title: Mesenchymal stem cells attenuate MRI-identifiable injury, protect white matter, and improve long-term functional outcomes after neonatal focal stroke in rats.
abstract: Cell therapy has emerged as a potential treatment for many neurodegenerative diseases including stroke and neonatal ischemic brain injury. Delayed intranasal administration of mesenchymal stem cells (MSCs) after experimental hypoxia-ischemia and after a transient middle cerebral artery occlusion (tMCAO) in neonatal rats has shown improvement in long-term functional outcomes, but the effects of MSCs on white matter injury (WMI) are insufficiently understood. In this study we used longitudinal T2-weighted (T2W) and diffusion tensor magnetic resonance imaging (MRI) to characterize chronic injury after tMCAO induced in postnatal day 10 (P10) rats and examined the effects of delayed MSC administration on WMI, axonal coverage, and long-term somatosensory function. We show unilateral injury- and region-dependent changes in diffusion fraction anisotropy 1 and 2 weeks after tMCAO that correspond to accumulation of degraded myelin basic protein, astrocytosis, and decreased axonal coverage. With the use of stringent T2W-based injury criteria at 72 hr after tMCAO to randomize neonatal rats to receive intranasal MSCs or vehicle, we show that a single MSC administration attenuates WMI and enhances somatosensory function 28 days after stroke. A positive correlation was found between MSC-enhanced white matter integrity and functional performance in injured neonatal rats. Collectively, these data indicate that the damage induced by tMCAO progresses over time and is halted by administration of MSCs. © 2016 Wiley Periodicals, Inc.
authors: Department of Neurology, University of California, San Francisco, San Francisco, California.
authors: Cindy T
authors: CT
authors: van Velthoven
authors: Department of Neurology, University of California, San Francisco, San Francisco, California.
authors: Mark
authors: M
authors: Dzietko
authors: Department of Neurology, University of California, San Francisco, San Francisco, California.
authors: Michael F
authors: MF
authors: Wendland
authors: Department of Neurology, University of California, San Francisco, San Francisco, California.
authors: Nikita
authors: N
authors: Derugin
authors: Department of Neurology, University of California, San Francisco, San Francisco, California.
authors: Joel
authors: J
authors: Faustino
authors: Laboratory of Neuroimmunology, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Cobi J
authors: CJ
authors: Heijnen
authors: Department of Neurology, University of California, San Francisco, San Francisco, California.|Department of Pediatrics, University of California, San Francisco, San Francisco, California.
authors: Donna M
authors: DM
authors: Ferriero
authors: Department of Neurology, University of California, San Francisco, San Francisco, California.
authors: Zinaida S
authors: ZS
authors: Vexler
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D020244:Infarction, Middle Cerebral Artery / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy; D037102:Lectins / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D004676:Myelin Basic Protein / Q000378:metabolism; D011596:Psychomotor Disorders / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D066127:White Matter / Q000378:metabolism / Q000473:pathology*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D037102:Lectins; D004676:Myelin Basic Protein; D001973:Bromodeoxyuridine
keywords: axon; brain repair; diffusion tensor imaging; fractional anisotropy; middle cerebral artery occlusion; perinatal stroke