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Jan 25, 2012

iPSC-Derived Progenitors Differentiate into Dopaminergic Neurons in Primate Model of PD

  • Scientists report on what they claim is the first evaluation of human induced pluripotent stem cell (iPSC)-derived neural progenitor cell (NPC) transplants in a primate model of Parkinson disease (PD). The Japanese team, led by investigators at Kyoto University’s Institute for Frontier Medical Sciences, and Center for iPS Cell Research and Application, first generated NPCs at different stages of predifferentiation using a feeder-free culture method. They then grafted the cells into the brains of NOD-SCID mice, and an adult male cynomolgus monkey induced to develop Parkinson disease symptoms through the intravenous administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) HCl. The team in addition developed a system to evaluate the transplanted cells using MRI and PET, along with behavioral analyses and histological examination.

    Their results demonstrated that the transplanted cells survived for six months in the brains of the primate PD model, and generated dopaminergic neurons. Jun Takahashi, M.D., and colleagues, describe their work in the Journal of Parkinson’s Disease, in a paper titled “Survival of Human Induced Pluripotent Stem Cell–Derived Midbrain Dopaminergic Neurons in the Brain of a Primate Model of Parkinson’s Disease.”

    Mouse and human iPSC-derived dopaminergic neurons have been shown to improve symptoms in rodent models of PD, but the characterization, behavior, and function of such cells hasn’t yet been evaluated in primates. To date, cell transplantation studies in primates has involved either monkey or human embryonic stem cell-derived neural progenitors, the researchers explain.

    They now report on a protocol for differentiating human iPSCs into NPCs without the requirement for feeder cells, using serum-free floating cultures, propagated in a series of defined media. As part of this process, Sonic hedgehog (Shh) and fibroblast growth factor (FGF8) were added on days 14–28, and then on day 28 the medium was replaced with neurobasal medium supplemented with B-27, glutamine, glial cell-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), dibutyryl cyclic AMP (dbcAMP), and ascorbic acid.

    MRI analyses six months after transplantation confirmed that the grafted cells survived and proliferated in the monkey brain. However, further evaluation demonstrated that only the NPCs pretreated with Shh and FGF-8, followed by GDNF, BDNF, ascorbic acid, and dbcAMP, resulted in a substantial number of functional DA neurons in the monkey’s brain.

    Further evaluation demonstrated that TH+ cells were present in the periphery of each graft, and these cells also expressed markers of mature midbrain DA neurons. Behavioral studies, based on a previously described behavioral rating scale, were carried out both before and after transplantation, and indicated a slight improvement after six months.

    “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,” the authors conclude. “Additional studies using other primate models and NPCs subjected to alternative pretreatment protocols will help elucidate the therapeutic potential of human iPSCs.” 


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