MSC-EV treatment significantly ameliorated inflammation-induced neuronal cellular degeneration reduced microgliosis and prevented reactive astrogliosis. Short-term myelination deficits and long-term microstructural abnormalities of the white matter were restored by MSC-EV administration. Morphological effects of MSC-EV treatment resulted in improved long-lasting cognitive functions INTERPRETATION: MSC-EVs ameliorate inflammation-induced cellular damage in a rat model of preterm brain injury. MSC-EVs may serve as a novel therapeutic option by prevention of neuronal cell death, restoration of white matter microstructure, reduction of gliosis and long-term functional improvement.
authors.affiliation: Department of Paediatrics I/Neonatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Karla
authors.initials: K
authors.lastname: Drommelschmidt
authors.affiliation: Department of Paediatrics I/Neonatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Meray
authors.initials: M
authors.lastname: Serdar
authors.affiliation: Department of Paediatrics I/Neonatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Ivo
authors.initials: I
authors.lastname: Bendix
authors.affiliation: Department of Paediatrics I/Neonatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Josephine
authors.initials: J
authors.lastname: Herz
authors.affiliation: Department of Paediatrics I/Neonatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Bertling
authors.affiliation: Department of Paediatrics I/Neonatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Prager
authors.affiliation: Department of Paediatrics I/Neonatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Keller
authors.affiliation: Institute of Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Anna-Kristin
authors.initials: AK
authors.lastname: Ludwig
authors.affiliation: Institute of Immunology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Vikas
authors.initials: V
authors.lastname: Duhan
authors.affiliation: Institute of Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Clinical Research Division, Fred Hutchinson Cancer Research Centre, Seattle, WA 98109, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Radtke
authors.affiliation: Institute of Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Kyra
authors.initials: K
authors.lastname: de Miroschedji
authors.affiliation: Institute of Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Horn
authors.affiliation: Division of Child Growth and Development, Department of Paediatrics, University of Geneva, Geneva, Switzerland; Laboratory of Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Yohan
authors.initials: Y
authors.lastname: van de Looij
authors.affiliation: Institute of Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. Electronic address: bernd.giebel@uk-essen.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Giebel
authors.affiliation: Department of Paediatrics I/Neonatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. Electronic address: ursula.felderhoff@uk-essen.de.
authors.forename: Ursula
authors.initials: U
authors.lastname: Felderhoff-Müser
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000378:metabolism*; D003071:Cognition / Q000502:physiology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000378:metabolism*; D000067128:Extracellular Vesicles / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D017208:Rats, Wistar; D066127:White Matter / Q000187:drug effects*
keywords: Exosomes; Extracellular vesicles; Inflammation; Lipopolysaccharide; Mesenchymal stem cells; Microvesicles; Perinatal brain injury; White matter injury