Floor plate-derived dopamine neurons from hESCs efficiently engraft in animal models of PD
By Sonja Kriks, Jae-won Shim, Jinghua Piao, Yosif M. Ganat, D. Wakeman, Zhong Xie, Luis Carrillo-Reid, Gordon Auyeung, Chris Antonacci, Amanda M. Buch and 6 more. Nature, 2011
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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.
Subfields: Cellular and Molecular Neuroscience, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/1b12e6cf24ba3abad2db92cb1d8f388e827323a6
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Citations in the corpus
- Generation of functional human pancreatic β cells in vitro (2014, background): “Recent research has moved the stem cell field closer to that goal through development of strategies to generate cells that would otherwise be difficult to obtain, like neurons or cardiomyocytes (Kriks et al., 2011; Shiba et al., 2012; Son et al., 2011).”
- Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin producing neurons (2016, background): “In contrast, we failed to detect Fontana-Masson-positive granules from 2D-DA neurons (Kriks et al., 2011) (data not shown) or human cerebral organoids (hCOs) (Figures S3B and S3C) grown at a comparable number of days in vitro.”
- Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions. (2012, background): “This is a significant advancement over existing protocols (Aubry et al., 2008; Brederlau et al., 2006; Chiba et al., 2008; Kriks et al., 2011; Seminatore et al., 2010) since it eliminates the need for prolonged culturing prior to transplantation, making it cost effective, and reducing the variation…”
- Induced pluripotent stem cells: past, present, and future. (2012, neutral): “…et al., 2007), scientists are now making progress toward using iPSCs in regenerative medicine, for example for the treatment of Parkinson’s disease (Kriks et al., 2011), platelet deficiency (Takayama et al., 2010), spinal cord injury (Nori et al., 2011; Tsuji et al., 2010), and macular…”