Time of transplantation and cell preparation determine neural stem cell survival in a mouse model of Huntington's disease.
Cell replacement therapies for neurodegenerative diseases, using multipotent neural stem cells (NSCs), require above all, a good survival of the graft. In this study, we unilaterally injected quinolinic acid (QA) into the striatum of adult mice and transplanted syngeneic NSCs of enhanced green fluorescent protein-transgenic mice into the lesioned striatum. The injection of QA leads to an excitotoxic lesion with selective cell death of the medium sized spiny neurons, the same cells that are affected in Huntington's disease. In order to investigate the best timing of transplantation for the survival of donor cells, we transplanted the stem cells at 2, 7 and 14 days after injury. In addition, the influence of graft preparation prior to transplantation, i.e., intact neurospheres versus dissociated cell suspension on graft survival was investigated. By far the best survival was found with the combination of early transplantation (i.e., 2 days after QA-lesion) with the use of neurospheres instead of dissociated cell suspension. This might be due to the different states of host's astrocytic and microglia activation which we found to be moderate at 2, but pronounced at 7 and 14 days after QA-lesion. We also investigated brain derived neurotrophic factor (BDNF)-expression in the striatum after QA-lesion and found no significant change in BDNF protein-level. We conclude that already the method of graft preparation of NSCs for transplantation, as well as the timing of the transplantation procedure strongly affects the survival of the donor cells when grafted into the QA-lesioned striatum of adult mice.
Johann
Verena
V
Department of Neurology, University Hospital RWTH, Pauwelsstr. 30, 52074 Aachen, Germany.
Schiefer
Johannes
J
Sass
Christian
C
Mey
Jörg
J
Brook
Gary
G
Krüttgen
Alexander
A
Schlangen
Christiane
C
Bernreuther
Christian
C
Schachner
Melitta
M
Dihné
Marcel
M
Kosinski
Christoph M
CM
D000818:Animals; D016380:Brain Tissue Transplantation / Q000379:methods*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D018929:Cell Culture Techniques / Q000379:methods; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000502:physiology / Q000637:transplantation; D003714:Denervation; D004195:Disease Models, Animal; D005260:Female; D005911:Gliosis / Q000503:physiopathology / Q000517:prevention & control; D006085:Graft Survival / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006816:Huntington Disease / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D009498:Neurotoxins; D018874:Spheroids, Cellular / Q000166:cytology / Q000502:physiology / Q000637:transplantation; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D009498:Neurotoxins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins