Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease
Sonja Kriks,Jae-Won Shim,Jinghua Piao,Yosif Ganat,Dustin R. Wakeman,Zhi-Zhong Xie,Luis Carrillo-Reid,Gordon Auyeung,Chris Antonacci,Amanda Buch,Lichuan Yang,M. Flint Beal,D. James Surmeier,Jeffrey H. Kordower,Viviane Tabar,Lorenz Studer +15 more
TLDR
A novel floor-plate-based strategy for the derivation of human DA neurons that efficiently engraft in vivo is presented, suggesting that past failures were due to incomplete specification rather than a specific vulnerability of the cells.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.read more
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Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions.
Agnete Kirkeby,Shane Grealish,Daniel Wolf,Jenny Nelander,James Wood,Martin Lundblad,Olle Lindvall,Malin Parmar +7 more
TL;DR: D dopamine neurons released dopamine and reversed motor deficits in an animal model of Parkinson's disease and were transplanted to the adult rat striatum where they formed neuron-rich and tumor-free grafts with maintained regional specification.
Journal ArticleDOI
Midbrain-like Organoids from Human Pluripotent Stem Cells Contain Functional Dopaminergic and Neuromelanin-Producing Neurons
Junghyun Jo,Yixin Xiao,Alfred Xuyang Sun,Engin Cukuroglu,Hoang Dai Tran,Hoang Dai Tran,Jonathan Göke,Zi Ying Tan,Zi Ying Tan,Tzuen Yih Saw,Cheng Peow Tan,Hidayat Lokman,Young-Hwan Lee,Dong-Hoon Kim,Han Seok Ko,Seong-Oh Kim,Jae Hyeon Park,Nam-Joon Cho,Nam-Joon Cho,Thomas M. Hyde,Joel E. Kleinman,Joo Heon Shin,Daniel R. Weinberger,Eng-King Tan,Hyunsoo Shawn Je,Huck-Hui Ng +25 more
TL;DR: A method to differentiate human pluripotent stem cells into a large multicellular organoid-like structure that contains distinct layers of neuronal cells expressing characteristic markers of human midbrain is developed.
Journal ArticleDOI
Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies
TL;DR: An overview of the mechanisms underlying the tumorigenic risk of human PSC–based therapies is presented and current advances in addressing these challenges are discussed.
Journal ArticleDOI
Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease
Lena F. Burbulla,Lena F. Burbulla,Pingping Song,Joseph R. Mazzulli,Joseph R. Mazzulli,Enrico Zampese,Yvette C. Wong,Sohee Jeon,David Santos,Judith Blanz,Carolin D. Obermaier,Carolin D. Obermaier,Chelsee Strojny,Jeffrey N. Savas,Evangelos Kiskinis,Xiaoxi Zhuang,Rejko Krüger,Rejko Krüger,Rejko Krüger,D. James Surmeier,Dimitri Krainc,Dimitri Krainc +21 more
TL;DR: Dopaminergic neurons derived from patients with idiopathic and familial PD are studied to identify a time-dependent pathological cascade beginning with mitochondrial oxidant stress leading to oxidized dopamine accumulation and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and α-synuclein accumulation.
Journal ArticleDOI
Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells
Asif M. Maroof,Sotirios Keros,Jennifer A. Tyson,Shui-Wang Ying,Yosif Ganat,Florian T. Merkle,Becky Liu,Adam L Goulburn,Edouard G. Stanley,Edouard G. Stanley,Andrew G. Elefanty,Andrew G. Elefanty,Hans Ruedi Widmer,Kevin Eggan,Peter A. Goldstein,Stewart A. Anderson,Stewart A. Anderson,Lorenz Studer +17 more
TL;DR: This study defines the signals sufficient for modeling human ventral forebrain development in vitro and lays the foundation for studying cortical interneuron involvement in human disease pathology.
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