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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Neurothreads: Development of supportive carriers for mature dopaminergic neuron differentiation and implantation.
Aleksandra Filippova,Fabien Bonini,Liudmila Efremova,Manon Locatelli,Olivier Preynat-Seauve,Amélie Beduer,Karl-Heinz Krause,Thomas Braschler +7 more
TL;DR: In this article, the use of elastic macroporous cryogels for differentiation and transplantation of mature neurons has been proposed for long-term neuronal culture, including stem cell differentiation by covalent immobilization of neural adhesion proteins.
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Applying stem cells and CRISPR engineering to uncover the etiology of schizophrenia.
TL;DR: In this paper, a review outlines key advances in HiPSC and CRISPR technology, describing their applications and future potential in the field of schizophrenia research, and describes their potential applications.
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Regenerative medicine: could Parkinson's be the first neurodegenerative disease to be cured?
TL;DR: DOPAminergic neurons derived from human pluripotent stem cells and human parthenogenetic cells are being clinically tested in China and Australia, respectively and good manufacturing practices have been developed.
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Application of CRISPR/Cas9 editing and digital droplet PCR in human iPSCs to generate novel knock-in reporter lines to visualize dopaminergic neurons.
Christa Überbacher,Julia Obergasteiger,Mattia Volta,Serena Venezia,Stefan C. Müller,Isabella Pesce,Sara Pizzi,Giulia Lamonaca,Anne Picard,Giada Cattelan,Giorgio Malpeli,Michele Zoli,Dayne Beccano-Kelly,Rowan Flynn,Richard Wade-Martins,Peter P. Pramstaller,Andrew A. Hicks,Sally A. Cowley,Corrado Corti +18 more
TL;DR: In this article, a reproducible knock-in strategy combined with a highly specific homologous directed repair (HDR) screening approach using digital droplet PCR (ddPCR) is presented.
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Stem Cells and Cancer Stem Cells, Volume 10
TL;DR: The object of this chapter is to discuss the basic data published as well as some data from the laboratory about immunoregulatory effects of humanMSCs isolated either from bone marrow or adipose tissue, and some indirect effects mediated through immunomodulatory cells.
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