Autologous mesenchymal stem cell–derived dopaminergic neurons function in parkinsonian macaques
Takuya Hayashi, … , Yasuhiko Tabata, Mari Dezawa
Takuya Hayashi, … , Yasuhiko Tabata, Mari Dezawa
Published December 3, 2012
Citation Information: J Clin Invest. 2013;123(1):272-284. https://doi.org/10.1172/JCI62516.
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Research Article Neuroscience

Autologous mesenchymal stem cell–derived dopaminergic neurons function in parkinsonian macaques

Abstract

A cell-based therapy for the replacement of dopaminergic neurons has been a long-term goal in Parkinson’s disease research. Here, we show that autologous engraftment of A9 dopaminergic neuron-like cells induced from mesenchymal stem cells (MSCs) leads to long-term survival of the cells and restoration of motor function in hemiparkinsonian macaques. Differentiated MSCs expressed markers of A9 dopaminergic neurons and released dopamine after depolarization in vitro. The differentiated autologous cells were engrafted in the affected portion of the striatum. Animals that received transplants showed modest and gradual improvements in motor behaviors. Positron emission tomography (PET) using [11C]-CFT, a ligand for the dopamine transporter (DAT), revealed a dramatic increase in DAT expression, with a subsequent exponential decline over a period of 7 months. Kinetic analysis of the PET findings revealed that DAT expression remained above baseline levels for over 7 months. Immunohistochemical evaluations at 9 months consistently demonstrated the existence of cells positive for DAT and other A9 dopaminergic neuron markers in the engrafted striatum. These data suggest that transplantation of differentiated autologous MSCs may represent a safe and effective cell therapy for Parkinson’s disease.

Authors

Takuya Hayashi, Shohei Wakao, Masaaki Kitada, Takayuki Ose, Hiroshi Watabe, Yasumasa Kuroda, Kanae Mitsunaga, Dai Matsuse, Taeko Shigemoto, Akihito Ito, Hironobu Ikeda, Hidenao Fukuyama, Hirotaka Onoe, Yasuhiko Tabata, Mari Dezawa

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Figure 3

Engrafting and neuroimaging of MSC-DP–engrafted animals.

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Engrafting and neuroimaging of MSC-DP–engrafted animals. (A) Twelve targ...
(A) Twelve target points (white dots) for engraftment in putamen in the coronal sections of standard space of cynomolgus macaque. Scale bar: 10 mm. (B) Representative 11C-CFT PET images of MSC-DP–engrafted animals. Seven days after engraftment (engraft), animal mon0703 showed the highest 11C-CFT BPND on the MPTP-treated side of striatum (yellow arrow), followed by animal mon0710 (white arrow). Animal mon0710 showed low signal (green arrow) in a T1-weighted MRI after engraftment, which diminished in later scans. Note that the BPND in the non-MPTP–treated (and nonengrafted) side of striatum was very high (white arrowheads) and not different by engraftments. (C) Significant effect of time on 11C-CFT BPND (P values range from yellow [P < 0.00] to red [P < 0.05]) overlaid on the study-specific MRI template in MNI space. A cluster with FWE-corrected P < 0.05 was located in the dorsal posterior putamen in the engrafted striatum. See also Table 2. (D) Time course of 11C-CFT BPND in the cluster (in C) and contralateral equivalent region. *P < 0.05 compared with sham, Bonferroni corrected. (E) Time course of 11C-CFT BPND values in the cluster (in C), fitted by the 1-hit (exponential) model of neurodegeneration. The dashed line and gray area indicate the mean and SEM for the baseline BPND. *P < 0.05 between the baseline BPND and the plateau of the fitted model. (F) The DArc and the 11C-CFT BPND values at 7 days and 1, 3, and 7 months after engraftment.