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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Human pluripotent stem cells: applications and challenges in neurological diseases.
Youssef Hibaoui,Anis Feki +1 more
TL;DR: In this review, recent progress, promises, and challenges of hPSC applications in human neurological disease modeling and therapies are highlighted.
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From the Cover: Manganese and Rotenone-Induced Oxidative Stress Signatures Differ in iPSC-Derived Human Dopamine Neurons.
TL;DR: The observed effects of manganese and rotenone in human-induced pluripotent stem cells-derived postmitotic mesencephalic dopamine neurons are compared to suggest that the cellular oxidative stress evoked by these 2 agents is distinct yielding unique oxidative stress signatures across outcome measures.
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Dopaminergic Differentiation of Human Pluripotent Cells
TL;DR: Two distinct protocols for the dopaminergic differentiation of pluripotent stem cells are optimized and compared, both of which are chemically defined and applicable to both embryonic and induced pluripoline stem cells.
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Concise Review: The Cellular Conspiracy of Amyotrophic Lateral Sclerosis
Andrea Serio,Rickie Patani +1 more
TL;DR: Integration of enriched human neuronal and glial experimental platforms into the existing repertoire of preclinical models might prove transformational for clinical trial outcomes in ALS and allow systematic elucidation of cell‐autonomous and non‐cell‐aut autonomous mechanisms of disease, which may then provide novel cellular targets for therapeutic intervention.
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Intracerebral transplantation of differentiated human embryonic stem cells to hemiparkinsonian monkeys
Marina E. Emborg,Zhi-Jian Zhang,Valerie Joers,Kevin Brunner,Viktorya Bondarenko,Sachiko Ohshima,Su-Chun Zhang +6 more
TL;DR: The study suggests that immunological issues are obstacles for preclinical evaluation of hES cells and that improved immunosuppression paradigms and/or alternative cell sources that do not elicit immune rejection are needed for long-term preclinical studies.
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