title: Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model.
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.
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Pia
authors.initials: P
authors.lastname: Rivetti di Val Cervo
authors.affiliation: Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria.|Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Roman A
authors.initials: RA
authors.lastname: Romanov
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Giada
authors.initials: G
authors.lastname: Spigolon
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Débora
authors.initials: D
authors.lastname: Masini
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.|Department of Pharmacology, Faculty of Medicine, Biomedical Research Institute of Malaga (IBIMA), Malaga University, Malaga, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Martín-Montañez
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Enrique M
authors.identifier: 0000-0002-1460-4708
authors.initials: EM
authors.lastname: Toledo
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gioele
authors.initials: G
authors.lastname: La Manno
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Michael
authors.identifier: 0000-0001-5849-905X
authors.initials: M
authors.lastname: Feyder
authors.affiliation: Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Pifl
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA.
authors.forename: Yi-Han
authors.initials: YH
authors.lastname: Ng
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sara Padrell
authors.initials: SP
authors.lastname: Sánchez
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sten
authors.initials: S
authors.lastname: Linnarsson
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA.
authors.forename: Marius
authors.initials: M
authors.lastname: Wernig
authors.affiliation: Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria.|Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Tibor
authors.initials: T
authors.lastname: Harkany
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Fisone
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ernest
authors.identifier: 0000-0003-0197-6577
authors.initials: E
authors.lastname: Arenas
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000637:transplantation*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D000067470:Cellular Reprogramming Techniques / Q000379:methods*; D059290:Dopaminergic Neurons / Q000166:cytology*; D006801:Humans; D051379:Mice; D009069:Movement Disorders / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D010300:Parkinson Disease / Q000150:complications / Q000473:pathology* / Q000628:therapy*; D016896:Treatment Outcome