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Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model
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Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model
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Journal Article
Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model
2017
Overview
In vivo
reprogramming of astrocytes to dopamine neurons improves motor behavior in a mouse model of Parkinson's disease.
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.
Publisher
Springer New York,Nature Publishing Group
Subject
/ 13/51
/ 14/1
/ 14/19
/ 14/34
/ 14/63
/ 38/39
/ 38/77
/ 38/91
/ 64/60
/ Animals
/ Astrocytes - transplantation
/ Biomedical and Life Sciences
/ Biomedical Engineering/Biotechnology
/ Cell Differentiation - genetics
/ Cells
/ Cellular Reprogramming Techniques - methods
/ Dopamine
/ Dopaminergic Neurons - cytology
/ Humans
/ Mice
/ miRNA
/ Movement Disorders - etiology
/ Movement Disorders - pathology
/ Movement Disorders - prevention & control
/ Neurons
/ Parkinson Disease - complications
