Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease.
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.
Lee
Jean-Pyo
JP
Stem Cell & Regeneration Program, Center for Neuroscience and Aging Research, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Jeyakumar
Mylvaganam
M
Gonzalez
Rodolfo
R
Takahashi
Hiroto
H
Lee
Pei-Jen
PJ
Baek
Rena C
RC
Clark
Dan
D
Rose
Heather
H
Fu
Gerald
G
Clarke
Jonathan
J
McKercher
Scott
S
Meerloo
Jennifer
J
Muller
Franz-Josef
FJ
Park
Kook In
KI
Butters
Terry D
TD
Dwek
Raymond A
RA
Schwartz
Philip
P
Tong
Gang
G
Wenger
David
D
Lipton
Stuart A
SA
Seyfried
Thomas N
TN
Platt
Frances M
FM
Snyder
Evan Y
EY
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
D017485:1-Deoxynojirimycin; C090092:migalastat; D001619:beta-N-Acetylhexosaminidases