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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Accelerated High-Yield Generation of Limb-Innervating Motor Neurons from Human Stem Cells
Mackenzie W. Amoroso,Gist F. Croft,Damian J. Williams,Sean O'Keeffe,Monica A. Carrasco,Anne R. Davis,Laurent Roybon,Derek H. Oakley,Tom Maniatis,Christopher E. Henderson,Hynek Wichterle +10 more
TL;DR: This novel protocol preferentially generates motor neurons expressing markers of limb-innervating lateral motor column motor neurons (FOXP1+/LHX3−) and will facilitate in-depth study of motor neuron subtype-specific properties, disease modeling, and development of large-scale cell-based screening assays.
Journal ArticleDOI
Cell‑based therapies for Parkinson disease —past insights and future potential
TL;DR: How the best clinical outcomes have been obtained with fetal ventral mesencephalic allografts are discussed, while acknowledging inconsistencies in the results owing to problems in trial design, patient selection, tissue preparation, and immunotherapy used post-grafting.
Journal ArticleDOI
Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease.
Ian Martin,Jungwoo Wren Kim,Byoung Dae Lee,Ho Chul Kang,Jinchong Xu,Hao Jia,Jeannette N. Stankowski,Min-Sik Kim,Jun Zhong,Manoj Kumar,Shaida A. Andrabi,Yulan Xiong,Dennis W. Dickson,Zbigniew K. Wszolek,Akhilesh Pandey,Ted M. Dawson,Valina L. Dawson +16 more
TL;DR: It is shown that ribosomal protein s15 is a key pathogenic LRRK2 substrate in Drosophila and human neuron PD models and can be prevented by phosphodeficient T136A s15, revealing a novel mechanism of PD pathogenesis linked to elevated L RRK2 kinase activity and aberrant protein synthesis in vivo.
Journal ArticleDOI
Evaluating cell reprogramming, differentiation and conversion technologies in neuroscience
TL;DR: The growth of methods to generate more robust and defined neural cell types through reprograming and direct conversion into induced neurons has led to the establishment of various human reprogramming-based neural disease models.
Journal ArticleDOI
Modeling Hippocampal Neurogenesis Using Human Pluripotent Stem Cells
Diana Xuan Yu,Francesco Paolo Di Giorgio,Jun Yao,Maria C. Marchetto,Kristen J. Brennand,Rebecca Wright,Arianna Mei,Lauren McHenry,David Lisuk,Jaeson M Grasmick,Pedro C. Silberman,Giovanna Silberman,Roberto Jappelli,Fred H. Gage +13 more
TL;DR: A differentiation paradigm for hPSCs that enriches for hippocampal dentate gyrus (DG) granule neurons is reported that recapitulates the expression patterns of key developmental genes during hippocampal neurogenesis, exhibits characteristics of neuronal network maturation, and produces PROX1+ neurons that functionally integrate into the DG.
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