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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Dopaminergic-like neurons derived from oral mucosa stem cells by developmental cues improve symptoms in the hemi-parkinsonian rat model.
Javier Ganz,Ina Arie,Sigal Buch,Tali Ben Zur,Yael Barhum,Sammy Pour,Shareef Araidy,Sandu Pitaru,Daniel Offen +8 more
TL;DR: It is demonstrated for the first time that soluble factors involved in the development of DA neurons, induced a DA phenotype in hOMSC in vitro that significantly improved the motor function of hemiparkinsonian rats.
Journal ArticleDOI
Stimulation of L-type calcium channels increases tyrosine hydroxylase and dopamine in ventral midbrain cells induced from somatic cells.
Malvin Jefri,Scott C. Bell,Huashan Peng,Nuwan C. Hettige,Gilles Maussion,Vincent Soubannier,Hanrong Wu,Heika Silveira,Jean-François Théroux,Luc Moquin,Xin Zhang,Zahia Aouabed,Jeyashree Krishnan,Liam Anuj O’Leary,Lilit Antonyan,Ying Zhang,Vincent McCarty,Naguib Mechawar,Alain Gratton,Andreas Schuppert,Thomas M. Durcan,Edward A. Fon,Carl Ernst +22 more
TL;DR: This work shows that an L‐type calcium agonist can significantly increase TH protein levels and DA content and release and provides an advance in the ability to increase DA and TH levels to improve the accuracy of disease modeling and small molecule screening for disorders of the ventral midbrain, including Parkinson's disease.
Journal ArticleDOI
Recombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models
Susy Prieto Huarcaya,Alice Drobny,André R. A. Marques,Alessandro Di Spiezio,Jan Philipp Dobert,Denise Balta,Christian Werner,Tania Vargas Rizo,Lisa Gallwitz,S Bub,Iva Stojkovska,Nandkishore R. Belur,Jens Fogh,Joseph R. Mazzulli,Wei Xiang,Amit Fulzele,Mario Dejung,Markus Sauer,Beate Winner,Stefan Rose-John,Philipp Arnold,Paul Saftig,Friederike Zunke +22 more
TL;DR: Boosting lysosomal CTSD activity not only enhanced SNCA clearance in human and murine neurons as well as tissue, but also restored endo-lysosome and autophagy function.
Journal ArticleDOI
A monolayer hiPSC culture system for autophagy/mitophagy studies in human dopaminergic neurons.
Petros Stathakos,Natalia Jiménez-Moreno,Lucy A. Crompton,Paul Nistor,Jennifer L Badger,Peter A. Barbuti,Talitha L Kerrigan,Talitha L Kerrigan,Andrew D. Randall,Maeve A. Caldwell,Maeve A. Caldwell,Jon D. Lane +11 more
TL;DR: A reliable, monolayer differentiation protocol for the rapid and reproducible production of high numbers of mDANs from hiPSC in a format that is amenable for autophagy/mitophagy research is described.
Journal ArticleDOI
Regenerative Therapies for Parkinson’s Disease: An Update
Thomas B Stoker,Roger A. Barker +1 more
TL;DR: The field of regenerative medicine for Parkinson’s disease is now increasingly focussed on how these treatments will be delivered, demonstrating the significant progress that has been made and the optimism surrounding these approaches.
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