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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Autologous iPSC-derived dopamine neuron transplantation in a nonhuman primate Parkinson's disease model.
Shuyan Wang,Chunlin Zou,Linlin Fu,Bin Wang,Jing An,Gongru Song,Jianyu Wu,Xihe Tang,Mo Li,Jian Zhang,Feng Yue,Chengyun Zheng,Piu Chan,Y. Alex Zhang,Zhiguo Chen +14 more
TL;DR: The study provided a proof-of-principle to employ iPSC-derived autologous DA cells for PD treatment using a nonhuman primate PD model and revealed no overgrowth of grafts and a significant number of surviving A9 region-specific graft-derived DA neurons.
Journal ArticleDOI
IAP-Based Cell Sorting Results in Homogeneous Transplantable Dopaminergic Precursor Cells Derived from Human Pluripotent Stem Cells.
Daniela Lehnen,Serena Barral,Tiago Cardoso,Shane Grealish,Andreas Heuer,Andrej Smiyakin,Agnete Kirkeby,Jutta Kollet,Harold Cremer,Malin Parmar,Andreas Bosio,Sebastian Knöbel +11 more
TL;DR: It is demonstrated that integrin-associated protein (IAP) is a cell surface marker suitable for enrichment of hPSC-derived mesDA progenitor cells that can relieve motor deficits in animal models of Parkinson's disease.
Journal ArticleDOI
Pluripotent Stem Cell–Based Cancer Therapy: Promise and Challenges
TL;DR: The potential therapeutic applications of iPSCs for treating cancer and other diseases are discussed and the current barriers restricting their use are highlighted.
Journal ArticleDOI
Target-specific forebrain projections and appropriate synaptic inputs of hESC-derived dopamine neurons grafted to the midbrain of parkinsonian rats.
Tiago Cardoso,Andrew F. Adler,Bengt Mattsson,Deirdre B. Hoban,Sara Nolbrant,Jenny Nelander Wahlestedt,Agnete Kirkeby,Agnete Kirkeby,Shane Grealish,Anders Björklund,Malin Parmar +10 more
TL;DR: VM patterned hESC‐derived progenitors grafted to midbrain have the capacity to extensively innervate appropriate forebrain targets, integrate into the host circuitry and that functional recovery can be achieved when grafting fetal or hESCs‐derived DA neurons to the midbrain.
Journal ArticleDOI
A stably self-renewing adult blood-derived induced neural stem cell exhibiting patternability and epigenetic rejuvenation.
Chao Sheng,Johannes Jungverdorben,Johannes Jungverdorben,Hendrik Wiethoff,Qiong Lin,Lea Jessica Flitsch,Daniela Eckert,Matthias Hebisch,Matthias Hebisch,Julia Fischer,Jaideep Kesavan,Beatrice Weykopf,Linda Schneider,Dominik Holtkamp,Heinz Beck,Andreas Till,Ullrich Wüllner,Michael J. Ziller,Wolfgang Wagner,Michael Peitz,Michael Peitz,Oliver Brüstle +21 more
TL;DR: It is demonstrated that blood-derived induced neural stem cells, despite lacking a pluripotency transit, lose age-related signatures, depicting blood-to-NSC conversion as a rapid alternative route for both disease modeling and neuroregeneration.
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