Induced pluripotent stem cells (iPS cells) are a promising source for a cell-based therapy to treat Parkinson's disease (PD), in which midbrain dopaminergic neurons progressively degenerate. However, long-term analysis of human iPS cell-derived dopaminergic neurons in primate PD models has never been performed to our knowledge. Here we show that human iPS cell-derived dopaminergic progenitor cells survived and functioned as midbrain dopaminergic neurons in a primate model of PD (Macaca fascicularis) treated with the neurotoxin MPTP. Score-based and video-recording analyses revealed an increase in spontaneous movement of the monkeys after transplantation. Histological studies showed that the mature dopaminergic neurons extended dense neurites into the host striatum; this effect was consistent regardless of whether the cells were derived from patients with PD or from healthy individuals. Cells sorted by the floor plate marker CORIN did not form any tumours in the brains for at least two years. Finally, magnetic resonance imaging and positron emission tomography were used to monitor the survival, expansion and function of the grafted cells as well as the immune response in the host brain. Thus, this preclinical study using a primate model indicates that human iPS cell-derived dopaminergic progenitors are clinically applicable for the treatment of patients with PD.

The banking of human leukocyte antigen (HLA)-homozygous-induced pluripotent stem cells (iPSCs) is considered a future clinical strategy for HLA-matched cell transplantation to reduce immunological graft rejection. Here we show the efficacy of major histocompatibility complex (MHC)-matched allogeneic neural cell grafting in the brain, which is considered a less immune-responsive tissue, using iPSCs derived from an MHC homozygous cynomolgus macaque. Positron emission tomography imaging reveals neuroinflammation associated with an immune response against MHC-mismatched grafted cells. Immunohistological analyses reveal that MHC-matching reduces the immune response by suppressing the accumulation of microglia (Iba-1+) and lymphocytes (CD45+) into the grafts. Consequently, MHC-matching increases the survival of grafted dopamine neurons (tyrosine hydroxylase: TH+). The effect of an immunosuppressant, Tacrolimus, is also confirmed in the same experimental setting. Our results demonstrate the rationale for MHC-matching in neural cell grafting to the brain and its feasibility in a clinical setting.

Takara S, Hatanaka N, Takada M, Nambu A. Differential activity patterns of putaminal neurons with inputs from the primary motor cortex and supplementary motor area in behaving monkeys. J Neurophysiol 106: 1203-1217, 2011. First published June 8, 2011 doi:10.1152/jn.00768.2010.-Activity patterns of projection neurons in the putamen were investigated in behaving monkeys. Stimulating electrodes were implanted chronically into the proximal (MI proximal ) and distal (MI distal ) forelimb regions of the primary motor cortex (MI) and the forelimb region of the supplementary motor area (SMA). Cortical inputs to putaminal neurons were identified by excitatory orthodromic responses to stimulation of these motor cortices. Then, neuronal activity was recorded during the performance of a goaldirected reaching task with delay. Putaminal neurons with inputs from the MI and SMA showed different activity patterns, i.e., movementand delay-related activity, during task performance. MI-recipient neurons increased activity in response to arm-reach movements, whereas SMA-recipient neurons increased activity during delay periods, as well as during movements. The activity pattern of MI ϩ SMA-recipient neurons was of an intermediate type between those of MI-and SMA-recipient neurons. Approximately one-half of MI proximal -, SMA-, and MI ϩ SMA-recipient neurons changed activities before the onset of movements, whereas a smaller number of MI distal -and MI proximal ϩ distal -recipient neurons did. Movementrelated activity of MI-recipient neurons was modulated by target directions, whereas SMA-and MI ϩ SMA-recipient neurons had a lower directional selectivity. MI-recipient neurons were located mainly in the ventrolateral part of the caudal aspect of the putamen, whereas SMA-recipient neurons were located in the dorsomedial part. MI ϩ SMA-recipient neurons were found in between. The present results suggest that a subpopulation of putaminal neurons displays specific activity patterns depending on motor cortical inputs. Each subpopulation receives convergent or nonconvergent inputs from the MI and SMA, retains specific motor information, and sends it to the globus pallidus and the substantia nigra through the direct and indirect pathways of the basal ganglia. basal ganglia; striatum; motor control; single-unit recording THE PRIMATE STRIATUM, composed of the putamen, the caudate nucleus, and the ventral striatum, is a main input station of the basal ganglia and receives neural signals from wide areas of the cerebral cortex. Every single striatal projection neuron is estimated to receive diverse inputs from ϳ750 to 7,500 cortical neurons (Bennet and Wilson 2000), and thus cortical information is massively integrated within the striatum. The activity of striatal projection neurons is strongly modulated by local interneurons that also receive cortical inputs (Tepper et al. 2008). The projection neurons finally send processed signals to the external and internal segments of the globus pallidus and the substantia nigra pars reticulata through the ...

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