title: Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease.
abstract: Human pluripotent stem cells (PSCs) are a promising source of cells for applications in regenerative medicine. Directed differentiation of PSCs into specialized cells such as spinal motoneurons or midbrain dopamine (DA) neurons has been achieved. However, the effective use of PSCs for cell therapy has lagged behind. Whereas mouse PSC-derived DA neurons have shown efficacy in models of Parkinson's disease, DA neurons from human PSCs generally show poor in vivo performance. There are also considerable safety concerns for PSCs related to their potential for teratoma formation or neural overgrowth. Here we present a novel floor-plate-based strategy for the derivation of human DA neurons that efficiently engraft in vivo, suggesting that past failures were due to incomplete specification rather than a specific vulnerability of the cells. Midbrain floor-plate precursors are derived from PSCs 11 days after exposure to small molecule activators of sonic hedgehog (SHH) and canonical WNT signalling. Engraftable midbrain DA neurons are obtained by day 25 and can be maintained in vitro for several months. Extensive molecular profiling, biochemical and electrophysiological data define developmental progression and confirm identity of PSC-derived midbrain DA neurons. In vivo survival and function is demonstrated in Parkinson's disease models using three host species. Long-term engraftment in 6-hydroxy-dopamine-lesioned mice and rats demonstrates robust survival of midbrain DA neurons derived from human embryonic stem (ES) cells, complete restoration of amphetamine-induced rotation behaviour and improvements in tests of forelimb use and akinesia. Finally, scalability is demonstrated by transplantation into parkinsonian monkeys. Excellent DA neuron survival, function and lack of neural overgrowth in the three animal models indicate promise for the development of cell-based therapies in Parkinson's disease.
authors: Center for Stem Cell Biology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
authors: Sonja
authors: S
authors: Kriks
authors: Jae-Won
authors: JW
authors: Shim
authors: Jinghua
authors: J
authors: Piao
authors: Yosif M
authors: YM
authors: Ganat
authors: Dustin R
authors: DR
authors: Wakeman
authors: Zhong
authors: Z
authors: Xie
authors: Luis
authors: L
authors: Carrillo-Reid
authors: Gordon
authors: G
authors: Auyeung
authors: Chris
authors: C
authors: Antonacci
authors: Amanda
authors: A
authors: Buch
authors: Lichuan
authors: L
authors: Yang
authors: M Flint
authors: MF
authors: Beal
authors: D James
authors: DJ
authors: Surmeier
authors: Jeffrey H
authors: JH
authors: Kordower
authors: Viviane
authors: V
authors: Tabar
authors: Lorenz
authors: L
authors: Studer
mesh_terms: D000818:Animals; D016380:Brain Tissue Transplantation; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival; D059290:Dopaminergic Neurons / Q000166:cytology* / Q000637:transplantation*; D053595:Embryonic Stem Cells / Q000166:cytology*; D005260:Female; D006801:Humans; D008253:Macaca mulatta; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010300:Parkinson Disease / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley