title: HuCNS-SC Human NSCs Fail to Differentiate, Form Ectopic Clusters, and Provide No Cognitive Benefits in a Transgenic Model of Alzheimer's Disease.
abstract: Transplantation of neural stem cells (NSCs) can improve cognition in animal models of Alzheimer's disease (AD). However, AD is a protracted disorder, and prior studies have examined only short-term effects. We therefore used an immune-deficient model of AD (Rag-5xfAD mice) to examine long-term transplantation of human NSCs (StemCells Inc.; HuCNS-SCs). Five months after transplantation, HuCNS-SCs had engrafted and migrated throughout the hippocampus and exhibited no differences in survival or migration in response to β-amyloid pathology. Despite robust engraftment, HuCNS-SCs failed to terminally differentiate and over a quarter of the animals exhibited ectopic human cell clusters within the lateral ventricle. Unlike prior short-term experiments with research-grade HuCNS-SCs, we also found no evidence of improved cognition, no changes in brain-derived neurotrophic factor, and no increase in synaptic density. These data, while disappointing, reinforce the notion that individual human NSC lines need to be carefully assessed for efficacy and safety in appropriate long-term models.
authors.affiliation: Department of Neurobiology & Behavior, University of California Irvine, 845 Health Sciences Road, 3200 Gross Hall, Irvine, CA 92697, USA; Sue & Bill Gross Stem Cell Research Center, University of California Irvine, 845 Health Sciences Road, 3200 Gross Hall, Irvine, CA 92697, USA; Institute for Memory Impairments & Neurological Disorders, University of California Irvine, 845 Health Sciences Road, 3200 Gross Hall, Irvine, CA 92697, USA.
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Marsh
authors.affiliation: Institute for Memory Impairments & Neurological Disorders, University of California Irvine, 845 Health Sciences Road, 3200 Gross Hall, Irvine, CA 92697, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Yeung
authors.affiliation: Institute for Memory Impairments & Neurological Disorders, University of California Irvine, 845 Health Sciences Road, 3200 Gross Hall, Irvine, CA 92697, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Torres
authors.affiliation: Institute for Memory Impairments & Neurological Disorders, University of California Irvine, 845 Health Sciences Road, 3200 Gross Hall, Irvine, CA 92697, USA.
authors.forename: Lydia
authors.initials: L
authors.lastname: Lau
authors.affiliation: Institute for Memory Impairments & Neurological Disorders, University of California Irvine, 845 Health Sciences Road, 3200 Gross Hall, Irvine, CA 92697, USA.
authors.forename: Joy L
authors.initials: JL
authors.lastname: Davis
authors.affiliation: Sue & Bill Gross Stem Cell Research Center, University of California Irvine, 845 Health Sciences Road, 3200 Gross Hall, Irvine, CA 92697, USA; Institute for Memory Impairments & Neurological Disorders, University of California Irvine, 845 Health Sciences Road, 3200 Gross Hall, Irvine, CA 92697, USA; Department of Pathology & Laboratory Medicine, University of California Irvine, 845 Health Sciences Road, 3200 Gross Hall, Irvine, CA 92697, USA.
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Monuki
authors.affiliation: Institute for Memory Impairments & Neurological Disorders, University of California Irvine, 845 Health Sciences Road, 3200 Gross Hall, Irvine, CA 92697, USA.
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Poon
authors.affiliation: Department of Neurobiology & Behavior, University of California Irvine, 845 Health Sciences Road, 3200 Gross Hall, Irvine, CA 92697, USA; Sue & Bill Gross Stem Cell Research Center, University of California Irvine, 845 Health Sciences Road, 3200 Gross Hall, Irvine, CA 92697, USA; Institute for Memory Impairments & Neurological Disorders, University of California Irvine, 845 Health Sciences Road, 3200 Gross Hall, Irvine, CA 92697, USA. Electronic address: mblurton@uci.edu.
authors.forename: Mathew
authors.initials: M
authors.lastname: Blurton-Jones
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000473:pathology* / Q000523:psychology* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002449:Cell Aggregation; D002454:Cell Differentiation; D002465:Cell Movement; D002470:Cell Survival; D003071:Cognition; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D020547:Lateral Ventricles / Q000378:metabolism / Q000473:pathology; D018782:Maze Learning; D008568:Memory; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D033581:Stem Cell Transplantation; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor
keywords: Alzheimer's disease; HuCNS-SC; NSC; cognition; dementia; hippocampus; stem cells; translation; transplantation; β-amyloid