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Survival of Human Induced Pluripotent Stem Cell–Derived Midbrain Dopaminergic Neurons in the Brain of a Primate Model of Parkinson's Disease

Article type: Research Article

Authors: Kikuchi, Tetsuhiro; ; | Morizane, Asuka; | Doi, Daisuke; ; | Onoe, Hirotaka | Hayashi, Takuya; | Kawasaki, Toshiyuki | Saiki, Hidemoto | Miyamoto, Susumu | Takahashi, Jun; ;

Affiliations: Department of Biological Repair, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan | Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan | Department of Neurosurgery, Clinical Neuroscience, Kyoto University Graduate School of Medicine, Kyoto, Japan | Functional Probe Research Laboratory, RIKEN Center for Molecular Imaging Science, Kobe, Japan | Department of Neurology, Kitano Hospital, Osaka, Japan

Note: [] Correspondence to: Jun Takahashi, M.D., Ph.D., Department of Biological Repair, Institute for Frontier Medical Sciences, Kyoto University, 53 Shogoin kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Tel.: 81 75 751 4840; Fax: 81 75 751 4840; E-mail: jbtaka@frontier.kyoto-u.ac.jp

Keywords: Induced pluripotent stem cells, Parkinson's disease, transplantation, dopaminergic neurons, positron emission tomography

DOI: 10.3233/JPD-2011-11070

Journal: Journal of Parkinson's Disease, vol. 1, no. 4, pp. 395-412, 2011

Published: 2011
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Abstract

Before induced pluripotent stem cells (iPSCs) can be used to treat neurologic diseases, human iPSC-derived neural cells must be analyzed in the primate brain. In fact, although mouse and human iPSCs have been used to generate dopaminergic (DA) neurons that are beneficial in rat models of Parkinson's disease (PD), human iPSC-derived neural progenitor cells (NPCs) have not been examined in primate brains. Here, we generated NPCs at different stages of predifferentiation using a feeder-free culture method, and grafted them into the brains of a monkey PD model and NOD-SCID mice. Magnetic resonance imaging (MRI), positron emission tomography (PET), immunocytochemistry, and behavioral analyses revealed that NPCs pretreated with Sonic hedgehog and fibroblast growth factor-8 followed by glial cell–derived neurotrophic factor, brain-derived neurotrophic factor, ascorbic acid, and dibutyryl cyclic AMP resulted in smaller grafts than those without these treatments, and survived as DA neurons in a monkey brain as long as six months. Thus, for the first time, we describe a feeder-free neural differentiation method from human iPSCs and an evaluation system that can be used to assess monkey PD models.

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