title: Serial in vivo imaging of transplanted allogeneic neural stem cell survival in a mouse model of amyotrophic lateral sclerosis.
abstract: Neural stem cells (NSCs) are being investigated as a possible treatment for amyotrophic lateral sclerosis (ALS) through intraspinal transplantation, but no longitudinal imaging studies exist that describe the survival of engrafted cells over time. Allogeneic firefly luciferase-expressing murine NSCs (Luc+-NSCs) were transplanted bilaterally (100,000 cells/2μl) into the cervical spinal cord (C5) parenchyma of pre-symptomatic (63day-old) SOD1G93AALS mice (n=14) and wild-type age-matched littermates (n=14). Six control SOD1G93AALS mice were injected with saline. Mice were immunosuppressed using a combination of tacrolimus+sirolimus (1mg/kg each, i.p.) daily. Compared to saline-injected SOD1G93AALS control mice, a transient improvement (p<0.05) in motor performance (rotarod test) was observed after NSC transplantation only at the early disease stage (weeks 2 and 3 post-transplantation). Compared to day one post-transplantation, there was a significant decline in bioluminescent imaging (BLI) signal in SOD1G93AALS mice at the time of disease onset (71.7±17.9% at 4weeks post-transplantation, p<0.05), with a complete loss of BLI signal at endpoint (120day-old mice). In contrast, BLI signal intensity was observed in wild-type littermates throughout the entire study period, with only a 41.4±8.7% decline at the endpoint. In SOD1G93AALS mice, poor cell survival was accompanied by accumulation of mature macrophages and the presence of astrogliosis and microgliosis. We conclude that the disease progression adversely affects the survival of engrafted murine Luc+-NSCs in SOD1G93AALS mice as a result of the hostile ALS spinal cord microenvironment, further emphasizing the challenges that face successful cell therapy of ALS.
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Srivastava
authors.affiliation: Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Gross
authors.affiliation: Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Akshata A
authors.initials: AA
authors.lastname: Almad
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Camille A
authors.initials: CA
authors.lastname: Bulte
authors.affiliation: Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Maragakis
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Chemical & Biomolecular Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: jwmbulte@mri.jhu.edu.
authors.forename: Jeff W M
authors.initials: JWM
authors.lastname: Bulte
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000000981:diagnostic imaging* / Q000235:genetics / Q000601:surgery*; D000818:Animals; D002470:Cell Survival; D004195:Disease Models, Animal; D018450:Disease Progression; D004622:Embryo, Mammalian; D005500:Follow-Up Studies; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000637:transplantation*; D011596:Psychomotor Disorders / Q000209:etiology / Q000601:surgery; D020123:Sirolimus / Q000494:pharmacology; D013116:Spinal Cord / Q000000981:diagnostic imaging / Q000601:surgery; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D009419:Nerve Tissue Proteins; D008156:Luciferases; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D020123:Sirolimus; D016559:Tacrolimus
keywords: Amyotrophic lateral sclerosis; Bioluminescence imaging; Cell survival; Neural stem cell; Transplantation