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Wnt5a-treated midbrain neural stem cells improve dopamine cell replacement therapy in parkinsonian mice
Clare L. Parish, … , Olle Lindvall, Ernest Arenas
Clare L. Parish, … , Olle Lindvall, Ernest Arenas
Published December 3, 2007
Citation Information: J Clin Invest. 2008;118(1):149-160. https://doi.org/10.1172/JCI32273.
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Research Article Article has an altmetric score of 6

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

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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.

Authors

Clare L. Parish, Gonçalo Castelo-Branco, Nina Rawal, Jan Tonnesen, Andreas Toft Sorensen, Carmen Salto, Merab Kokaia, Olle Lindvall, Ernest Arenas

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Figure 2

Wnt5a mediates effects on DA differentiation via noncanonical signaling across rodent species.

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Wnt5a mediates effects on DA differentiation via noncanonical signaling ...
(A and B) Effects of Wnt5a overexpression were abolished by using a Wnt5a-blocking antibody (W5-ab) or the D4476 CKI inhibitor (CKI), but not the canonical Wnt blocker dickkopf-1 (DKF1). Mouse recombinant Wnt5a protein (r.m.W5) induced effects comparable to those of Wnt5a overexpression in control-transfected spheres. (C and D) Comparable trends for number of TH+ cells per sphere (C) and percentage of TH+ spheres per Tuj1/βIII-tubulin+ spheres (D) were observed in E12.5 rat compared with E10.5 mouse cultures. However, significantly more TH+ cells were present in rat cultures than in mouse cultures. Data are mean ± SD (n = 4). *P < 0.05; **P < 0.01; ***P < 0.001, 1-way ANOVA with Tukey post-hoc test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 4 patents
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