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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Journal ArticleDOI
Induced pluripotent stem cell-based studies of Parkinson's disease: challenges and promises.
Adriana Sánchez-Danés,Patrizia Benzoni,Maurizio Memo,Patrizia Dell'Era,Angel Raya,Antonella Consiglio +5 more
TL;DR: This review highlights the current PD iPSC-based models and discusses the potential future research directions of this field, including PD-related cell phenotypes and alterations in the autophagy machinery.
Journal ArticleDOI
Reducing Glypican-4 in ES Cells Improves Recovery in a Rat Model of Parkinson's Disease by Increasing the Production of Dopaminergic Neurons and Decreasing Teratoma Formation
Annalisa Fico,Antoine de Chevigny,Christophe Melon,Manon Bohic,Lydia Kerkerian-Le Goff,Flavio Maina,Rosanna Dono,Harold Cremer +7 more
TL;DR: Control of Gpc4 activity level represents a new potential strategy to reduce ES cell tumorigenic features while at the same time increasing neuronal differentiation and integration.
Journal ArticleDOI
Pharmacological Transdifferentiation of Human Nasal Olfactory Stem Cells into Dopaminergic Neurons.
Audrey Chabrat,Emmanuelle Lacassagne,Rodolphe Billiras,Sophie Landron,Amélie Pontisso-Mahout,Hélène Darville,Alain Dupront,Francis Cogé,Esther Schenker,David Piwnica,Emmanuel Nivet,Francois Feron,Francois Feron,Clotilde Mannoury la Cour +13 more
TL;DR: A six-step chemically defined protocol that drives the transdifferentiation of human nasal olfactory stem cells into dopaminergic neurons is reported, paving the way to develop more disease-relevant models by establishing reprogramming-free patient-specific dopaminaergic cell models for drug screening and/or target validation for neurodegenerative diseases.
Patent
Methods of mammalian retinal stem cell production and applications
TL;DR: In this article, an in vitro method for producing isolated mammalian primitive retinal stem cells (pRSCs) was proposed, consisting of culturing isolated embryonic stem cells from a mammal in a cell culture medium that is free of feeder cells, feeder-conditioned medium or serum so as to produce and grow a culture of the isolated ESCs.
Journal ArticleDOI
Fine Tuning of Canonical Wnt Stimulation Enhances Differentiation of Pluripotent Stem Cells Independent of β-Catenin-Mediated T-Cell Factor Signaling.
Joseph Chen,Joseph Chen,Christian M. Nefzger,Christian M. Nefzger,Fernando J. Rossello,Yu Bo Yang Sun,Sue Mei Lim,Sue Mei Lim,Xiaodong Liu,Xiaodong Liu,Suzan de Boer,Anja S Knaupp,Anja S Knaupp,Jinhua Li,Kathryn C. Davidson,Jose M. Polo,Jose M. Polo,Tiziano Barberi,Tiziano Barberi +18 more
TL;DR: Fine‐tuning of Wnt signaling to subthreshold levels for detectable nuclear β‐catenin function appears to act as a switch to enhance differentiation of PSCs into multiple lineages.
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