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Nat Biotechnol. 2017 May;35(5):444-452. doi: 10.1038/nbt.3835. Epub 2017 Apr 10.

Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model.

Author information

1
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
2
Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria.
3
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
4
Department of Pharmacology, Faculty of Medicine, Biomedical Research Institute of Malaga (IBIMA), Malaga University, Malaga, Spain.
5
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA.

Abstract

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 TGFβ, 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.

Comment in

PMID:
28398344
DOI:
10.1038/nbt.3835
[Indexed for MEDLINE]

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