期刊
NATURE BIOTECHNOLOGY
卷 35, 期 5, 页码 444-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nbt.3835
关键词
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资金
- Swedish Research Council (VR: DBRM) [2011-3116/3318, 2016-01526]
- Swedish Foundation for Strategic Research (SRL)
- EU
- Karolinska Institutet, Strat Regen, Hjarnfonden [FO2013:0108, FO2015:0202]
- Cancerfonden [CAN 2016/572]
- VR [2012-13482, 2015-02886]
- StratNeuro
- Parkinsonfonden
- Hjarnfonden
- KI/NIH
- EU (PAINCAGE)
- NovoNordisk Foundation
- European Research Council
- New York Stem Cell Foundation
- NIH
- CIRM
- EMBO [ALTF583-2011, ALTF596-2014]
- Marie Curie [GA-2012-600394]
- Brasilian Ministry of Education (CAPES)
- Spanish Ministry of Education
- Science for Life Laboratory
- Knut and Alice Wallenberg Foundation
- National Genomics Infrastructure - Swedish Research Council
- Uppsala Multidisciplinary Center for Advanced Computational Science
- Alzheimers Research UK [ART-EG2009A-1] Funding Source: researchfish
- Novo Nordisk Fonden [NNF15OC0015964, NNF17OC0027294, NNF14OC0010695] Funding Source: researchfish
- Swedish Research Council [2016-01526, 2015-02886] Funding Source: Swedish Research Council
- Vinnova [2016-01526] Funding Source: Vinnova
Cell replacement therapies for neurodegenerative disease have focused on transplantation of the cell types affected by the pathological process. Here we describe an alternative strategy for Parkinson's disease in which dopamine neurons are generated by direct conversion of astrocytes. Using three transcription factors, NEUROD1, ASCL1 and LMX1A, and the microRNA miR218, collectively designated NeAL218, we reprogram human astrocytes in vitro, and mouse astrocytes in vivo, into induced dopamine neurons (iDANs). Reprogramming efficiency in vitro is improved by small molecules that promote chromatin remodeling and activate the TGF beta, Shh and Wnt signaling pathways. The reprogramming efficiency of human astrocytes reaches up to 16%, resulting in iDANs with appropriate midbrain markers and excitability. In a mouse model of Parkinson's disease, NeAL218 alone reprograms adult striatal astrocytes into iDANs that are excitable and correct some aspects of motor behavior in vivo, including gait impairments. With further optimization, this approach may enable clinical therapies for Parkinson's disease by delivery of genes rather than cells.
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