Clinical potential of intravenous neural stem cell delivery for treatment of neuro-inflammatory disease in mice?
Faculty of Medicine and Health Sciences
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Cell transplantation. - Amsterdam
, p. 851-869
University of Antwerp
While neural stem cells (NSC) 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 pre-clinical studies linking cell fate with experimental outcome. In this study, we aimed to validate whether intravenous (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 NSC (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 labelling with green fluorescent micron-sized iron oxide particles (f-MPIO-labelled 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 analysed 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 post-induction 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 neuro-inflammation. 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-minute post-injection, resulting in massive inflammation and apoptosis in lung tissue. In summary, we conclude that IV administration of NSC currently has limited or no therapeutic potential for neuro-inflammatory disease in mice, and presumably also for human MS. However, given the fact that grafted NSC 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.