title: Magnetic-resonance-based tracking and quantification of intravenously injected neural stem cell accumulation in the brains of mice with experimental multiple sclerosis.
abstract: Eliciting the in situ accumulation and persistence patterns of stem cells following transplantation would provide critical insight toward human translation of stem cell-based therapies. To this end, we have developed a strategy to track neural stem/precursor cells (NPCs) in vivo using magnetic resonance (MR) imaging. Initially, we evaluated three different human-grade superparamagnetic iron oxide particles for labeling NPCs and found the optimal labeling to be achieved with Resovist. Next, we carried out in vivo experiments to monitor the accumulation of Resovist-labeled NPCs following i.v. injection in mice with experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. With a human MR scanner, we were able to visualize transplanted cells as early as 24 hours post-transplantation in up to 80% of the brain demyelinating lesions. Interestingly, continued monitoring of transplanted mice indicated that labeled NPCs were still present 20 days postinjection. Neuropathological analysis confirmed the presence of transplanted NPCs exclusively in inflammatory demyelinating lesions and not in normal-appearing brain areas. Quantification of transplanted cells by means of MR-based ex vivo relaxometry (R2*) showed significantly higher R2* values in focal inflammatory brain lesions from EAE mice transplanted with labeled NPCs as compared with controls. Indeed, sensitive quantification of low numbers of NPCs accumulating into brain inflammatory lesions (33.3-164.4 cells per lesion; r(2) = .998) was also obtained. These studies provide evidence that clinical-grade human MR can be used for noninvasive monitoring and quantification of NPC accumulation in the central nervous system upon systemic cell injection. Disclosure of potential conflicts of interest is found at the end of this article.
authors.affiliation: Neuroradiology Unit, Centro Eccellenza Risonanza Magnetica ad Alto Campo, Italy.
authors.forename: Letterio S
authors.initials: LS
authors.lastname: Politi
authors.forename: Marco
authors.initials: M
authors.lastname: Bacigaluppi
authors.forename: Elena
authors.initials: E
authors.lastname: Brambilla
authors.forename: Marcello
authors.initials: M
authors.lastname: Cadioli
authors.forename: Andrea
authors.initials: A
authors.lastname: Falini
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Scotti
authors.forename: Gianvito
authors.initials: G
authors.lastname: Martino
authors.forename: Stefano
authors.initials: S
authors.lastname: Pluchino
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D019070:Cell Lineage; D003911:Dextrans; D018450:Disease Progression; D017352:Echo-Planar Imaging / Q000295:instrumentation / Q000379:methods; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology* / Q000601:surgery; D005260:Female; D052203:Ferrosoferric Oxide; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D007275:Injections, Intravenous; D007501:Iron / Q000032:analysis; D008279:Magnetic Resonance Imaging / Q000295:instrumentation / Q000379:methods*; D058185:Magnetite Nanoparticles; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000601:surgery; D009474:Neurons / Q000166:cytology*; D010087:Oxides / Q000032:analysis; D033581:Stem Cell Transplantation / Q000379:methods*
chemical_list: D003911:Dextrans; D058185:Magnetite Nanoparticles; D010087:Oxides; C097921:ferumoxtran-10; D049452:Green Fluorescent Proteins; D007501:Iron; D052203:Ferrosoferric Oxide