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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What is the most promising treatment for Parkinson's disease: genes, cells, growth factors or none of the above?
Gemma Cummins,Roger A. Barker +1 more
TL;DR: There is a clear need for new therapies in PD that not only are capable of providing dopamine replacement more effectively, but also serve to replace or protect the substantia nigra pars compacta dopamine neurons from further degeneration.
Journal ArticleDOI
Microfabricated disk technology: rapid scale up in midbrain organoid generation
Nguyen-Vi Mohamed,Paula Lépine,María Lacalle-Aurioles,Julien Sirois,Meghna Mathur,Wolfgang Reintsch,Lenore K. Beitel,Edward A. Fon,Thomas M. Durcan +8 more
TL;DR: In this article, the authors developed a method with microfabricated disks to scale up the generation of human midbrain organoids, in a manner that minimizes the amount of labor required, while decreasing variability and maintaining the viability of these organoids over time.
Journal ArticleDOI
Epigenetic Analysis in Human Neurons: Considerations for Disease Modeling in PD.
Laura de Boni,Ullrich Wüllner +1 more
TL;DR: It is demonstrated that human neurons have the potential to be used as model systems for the study of epigenetic modifications in PD such as characterizing epigenetic changes, correlating epigeneticChanges to gene expression alterations and hopefully using these insights for the development of novel therapeutics.
Journal ArticleDOI
Parkinson’s Disease in a Dish: What Patient Specific-Reprogrammed Somatic Cells Can Tell Us about Parkinson’s Disease, If Anything?
TL;DR: The advances made in the field of cellular reprogramming to model PD are discussed and the pros and cons associated with the use of such cells are discussed.
Journal ArticleDOI
MicroRNA profiling during directed differentiation of cortical interneurons from human-induced pluripotent stem cells
Jiajie Tu,Jiajie Tu,Dandan Cao,Lu Li,Hoi-Hung Cheung,Hoi-Hung Cheung,Wai-Yee Chan,Wai-Yee Chan +7 more
TL;DR: The temporal in vitro neurogenesis from iPSCs to mature cortical interneurons is captured and specific miRNAs identified at each stage of differentiation are of potential use for drug discovery and prospective clinical applications.
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