title: Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease.
abstract: Intracranial transplantation of neural stem cells (NSCs) delayed disease onset, preserved motor function, reduced pathology and prolonged survival in a mouse model of Sandhoff disease, a lethal gangliosidosis. Although donor-derived neurons were electrophysiologically active within chimeric regions, the small degree of neuronal replacement alone could not account for the improvement. NSCs also increased brain beta-hexosaminidase levels, reduced ganglioside storage and diminished activated microgliosis. Additionally, when oral glycosphingolipid biosynthesis inhibitors (beta-hexosaminidase substrate inhibitors) were combined with NSC transplantation, substantial synergy resulted. Efficacy extended to human NSCs, both to those isolated directly from the central nervous system (CNS) and to those derived secondarily from embryonic stem cells. Appreciating that NSCs exhibit a broad repertoire of potentially therapeutic actions, of which neuronal replacement is but one, may help in formulating rational multimodal strategies for the treatment of neurodegenerative diseases.
authors.affiliation: Stem Cell & Regeneration Program, Center for Neuroscience and Aging Research, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
authors.forename: Jean-Pyo
authors.initials: JP
authors.lastname: Lee
authors.forename: Mylvaganam
authors.initials: M
authors.lastname: Jeyakumar
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Gonzalez
authors.forename: Hiroto
authors.initials: H
authors.lastname: Takahashi
authors.forename: Pei-Jen
authors.initials: PJ
authors.lastname: Lee
authors.forename: Rena C
authors.initials: RC
authors.lastname: Baek
authors.forename: Dan
authors.initials: D
authors.lastname: Clark
authors.forename: Heather
authors.initials: H
authors.lastname: Rose
authors.forename: Gerald
authors.initials: G
authors.lastname: Fu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Clarke
authors.forename: Scott
authors.initials: S
authors.lastname: McKercher
authors.forename: Jennifer
authors.initials: J
authors.lastname: Meerloo
authors.forename: Franz-Josef
authors.initials: FJ
authors.lastname: Muller
authors.forename: Kook In
authors.initials: KI
authors.lastname: Park
authors.forename: Terry D
authors.initials: TD
authors.lastname: Butters
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Dwek
authors.forename: Philip
authors.initials: P
authors.lastname: Schwartz
authors.forename: Gang
authors.initials: G
authors.lastname: Tong
authors.forename: David
authors.initials: D
authors.lastname: Wenger
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Seyfried
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
authors.forename: Evan Y
authors.initials: EY
authors.lastname: Snyder
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000166:cytology*; D053595:Embryonic Stem Cells / Q000166:cytology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D018408:Patch-Clamp Techniques; D012497:Sandhoff Disease / Q000188:drug therapy / Q000628:therapy*; D033581:Stem Cell Transplantation; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D017485:1-Deoxynojirimycin; C090092:migalastat; D001619:beta-N-Acetylhexosaminidases