title: Clinical potential of intravenous neural stem cell delivery for treatment of neuroinflammatory disease in mice?
abstract: While neural stem cells (NSCs) are widely expected to become a therapeutic agent for treatment of severe injuries to the central nervous system (CNS), currently there are only few detailed preclinical studies linking cell fate with experimental outcome. In this study, we aimed to validate whether IV administration of allogeneic NSC can improve experimental autoimmune encephalomyelitis (EAE), a well-established animal model for human multiple sclerosis (MS). For this, we cultured adherently growing luciferase-expressing NSCs (NSC-Luc), which displayed a uniform morphology and expression profile of membrane and intracellular markers, and which displayed an in vitro differentiation potential into neurons and astrocytes. Following labeling with green fluorescent micron-sized iron oxide particles (f-MPIO-labeled NSC-Luc) or lentiviral transduction with the enhanced green fluorescent protein (eGFP) reporter gene (NSC-Luc/eGFP), cell implantation experiments demonstrated the intrinsic survival capacity of adherently cultured NSC in the CNS of syngeneic mice, as analyzed by real-time bioluminescence imaging (BLI), magnetic resonance imaging (MRI), and histological analysis. Next, EAE was induced in C57BL/6 mice followed by IV administration of NSC-Luc/eGFP at day 7 postinduction with or without daily immunosuppressive therapy (cyclosporine A, CsA). During a follow-up period of 20 days, the observed clinical benefit could be attributed solely to CsA treatment. In addition, histological analysis demonstrated the absence of NSC-Luc/eGFP at sites of neuroinflammation. In order to investigate the absence of therapeutic potential, BLI biodistribution analysis of IV-administered NSC-Luc/eGFP revealed cell retention in lung capillaries as soon as 1-min postinjection, resulting in massive inflammation and apoptosis in lung tissue. In summary, we conclude that IV administration of NSCs currently has limited or no therapeutic potential for neuroinflammatory disease in mice, and presumably also for human MS. However, given the fact that grafted NSCs have an intrinsic survival capacity in the CNS, their therapeutic exploitation should be further investigated, and-in contrast to several other reports-will most likely be highly complex.
authors.affiliation: Laboratory of Experimental Hematology, University of Antwerp, Belgium.
authors.forename: Kristien P
authors.initials: KP
authors.lastname: Reekmans
authors.forename: Jelle
authors.initials: J
authors.lastname: Praet
authors.forename: Nathalie
authors.initials: N
authors.lastname: De Vocht
authors.forename: Bart R
authors.initials: BR
authors.lastname: Tambuyzer
authors.forename: Irene
authors.initials: I
authors.lastname: Bergwerf
authors.forename: Jasmijn
authors.initials: J
authors.lastname: Daans
authors.forename: Veerle
authors.initials: V
authors.lastname: Baekelandt
authors.forename: Greetje
authors.initials: G
authors.lastname: Vanhoutte
authors.forename: Herman
authors.initials: H
authors.lastname: Goossens
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Jorens
authors.forename: Dirk K
authors.initials: DK
authors.lastname: Ysebaert
authors.forename: Shyama
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Patrick
authors.initials: P
authors.lastname: Pauwels
authors.forename: Eric
authors.initials: E
authors.lastname: Van Marck
authors.forename: Zwi N
authors.initials: ZN
authors.lastname: Berneman
authors.forename: Annemie
authors.initials: A
authors.lastname: Van der Linden
authors.forename: Peter
authors.initials: P
authors.lastname: Ponsaerts
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002490:Central Nervous System / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology / Q000628:therapy*; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D007275:Injections, Intravenous; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements; D051379:Mice; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000187:drug effects / Q000637:transplantation*; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D008156:Luciferases