Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model
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 alternati...
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| Published in: | Nature biotechnology Vol. 35; no. 5; pp. 444 - 452 |
|---|---|
| Main Authors: | , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
New York
Springer New York
01.05.2017
Nature Publishing Group |
| Subjects: | |
| ISSN: | 1087-0156, 1546-1696, 1546-1696 |
| Online Access: | Get full text |
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| Abstract | 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. |
|---|---|
| AbstractList | 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.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. 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. 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. 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. 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. |
| Audience | Academic |
| Author | Harkany, Tibor Wernig, Marius Rivetti di Val Cervo, Pia Ng, Yi-Han Masini, Débora Martín-Montañez, Elisa Feyder, Michael Pifl, Christian Arenas, Ernest Spigolon, Giada Romanov, Roman A Toledo, Enrique M Linnarsson, Sten La Manno, Gioele Sánchez, Sara Padrell Fisone, Gilberto |
| Author_xml | – sequence: 1 givenname: Pia surname: Rivetti di Val Cervo fullname: Rivetti di Val Cervo, Pia organization: Department of Medical Biochemistry and Biophysics, Laboratory of Molecular Neurobiology, Karolinska Institutet – sequence: 2 givenname: Roman A surname: Romanov fullname: Romanov, Roman A organization: Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Department of Neuroscience, Karolinska Institutet – sequence: 3 givenname: Giada surname: Spigolon fullname: Spigolon, Giada organization: Department of Neuroscience, Karolinska Institutet – sequence: 4 givenname: Débora surname: Masini fullname: Masini, Débora organization: Department of Neuroscience, Karolinska Institutet – sequence: 5 givenname: Elisa surname: Martín-Montañez fullname: Martín-Montañez, Elisa organization: Department of Medical Biochemistry and Biophysics, Laboratory of Molecular Neurobiology, Karolinska Institutet, Department of Pharmacology, Faculty of Medicine, Biomedical Research Institute of Malaga (IBIMA), Malaga University – sequence: 6 givenname: Enrique M orcidid: 0000-0002-1460-4708 surname: Toledo fullname: Toledo, Enrique M organization: Department of Medical Biochemistry and Biophysics, Laboratory of Molecular Neurobiology, Karolinska Institutet – sequence: 7 givenname: Gioele surname: La Manno fullname: La Manno, Gioele organization: Department of Medical Biochemistry and Biophysics, Laboratory of Molecular Neurobiology, Karolinska Institutet – sequence: 8 givenname: Michael orcidid: 0000-0001-5849-905X surname: Feyder fullname: Feyder, Michael organization: Department of Neuroscience, Karolinska Institutet – sequence: 9 givenname: Christian surname: Pifl fullname: Pifl, Christian organization: Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna – sequence: 10 givenname: Yi-Han surname: Ng fullname: Ng, Yi-Han organization: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University – sequence: 11 givenname: Sara Padrell surname: Sánchez fullname: Sánchez, Sara Padrell organization: Department of Medical Biochemistry and Biophysics, Laboratory of Molecular Neurobiology, Karolinska Institutet – sequence: 12 givenname: Sten surname: Linnarsson fullname: Linnarsson, Sten organization: Department of Medical Biochemistry and Biophysics, Laboratory of Molecular Neurobiology, Karolinska Institutet – sequence: 13 givenname: Marius surname: Wernig fullname: Wernig, Marius organization: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University – sequence: 14 givenname: Tibor surname: Harkany fullname: Harkany, Tibor organization: Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Department of Neuroscience, Karolinska Institutet – sequence: 15 givenname: Gilberto surname: Fisone fullname: Fisone, Gilberto organization: Department of Neuroscience, Karolinska Institutet – sequence: 16 givenname: Ernest orcidid: 0000-0003-0197-6577 surname: Arenas fullname: Arenas, Ernest email: ernest.arenas@ki.se organization: Department of Medical Biochemistry and Biophysics, Laboratory of Molecular Neurobiology, Karolinska Institutet |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28398344$$D View this record in MEDLINE/PubMed http://kipublications.ki.se/Default.aspx?queryparsed=id:135777783$$DView record from Swedish Publication Index (Karolinska Institutet) |
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| Snippet | In vivo
reprogramming of astrocytes to dopamine neurons improves motor behavior in a mouse model of Parkinson's disease.
Cell replacement therapies for... Cell replacement therapies for neurodegenerative disease have focused on transplantation of the cell types affected by the pathological process. Here we... In vivo reprogramming of astrocytes to dopamine neurons improves motor behavior in a mouse model of Parkinson's disease.Cell replacement therapies for... |
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| SubjectTerms | 13/106 13/51 14/1 14/19 14/34 14/63 38/39 38/77 38/91 631/378/1687 631/61/490 64/60 Agriculture Animals ASCL1 protein Astrocytes Astrocytes - cytology Astrocytes - transplantation Beta2 protein Bioinformatics Biomedical and Life Sciences Biomedical Engineering/Biotechnology Biomedicine Biotechnology Cell Differentiation - genetics Cells Cells, Cultured Cellular Reprogramming Techniques - methods Chromatin remodeling Direct conversion Dopamine Dopaminergic Neurons - cytology Efficiency Excitability Fibroblasts Health aspects Humans Infections Life Sciences Mesencephalon Mice miRNA Morphology Movement disorders Movement Disorders - etiology Movement Disorders - pathology Movement Disorders - prevention & control Neostriatum Neural circuitry Neurodegeneration Neurodegenerative diseases Neurogenesis Neurons Neurosciences Parkinson disease Parkinson Disease - complications Parkinson Disease - pathology Parkinson Disease - therapy Parkinson's disease Physiological aspects Sample variance Transcription factors Treatment Outcome Wnt protein |
| Title | Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model |
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