Autologous mesenchymal stem cell–derived dopaminergic neurons function in parkinsonian macaques
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
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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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 1

Monkey bone marrow MSCs and MSC-DP cells.

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Monkey bone marrow MSCs and MSC-DP cells. (A) Morphological changes were...
(A) Morphological changes were evident in cynomolgus naive MSCs (phase-contrast microscopy) and (B) MSC-DP cells (phase-contrast microscopy). The MSC-DP cells possessed neurite-like processes. Immunocytochemistry of MSC-DP cells showed that the cells were immunoreactive for the neuronal markers (C) Tuj1 and (D) MAP-2; for the markers of dopaminergic neurons (E) TH, (F) DAT, (G) GIRK2, and (H) FOXA2; and for the marker of neurons, (I) sodium channel (SCN). DAPI was used for counterstaining of nuclei. Scale bar: 30 μm. (J) Results of RT-PCR in naive MSCs, MSC-DP cells, and tissue samples from the SNc and VTA. Naive MSCs expressed no GIRK2, FOXA2, and CALB1 mRNA, while the MSC-DP cells expressed GIRK2 and FOXA2 mRNA. SNc tissue samples from an embryo and an adult cynomolgus monkey also contained high levels of GIRK2 and FOXA2 mRNA but only low levels of CALB1 mRNA, while the VTA contained high levels of CALB1 mRNA and only very low levels of GIRK2 and FOXA2 mRNA. NC, negative control. (K) Percentages of cells immunoreactive for TH, DAT, GIRK2, and FOXA2 in MSC-DP cells.