Survival of human induced pluripotent stem cell-derived midbrain dopaminergic neurons in the brain of a primate model of Parkinson's disease.
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.
Department of Biological Repair, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
Tetsuhiro
T
Kikuchi
Asuka
A
Morizane
Daisuke
D
Doi
Hirotaka
H
Onoe
Takuya
T
Hayashi
Toshiyuki
T
Kawasaki
Hidemoto
H
Saiki
Susumu
S
Miyamoto
Jun
J
Takahashi
D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D002352:Carrier Proteins; D002454:Cell Differentiation / Q000187:drug effects; D000242:Cyclic AMP / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000473:pathology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation*; D036341:Intercellular Signaling Peptides and Proteins; D008252:Macaca fascicularis; D008297:Male; D008636:Mesencephalon / Q000000981:diagnostic imaging / Q000473:pathology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D010300:Parkinson Disease / Q000473:pathology* / Q000601:surgery*; D011877:Radionuclide Imaging; D012794:Sialic Acids / Q000378:metabolism; D013997:Time Factors
D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D039842:Neural Cell Adhesion Molecule L1; D012794:Sialic Acids; C103469:polysialyl neural cell adhesion molecule; C070699:FGFBP1 protein, human; D000242:Cyclic AMP; D001205:Ascorbic Acid; D004298:Dopamine