title: Human Cortical Neural Stem Cells Expressing Insulin-Like Growth Factor-I: A Novel Cellular Therapy for Alzheimer's Disease.
abstract: Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder and a leading cause of dementia. Current treatment fails to modify underlying disease pathologies and very little progress has been made to develop effective drug treatments. Cellular therapies impact disease by multiple mechanisms, providing increased efficacy compared with traditional single-target approaches. In amyotrophic lateral sclerosis, we have shown that transplanted spinal neural stem cells (NSCs) integrate into the spinal cord, form synapses with the host, improve inflammation, and reduce disease-associated pathologies. Our current goal is to develop a similar "best in class" cellular therapy for AD. Here, we characterize a novel human cortex-derived NSC line modified to express insulin-like growth factor-I (IGF-I), HK532-IGF-I. Because IGF-I promotes neurogenesis and synaptogenesis in vivo, this enhanced NSC line offers additional environmental enrichment, enhanced neuroprotection, and a multifaceted approach to treating complex AD pathologies. We show that autocrine IGF-I production does not impact the cell secretome or normal cellular functions, including proliferation, migration, or maintenance of progenitor status. However, HK532-IGF-I cells preferentially differentiate into gamma-aminobutyric acid-ergic neurons, a subtype dysregulated in AD; produce increased vascular endothelial growth factor levels; and display an increased neuroprotective capacity in vitro. We also demonstrate that HK532-IGF-I cells survive peri-hippocampal transplantation in a murine AD model and exhibit long-term persistence in targeted brain areas. In conclusion, we believe that harnessing the benefits of cellular and IGF-I therapies together will provide the optimal therapeutic benefit to patients, and our findings support further preclinical development of HK532-IGF-I cells into a disease-modifying intervention for AD.
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: McGinley
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Sims
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: J Simon
authors.initials: JS
authors.lastname: Lunn
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Osama N
authors.initials: ON
authors.lastname: Kashlan
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Chen
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Bruno
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Crystal M
authors.initials: CM
authors.lastname: Pacut
authors.affiliation: Neuralstem, Inc., Germantown, Maryland, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Hazel
authors.affiliation: Neuralstem, Inc., Germantown, Maryland, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Johe
authors.affiliation: A. Alfred Taubman Medical Research Institute, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Sakowski
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA A. Alfred Taubman Medical Research Institute, University of Michigan, Ann Arbor, Michigan, USA efeldman@med.umich.edu.
authors.forename: Eva L
authors.initials: EL
authors.lastname: Feldman
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology / Q000628:therapy*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D064987:Cell- and Tissue-Based Therapy; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000637:transplantation*; D055495:Neurogenesis; D009474:Neurons / Q000473:pathology / Q000637:transplantation; D013569:Synapses / Q000502:physiology
chemical_list: D007334:Insulin-Like Growth Factor I
keywords: Alzheimer’s disease; Cellular therapy; Insulin-like growth factor-I; Neural stem cell; Neurodegeneration; Stem cell transplantation