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Wnt5a-treated midbrain neural stem cells improve dopamine cell replacement therapy in parkinsonian mice

Parish, CL; Castelo-Branco, G; Rawal, N; Tönnesen, Jan LU ; Toft Sörensen, Andreas LU ; Salto, C; Kokaia, Merab LU ; Lindvall, Olle LU and Arenas, E (2008) In Journal of Clinical Investigation 118(1). p.149-160
Abstract
Dopamine (DA) cell replacement therapy in Parkinson disease (PD) can be achieved using human fetal mesencephalic tissue; however, limited tissue availability has hindered further developments. Embryonic stem cells provide a promising alternative, but poor survival and risk of teratoma formation have prevented their clinical application. We present here a method for generating large numbers of DA neurons based on expanding and differentiating ventral midbrain (VM) neural stem cells/progenitors in the presence of key signals necessary for VM DA neuron development. Mouse VM neurospheres (VMNs) expanded with FGF2, differentiated with sonic hedgehog and FGF8, and transfected with Wnt5a (VMN-Wnt5a) generated 10-fold more DA neurons than did... (More)
Dopamine (DA) cell replacement therapy in Parkinson disease (PD) can be achieved using human fetal mesencephalic tissue; however, limited tissue availability has hindered further developments. Embryonic stem cells provide a promising alternative, but poor survival and risk of teratoma formation have prevented their clinical application. We present here a method for generating large numbers of DA neurons based on expanding and differentiating ventral midbrain (VM) neural stem cells/progenitors in the presence of key signals necessary for VM DA neuron development. Mouse VM neurospheres (VMNs) expanded with FGF2, differentiated with sonic hedgehog and FGF8, and transfected with Wnt5a (VMN-Wnt5a) generated 10-fold more DA neurons than did conventional FGF2-treated VMNs. VMN-Wnt5a cells exhibited the transcriptional and biochemical profiles and intrinsic electrophysiological properties of midbrain DA cells. Transplantation of these cells into parkinsonian mice resulted in significant cellular and functional recovery. Importantly, no tumors were detected and only a few transplanted grafts contained sporadic nestin-expressing progenitors. Our findings show that Wnt5a improves the differentiation and functional integration of stem cell-derived DA neurons in vivo and define Wnt5a-treated neural stem cells as an efficient and safe source of DA neurons for cell replacement therapy in PD. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Clinical Investigation
volume
118
issue
1
pages
149 - 160
publisher
The Journal of Clinical Investigation
external identifiers
  • pmid:18060047
  • wos:000252122900017
  • scopus:38149126482
ISSN
0021-9738
DOI
10.1172/JCI32273
language
English
LU publication?
yes
id
5947d60c-6960-45cf-9515-ad93d7ec8c77 (old id 1141364)
date added to LUP
2008-08-05 12:27:46
date last changed
2017-09-24 04:01:17
@article{5947d60c-6960-45cf-9515-ad93d7ec8c77,
  abstract     = {Dopamine (DA) cell replacement therapy in Parkinson disease (PD) can be achieved using human fetal mesencephalic tissue; however, limited tissue availability has hindered further developments. Embryonic stem cells provide a promising alternative, but poor survival and risk of teratoma formation have prevented their clinical application. We present here a method for generating large numbers of DA neurons based on expanding and differentiating ventral midbrain (VM) neural stem cells/progenitors in the presence of key signals necessary for VM DA neuron development. Mouse VM neurospheres (VMNs) expanded with FGF2, differentiated with sonic hedgehog and FGF8, and transfected with Wnt5a (VMN-Wnt5a) generated 10-fold more DA neurons than did conventional FGF2-treated VMNs. VMN-Wnt5a cells exhibited the transcriptional and biochemical profiles and intrinsic electrophysiological properties of midbrain DA cells. Transplantation of these cells into parkinsonian mice resulted in significant cellular and functional recovery. Importantly, no tumors were detected and only a few transplanted grafts contained sporadic nestin-expressing progenitors. Our findings show that Wnt5a improves the differentiation and functional integration of stem cell-derived DA neurons in vivo and define Wnt5a-treated neural stem cells as an efficient and safe source of DA neurons for cell replacement therapy in PD.},
  author       = {Parish, CL and Castelo-Branco, G and Rawal, N and Tönnesen, Jan and Toft Sörensen, Andreas and Salto, C and Kokaia, Merab and Lindvall, Olle and Arenas, E},
  issn         = {0021-9738},
  language     = {eng},
  number       = {1},
  pages        = {149--160},
  publisher    = {The Journal of Clinical Investigation},
  series       = {Journal of Clinical Investigation},
  title        = {Wnt5a-treated midbrain neural stem cells improve dopamine cell replacement therapy in parkinsonian mice},
  url          = {http://dx.doi.org/10.1172/JCI32273},
  volume       = {118},
  year         = {2008},
}