期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-30777-8
关键词
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资金
- Knut and Alice Wallenberg Foundation [KAW2011.0661, KAW2012.0101]
- Swedish Research Council [2013-4155, 2017-02089]
- Swedish Foundation for Strategic Research [SRL10-0030]
- Hjarnfonden [FO2017-0037, F02019-0154, F02021-0159]
- Parkinson Fonden [1189/19, 1257/20, 1326/21]
- Novo Nordisk Foundation [NNF20OC0062355]
- Karolinska Institutet
- Swedish Research Council [2017-02089] Funding Source: Swedish Research Council
- Vinnova [2017-02089] Funding Source: Vinnova
- Swedish Foundation for Strategic Research (SSF) [SRL10-0030] Funding Source: Swedish Foundation for Strategic Research (SSF)
- Formas [2017-02089] Funding Source: Formas
Stem cell therapies utilizing retinoic acid (RA) signaling have shown promise in providing treatment for Parkinson's disease, by deriving dopamine neurons and restoring motor deficits in animal models.
Stem cell based replacement therapies could provide a treatment for Parkinson's disease. Here the authors outline a retinoic acid-based approach for robust derivation of dopamine neurons from stem cells that restore motor deficits in parkinsonian rats. Stem cell therapies for Parkinson's disease (PD) have entered first-in-human clinical trials using a set of technically related methods to produce mesencephalic dopamine (mDA) neurons from human pluripotent stem cells (hPSCs). Here, we outline an approach for high-yield derivation of mDA neurons that principally differs from alternative technologies by utilizing retinoic acid (RA) signaling, instead of WNT and FGF8 signaling, to specify mesencephalic fate. Unlike most morphogen signals, where precise concentration determines cell fate, it is the duration of RA exposure that is the key-parameter for mesencephalic specification. This concentration-insensitive patterning approach provides robustness and reduces the need for protocol-adjustments between hPSC-lines. RA-specified progenitors promptly differentiate into functional mDA neurons in vitro, and successfully engraft and relieve motor deficits after transplantation in a rat PD model. Our study provides a potential alternative route for cell therapy and disease modelling that due to its robustness could be particularly expedient when use of autologous- or immunologically matched cells is considered.
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