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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Eph receptors: New players in Alzheimer's disease pathogenesis
Moustapha Cisse,Frédéric Checler +1 more
TL;DR: Recent discoveries on Eph receptors-mediated protection against Aβ oligomers neurotoxicity as well as their potential as therapeutic targets in AD pathogenesis are reviewed.
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Species-specific developmental timing is maintained by pluripotent stem cells ex utero
Christopher Barry,Matthew T. Schmitz,Peng Jiang,Michael P. Schwartz,Bret Duffin,Scott Swanson,Rhonda Bacher,Jennifer M. Bolin,Angela L. Elwell,Brian E. McIntosh,Ron Stewart,James A. Thomson,James A. Thomson,James A. Thomson +13 more
TL;DR: The results suggest the existence of a cell autonomous, species-specific developmental clock that pluripotent stem cells maintain even out of context of an intact embryo.
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Using stem cell-derived neurons in drug screening for neurological diseases.
TL;DR: Whether induced pluripotent stem cell-derived neurons will come to fruition as a model that is regularly used to screen for drugs to treat neurological diseases is critically discussed.
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Efficient expansion and dopaminergic differentiation of human fetal ventral midbrain neural stem cells by midbrain morphogens
Diogo Ribeiro,Rocio Laguna Goya,Geeta Ravindran,Romina Vuono,Clare L. Parish,Claire J. Foldi,Tobias Piroth,Shanzheng Yang,Malin Parmar,Guido Nikkhah,Jens Hjerling-Leffler,Olle Lindvall,Roger A. Barker,Ernest Arenas +13 more
TL;DR: This method could substantially reduce the amount of human fetal midbrain tissue necessary for CRT in patients with PD, which could have major implications for the widespread adoption of this approach.
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Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson’s disease
Nikhil Panicker,T. I. Kam,Hu Wang,Stewart Neifert,Shih Ching Chou,Manoj Kumar,Saurav Brahmachari,Aanishaa Jhaldiyal,Jared T. Hinkle,Fatih Akkentli,Xiaobo Mao,Enquan Xu,Senthilkumar S. Karuppagounder,Eric Hsu,Sung Ung Kang,Olga Pletnikova,Juan C. Troncoso,Valina L. Dawson,Ted M. Dawson +18 more
TL;DR: In this paper , Parkin activation was found to contribute to the assembly of an active NLRP3 inflammasome complex via mitochondrial-derived reactive oxygen species (mitoROS) generation through the accumulation of another parkin ubiquitination substrate, ZNF746/PARIS.
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