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
Citations
More filters
Journal ArticleDOI
FolR1: a novel cell surface marker for isolating midbrain dopamine neural progenitors and nascent dopamine neurons.
TL;DR: FolR1 is identified as a new cell surface marker selectively expressed in mesDA progenitors in vivo and in vitro and that can be used to enrich in vitro differentiated TH neurons.
Journal ArticleDOI
Patient-specific induced pluripotent stem cells in neurological disease modeling: the importance of nonhuman primate models
TL;DR: For complete modeling of the disease, it is proposed that the introduction of genetic changes into NHP iPS cells, followed by studying the phenotype of the genetic change in cells transplanted into the NHP as host animal, will yield new insights into disease processes not possible with rodent models alone.
Journal ArticleDOI
Efficient generation of dopaminergic induced neuronal cells with midbrain characteristics.
TL;DR: In this article, the authors systematically explored the generation of dopaminergic induced neuronal cells from mouse and human pluripotent stem cells, and found that the proneural factor Ascl1 in combination with mesencephalic factors Lmx1a and Nurr1 induce peripheral dopaminaergic neurons, and the co-delivery of additional midbrain transcription factors En1, FoxA2, and Pitx3 resulted in facile and robust generation of functional dopamine neurons of midbrain character.
Journal ArticleDOI
Survival and Integration of Neurons Derived from Human Embryonic Stem Cells in MPTP-Lesioned Primates:
Dustin R. Wakeman,Stephanie Weiss,John R. Sladek,John D. Elsworth,Brian Bauereis,Csaba Leranth,Patrick J Hurley,Robert H. Roth,D. Eugene Redmond,D. Eugene Redmond +9 more
TL;DR: The results suggest that dopamine neuronal cells derived from neuroectoderm in vitro will not maintain the correct midbrain phenotype in vivo in nonhuman primates, contrasted with recent studies showing dopamine neuronal survival using an alternative floorplate method.
Journal ArticleDOI
Migration of bone marrow progenitor cells in the adult brain of rats and rabbits
TL;DR: It is shown that the cell membrane chemokine receptor, CCR5, and its ligands, enhance CNS inflammation and seizure activity in a model of neuronal excitotoxicity and reduces neuroinflammation and increases neuronal regeneration following this type of insult.
References
More filters
Journal ArticleDOI
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.
TL;DR: By following this protocol, investigators are able to gain an in-depth understanding of the biological themes in lists of genes that are enriched in genome-scale studies.
Journal ArticleDOI
Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling
Stuart M. Chambers,Christopher A. Fasano,Eirini P. Papapetrou,Mark J. Tomishima,Michel Sadelain,Lorenz Studer +5 more
TL;DR: Noggin/SB431542-based neural induction should facilitate the use of hES and hiPS cells in regenerative medicine and disease modeling and obviate the need for protocols based on stromal feeders or embryoid bodies.
Journal ArticleDOI
Efficient tumour formation by single human melanoma cells
Elsa Quintana,Mark Shackleton,Michael S. Sabel,Douglas R. Fullen,Timothy M. Johnson,Sean J. Morrison +5 more
TL;DR: Modifications to xenotransplantation assays can dramatically increase the detectable frequency of tumorigenic cells, demonstrating that they are common in some human cancers.
Journal ArticleDOI
Parkinson’s Disease Patient-Derived Induced Pluripotent Stem Cells Free of Viral Reprogramming Factors
Frank Soldner,Dirk Hockemeyer,Caroline Beard,Qing Gao,George W. Bell,Elizabeth G. Cook,Gunnar Hargus,Alexandra Blak,Oliver Cooper,Maisam Mitalipova,Ole Isacson,Rudolf Jaenisch +11 more
TL;DR: In this paper, the authors showed that fibroblasts from five patients with idiopathic Parkinson's disease can be efficiently reprogrammed and subsequently differentiated into dopaminergic neurons using Cre-recombinase excisable viruses.
Journal ArticleDOI
Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease.
Jeffrey H. Kordower,Marina E. Emborg,Jocelyne Bloch,Shuang Y. Ma,Yaping Chu,Liza Leventhal,Jodi L. McBride,Er-Yun Chen,Stéphane Palfi,Ben Roitberg,W. Douglas Brown,James E. Holden,Robert W. Pyzalski,Michael D. Taylor,Paul M. Carvey,Zaodung Ling,Didier Trono,Philippe Hantraye,Nicole Déglon,Patrick Aebischer,Patrick Aebischer +20 more
TL;DR: Data indicate that GDNF delivery using a lentiviral vector system can prevent nigrostriatal degeneration and induce regeneration in primate models of PD and might be a viable therapeutic strategy for PD patients.