title: Targeted delivery of neural stem cells to the brain using MRI-guided focused ultrasound to disrupt the blood-brain barrier.
abstract: Stem cell therapy is a promising strategy to treat neurodegenerative diseases, traumatic brain injury, and stroke. For stem cells to progress towards clinical use, the risks associated with invasive intracranial surgery used to deliver the cells to the brain, needs to be reduced. Here, we show that MRI-guided focused ultrasound (MRIgFUS) is a novel method for non-invasive delivery of stem cells from the blood to the brain by opening the blood brain barrier (BBB) in specific brain regions. We used MRI guidance to target the ultrasound beam thereby delivering the iron-labeled, green fluorescent protein (GFP)-expressing neural stem cells specifically to the striatum and the hippocampus of the rat brain. Detection of cellular iron using MRI established that the cells crossed the BBB to enter the brain. After sacrifice, 24 hours later, immunohistochemical analysis confirmed the presence of GFP-positive cells in the targeted brain regions. We determined that the neural stem cells expressed common stem cell markers (nestin and polysialic acid) suggesting they survived after transplantation with MRIgFUS. Furthermore, delivered stem cells expressed doublecortin in vivo indicating the stem cells were capable of differentiating into neurons. Together, we demonstrate that transient opening of the BBB with MRIgFUS is sufficient for transplantation of stem cells from the blood to targeted brain structures. These results suggest that MRIgFUS may be an effective alternative to invasive intracranial surgery for stem cell transplantation.
authors: Imaging Research, Sunnybrook Research Institute, Toronto, Ontario, Canada. aburgess@sri.utoronto.ca
authors: Alison
authors: A
authors: Burgess
authors: Carlos A
authors: CA
authors: Ayala-Grosso
authors: Milan
authors: M
authors: Ganguly
authors: Jessica F
authors: JF
authors: Jordão
authors: Isabelle
authors: I
authors: Aubert
authors: Kullervo
authors: K
authors: Hynynen
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D000089662:Doublecortin Protein; D016503:Drug Delivery Systems; D053595:Embryonic Stem Cells / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007381:Intermediate Filament Proteins / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D058953:Neural Stem Cells / Q000378:metabolism / Q000637:transplantation*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012794:Sialic Acids / Q000378:metabolism; D014463:Ultrasonography
chemical_list: C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D012794:Sialic Acids; C021319:polysialic acid; D049452:Green Fluorescent Proteins; D007501:Iron