Karla Drommelschmidt1, Meray Serdar1, Ivo Bendix1, Josephine Herz1, Frederik Bertling1, Sebastian Prager1, Matthias Keller1, Anna-Kristin Ludwig2, Vikas Duhan3, Stefan Radtke4, Kyra de Miroschedji2, Peter A Horn2, Yohan van de Looij5, Bernd Giebel6, Ursula Felderhoff-Müser7. 1. Department of Paediatrics I/Neonatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 2. Institute of Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 3. Institute of Immunology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 4. 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. 5. 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. 6. Institute of Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. Electronic address: bernd.giebel@uk-essen.de. 7. Department of Paediatrics I/Neonatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. Electronic address: ursula.felderhoff@uk-essen.de.
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 1×108 cell 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.
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 1×108 cell 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: María F Zappa Villar; Juliette López Hanotte; Joaquín Pardo; Gustavo R Morel; Guillermo Mazzolini; Mariana G García; Paula C Reggiani Journal: Mol Neurobiol Date: 2019-08-10 Impact factor: 5.590