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
Using intracellular markers to identify a novel set of surface markers for live cell purification from a heterogeneous hIPSC culture.
TL;DR: This work has identified mDA NPC specific cell surface markers for fluorescence activated cell sorting (FACS) that can enrich floor plate NPCs to 90% purity, and the sorted NPCs more efficiently differentiate to mature dopaminergic neurons compared to unsorted or CORIN+ alone mDA NPCs.
Posted ContentDOI
Targeted attenuation of elevated histone marks at SNCA alleviates α-synuclein in Parkinson's disease
Subhrangshu Guhathakurta,Jinil Kim,Sambuddha Basu,Evan Adler,Goun Je,Mariana Bernardo Fiadeiro,Yoon Seong Kim +6 more
TL;DR: Modification of the histone landscape of SNCA can reduce α-synuclein expression and CRISPR/dCas9 SunTag-JARID1A significantly reduced H3K4me3 at S NCA promoter and concomitantly decreased α- synuclein both in the neuronal cell line SH-SY5Y and idiopathic PD-iPSC derived dopaminergic neurons.
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HESC-derived neural progenitors prevent xenograft rejection through neonatal desensitisation
TL;DR: It is shown that differentiated human embryonic stem cells (hESCs) can be used for desensitisation to achieve long-term graft survival of human stem cell-derived neurons in a xenograft setting, surpassing the time of conventional pharmacological immune-suppressive treatments.
Book ChapterDOI
The Role of Smad Proteins for Development, Differentiation and Dedifferentiation of Neurons
Uwe Ueberham,Thomas Arendt +1 more
TL;DR: This chapter develops a view at Smad molecules, which attributes them a basic significance and allow proving their specific contextual molecular, cellular and tissue relationships, and an overview of the canonical Smad signalling pathway.
Book ChapterDOI
Investigation of Schizophrenia with Human Induced Pluripotent Stem Cells.
TL;DR: A review of the clinical, epidemiological, and genetic aspects of schizophrenia, with a focus on schizophrenia as a neurodevelopmental disorder, and a critical appraisal of the developments necessary for both further expanding knowledge of schizophrenia and the translation of new insights into therapeutic innovations.
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