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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Solving the puzzle of Parkinson’s disease using induced pluripotent stem cells:
Ping Zhao,Zhiwei Luo,Weihua Tian,Jiayin Yang,David P. Ibañez,Zhijian Huang,Micky D. Tortorella,Miguel A. Esteban,Wenxia Fan +8 more
TL;DR: PD modeling with iPSCs is nowadays facilitated by the growing availability of high-efficiency neural-specific differentiation protocols and the possibility to correct or induce mutations as well as creating marker cell lines using designer nucleases.
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Novel genetic features of human and mouse Purkinje cell differentiation defined by comparative transcriptomics.
David E. Buchholz,Thomas L. Carroll,Arif Kocabas,Xiaodong Zhu,Hourinaz Behesti,Phyllis L. Faust,Lauren Stalbow,Yin Fang,Mary E. Hatten +8 more
TL;DR: A direct comparison of hPSC-PC and mouse PC gene expression and a robust method for generating differentiated hPSS-PCs with human-specific gene expression for modeling developmental and degenerative cerebellar disorders are provided.
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Drugging Hedgehog: signaling the pathway to translation.
TL;DR: First discovered in Drosophila, the Hedgehog signaling pathway controls a wide range of developmental processes and is implicated in a variety of cancers.
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Concise Review: Patient-Derived Stem Cell Research for Monogenic Disorders
Yiren Qin,Wei-Qiang Gao +1 more
TL;DR: The latest progress in research into the use of patient‐derived stem cells for the potential treatment of MGDs is summarized and predictions regarding the direction of future investigations are provided.
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From mice to mind: Strategies and progress in translating neuroregeneration.
TL;DR: It is concluded that not only are appropriate animal models critical to the development of safe and effective therapies, but that the multiple mechanisms of stem cell-mediated therapies may be particularly well suited to the mechanistically diverse nature of central nervous system diseases in mice and man.
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