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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Directed differentiation and direct reprogramming: Applying stem cell technologies to hearing research
TL;DR: In this article, a review of the state-of-the-art in the field of stem cell technologies for hearing loss in humans is presented, focusing specifically on two technologies: directed differentiation of pluripotent stem cells and direct reprogramming of somatic cell types to sensory hair cells and neurons.
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Parkinson's disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegeneration.
Giulia Carola,Giulia Carola,Daniel Malagarriga,Daniel Malagarriga,Carles Calatayud,Carles Calatayud,Meritxell Pons-Espinal,Meritxell Pons-Espinal,L Blasco-Agell,L Blasco-Agell,Yvonne Richaud-Patin,Irene Fernandez-Carasa,Irene Fernandez-Carasa,V Baruffi,V Baruffi,S Beltramone,S Beltramone,S Beltramone,E Molina,Patrizia Dell'Era,J J Toledo-Aral,Eduard Tolosa,Alysson R. Muotri,J. Garcia Ojalvo,Jordi Soriano,Angel Raya,Antonella Consiglio,Antonella Consiglio,Antonella Consiglio +28 more
TL;DR: In this article, human induced pluripotent stem cell (iPSC)-derived dopaminergic neurons (DAn) obtained from healthy individuals or patients harboring LRRK2 PD-causing mutation can create highly complex networks with evident signs of functional maturation over time.
Journal ArticleDOI
The penalty of stress - Epichaperomes negatively reshaping the brain in neurodegenerative disorders.
Stephen D. Ginsberg,Stephen D. Ginsberg,Suhasini Joshi,Sahil Sharma,Gianny Guzman,Tai Wang,Ottavio Arancio,Gabriela Chiosis +7 more
TL;DR: In this paper, the authors discuss maladaptive stressor-induced changes in protein connectivity through epichaperomes, disease-associated pathologic scaffolds composed of tightly bound chaperones, co-chaperones and other factors, impact intracellular protein functionality altering phenotypes, that in turn disrupt and remodel brain networks ranging from intercellular to brain connectome levels.
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Genetic correction of stem cells in the treatment of inherited diseases and focus on xeroderma pigmentosum.
Sophie Rouanet,Emilie Warrick,Yannick Gache,Sabine Scarzello,Marie-Françoise Avril,Françoise Bernerd,Thierry Magnaldo +6 more
TL;DR: Preclinical and safety assessments indicate successful correction of XP epidermal stem cells in the long term and their capacity to regenerate a normal skin with full capacities of DNA repair.
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Generating induced pluripotent stem cells for multiple sclerosis therapy.
TL;DR: iPSCs play a central role in an increasing number of studies focusing on both disease modeling and cell-replacement therapies including those for neurological, muscular, ocular, cardiac, hematological, metabolic and skin disorders, and the question arises of whether iPSCs can effectively impact MS research.
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