Mesenchymal stem cell transplantation and DMEM administration in a 3NP rat model of Huntington's disease: morphological and behavioral outcomes.
Transplantation of mesenchymal stem cells (MSCs) may offer a viable treatment for Huntington's disease (HD). We tested the efficacy of MSC transplants to reduce deficits in a 3-nitropropionic acid (3NP) rat model of HD. Five groups of rats (Sham, 3NP, 3NP+vehicle, 3NP+TP(low), 3NP+TP(high)), were given PBS or 3NP intraperitoneally, twice daily for 42 days. On day 28, rats in all groups except Sham and 3NP, received intrastriatal injections of either 200,000 MSCs (TP(low)), 400,000 (TP(high)) MSCs or DMEM (VH, the vehicle for transplantation). MSCs survived 72 days without inducing a strong inflammatory response from the striatum. Behavioral sparing was observed on tests of supported-hindlimb-retraction, unsupported-hindlimb-retraction, visual paw placement and stepping ability for 3NP+TP(low) rats and on the unsupported-hindlimb-retraction and rotarod tasks for 3NP+VH rats. Relative to 3NP controls, all treated groups were protected from 3NP-induced enlargement of the lateral ventricles. In vitro, MSCs expressed transcripts for numerous neurotrophic factors. In vivo, increased striatal labeling in BDNF, collagen type-I and fibronectin (but not GDNF or CNTF) was observed in the brains of MSC-transplanted rats but not in DMEM-treated rats. In addition, none of the transplanted MSCs expressed neural phenotypes. These findings suggest that factors other than neuronal replacement underlie the behavioral sparing observed in 3NP rats after MSC transplantation.
INSERM U643, Nantes F44093, France.
Julien
J
Rossignol
Cécile
C
Boyer
Xavier
X
Lévèque
Kyle D
KD
Fink
Reynald
R
Thinard
Frédéric
F
Blanchard
Gary L
GL
Dunbar
Laurent
L
Lescaudron
D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003292:Convulsants / Q000633:toxicity*; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006614:Hindlimb / Q000187:drug effects / Q000503:physiopathology; D006816:Huntington Disease / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D009574:Nitro Compounds / Q000633:toxicity*; D010006:Osteoblasts / Q000187:drug effects / Q000502:physiology; D010751:Phosphopyruvate Hydratase / Q000235:genetics / Q000378:metabolism; D011422:Propionates / Q000633:toxicity*; D011597:Psychomotor Performance / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D003292:Convulsants; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009414:Nerve Growth Factors; D009574:Nitro Compounds; C497930:Ppp1r1b protein, rat; D011422:Propionates; D012333:RNA, Messenger; D010751:Phosphopyruvate Hydratase; C015392:3-nitropropionic acid