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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Rapid and Efficient Generation of Transgene-Free iPSC from a Small Volume of Cryopreserved Blood.
Hongyan Zhou,Hector Martinez,Bruce Sun,Aiqun Li,Matthew Zimmer,Nicholas Katsanis,Erica E. Davis,Joanne Kurtzberg,Scott Lipnick,Scott Noggle,Mahendra Rao,Stephen Chang +11 more
TL;DR: It is demonstrated that peripheral blood can be utilized for medium-throughput iPSC production without the need to maintain cell culture prior to reprogramming induction, and small volumes of cryopreserved peripheral blood or cord blood cells can be reprogrammed efficiently at a convenient, cost effective and scalable way.
Journal ArticleDOI
Non-human primate models of PD to test novel therapies
Marc Morissette,Thérèse Di Paolo +1 more
TL;DR: Non-human primate models of Parkinson disease show many similarities with the human disease and have been useful to seek new drug targets, since they reproduce motor complications observed in parkinsonian patients as reviewed here.
Journal ArticleDOI
Using Patient-Derived Induced Pluripotent Stem Cells to Model and Treat Epilepsies.
Xixi Du,Jack M. Parent +1 more
TL;DR: The application of powerful new tools such as genome editing and multi-well, multi-electrode array recording platforms to iPSC disease modeling and therapy development for the epilepsies is discussed.
Journal ArticleDOI
Synthetic mRNAs Drive Highly Efficient iPS Cell Differentiation to Dopaminergic Neurons
Yingchao Xue,Yingchao Xue,Xiping Zhan,Shisheng Sun,Senthilkumar S. Karuppagounder,Shuli Xia,Shuli Xia,Valina L. Dawson,Ted M. Dawson,John Laterra,Jianmin Zhang,Mingyao Ying,Mingyao Ying +12 more
TL;DR: These findings established the first mRNA‐driven strategy for efficient iPSC differentiation to mDA neurons, and identified the NM‐II complex as a positive modulator of Atoh1‐driven neuron differentiation.
Journal ArticleDOI
Detailed expression analysis of regulatory genes in the early developing human neural tube.
Ulrika Marklund,Zhanna Alekseenko,Elisabet Andersson,Scott Falci,Magnus Westgren,Thomas Perlmann,Anthony Graham,Erik Sundström,Johan Ericson +8 more
TL;DR: Examination of expression patterns of key regulatory genes in neural progenitor cells and their neuronal and glial descendants in the developing human spinal cord, hindbrain, and midbrain and compared these with developing mouse and chicken embryos finds that neither tyrosine hydroxylase nor Nurr1 are specific markers for mesencephalic dopamine neurons.
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