ESC-Derived BDNF-Overexpressing Neural Progenitors Differentially Promote Recovery in Huntington's Disease Models by Enhanced Striatal Differentiation.
Huntington's disease (HD) is characterized by fatal motoric failures induced by loss of striatal medium spiny neurons. Neuronal cell death has been linked to impaired expression and axonal transport of the neurotrophin BDNF (brain-derived neurotrophic factor). By transplanting embryonic stem cell-derived neural progenitors overexpressing BDNF, we combined cell replacement and BDNF supply as a potential HD therapy approach. Transplantation of purified neural progenitors was analyzed in a quinolinic acid (QA) chemical and two genetic HD mouse models (R6/2 and N171-82Q) on the basis of distinct behavioral parameters, including CatWalk gait analysis. Explicit rescue of motor function by BDNF neural progenitors was found in QA-lesioned mice, whereas genetic mouse models displayed only minor improvements. Tumor formation was absent, and regeneration was attributed to enhanced neuronal and striatal differentiation. In addition, adult neurogenesis was preserved in a BDNF-dependent manner. Our findings provide significant insight for establishing therapeutic strategies for HD to ameliorate neurodegenerative symptoms.
Institute of Physiological Chemistry, University Medical Center, Johannes Gutenberg University, Duesbergweg 6, 55128 Mainz, Germany.
Tina
T
Zimmermann
Institute of Physiological Chemistry, University Medical Center, Johannes Gutenberg University, Duesbergweg 6, 55128 Mainz, Germany.
Floortje
F
Remmers
Institute of Physiological Chemistry, University Medical Center, Johannes Gutenberg University, Duesbergweg 6, 55128 Mainz, Germany.
Beat
B
Lutz
Institute of Physiological Chemistry, University Medical Center, Johannes Gutenberg University, Duesbergweg 6, 55128 Mainz, Germany. Electronic address: leschik@uni-mainz.de.
Julia
J
Leschik
D000818:Animals; D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D002454:Cell Differentiation; D002470:Cell Survival; D003342:Corpus Striatum; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D015870:Gene Expression; D017930:Genes, Reporter; D006816:Huntington Disease / Q000235:genetics* / Q000503:physiopathology*; D008124:Locomotion; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D033581:Stem Cell Transplantation
D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor
Huntington’s disease; brain-derived neurotrophic factor; embryonic stem cells; striatal differentiation
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