title: Intranasal mesenchymal stem cell treatment for neonatal brain damage: long-term cognitive and sensorimotor improvement.
abstract: Mesenchymal stem cell (MSC) administration via the intranasal route could become an effective therapy to treat neonatal hypoxic-ischemic (HI) brain damage. We analyzed long-term effects of intranasal MSC treatment on lesion size, sensorimotor and cognitive behavior, and determined the therapeutic window and dose response relationships. Furthermore, the appearance of MSCs at the lesion site in relation to the therapeutic window was examined. Nine-day-old mice were subjected to unilateral carotid artery occlusion and hypoxia. MSCs were administered intranasally at 3, 10 or 17 days after hypoxia-ischemia (HI). Motor, cognitive and histological outcome was investigated. PKH-26 labeled cells were used to localize MSCs in the brain. We identified 0.5 × 10(6) MSCs as the minimal effective dose with a therapeutic window of at least 10 days but less than 17 days post-HI. A single dose was sufficient for a marked beneficial effect. MSCs reach the lesion site within 24 h when given 3 or 10 days after injury. However, no MSCs were detected in the lesion when administered 17 days following HI. We also show for the first time that intranasal MSC treatment after HI improves cognitive function. Improvement of sensorimotor function and histological outcome was maintained until at least 9 weeks post-HI. The capacity of MSCs to reach the lesion site within 24 h after intranasal administration at 10 days but not at 17 days post-HI indicates a therapeutic window of at least 10 days. Our data strongly indicate that intranasal MSC treatment may become a promising non-invasive therapeutic tool to effectively reduce neonatal encephalopathy.
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Donega
authors.forename: Cindy T J
authors.initials: CT
authors.lastname: van Velthoven
authors.forename: Cora H
authors.initials: CH
authors.lastname: Nijboer
authors.forename: Frank
authors.initials: F
authors.lastname: van Bel
authors.forename: Martien J H
authors.initials: MJ
authors.lastname: Kas
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kavelaars
authors.forename: Cobi J
authors.initials: CJ
authors.lastname: Heijnen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology; D001930:Brain Injuries / Q000517:prevention & control / Q000628:therapy*; D002339:Carotid Arteries / Q000473:pathology; D003071:Cognition; D020925:Hypoxia-Ischemia, Brain / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009048:Motor Skills; D013997:Time Factors