title: Rapid Conversion of Fibroblasts into Functional Forebrain GABAergic Interneurons by Direct Genetic Reprogramming.
abstract: Transplantation of GABAergic interneurons (INs) can provide long-term functional benefits in animal models of epilepsy and other neurological disorders. Whereas GABAergic INs can be differentiated from embryonic stem cells, alternative sources of GABAergic INs may be more tractable for disease modeling and transplantation. We identified five factors (Foxg1, Sox2, Ascl1, Dlx5, and Lhx6) that convert mouse fibroblasts into induced GABAergic INs (iGABA-INs) possessing molecular signatures of telencephalic INs. Factor overexpression activates transcriptional networks required for GABAergic fate specification. iGABA-INs display progressively maturing firing patterns comparable to cortical INs, form functional synapses, and release GABA. Importantly, iGABA-INs survive and mature upon being grafted into mouse hippocampus. Optogenetic stimulation demonstrated functional integration of grafted iGABA-INs into host circuitry, triggering inhibition of host granule neuron activity. These five factors also converted human cells into functional GABAergic INs. These properties suggest that iGABA-INs have potential for disease modeling and cell-based therapeutic approaches to neurological disorders.
authors.affiliation: Division of Neuroscience, Ospedale San Raffaele, 20132 Milan, Italy.
authors.forename: Gaia
authors.initials: G
authors.lastname: Colasante
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Lignani
authors.affiliation: Division of Neuroscience, Ospedale San Raffaele, 20132 Milan, Italy.
authors.forename: Alicia
authors.initials: A
authors.lastname: Rubio
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy.
authors.forename: Lucian
authors.initials: L
authors.lastname: Medrihan
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy; Neuroimmunology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Latefa
authors.initials: L
authors.lastname: Yekhlef
authors.affiliation: Division of Neuroscience, Ospedale San Raffaele, 20132 Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sessa
authors.affiliation: Division of Neuroscience, Ospedale San Raffaele, 20132 Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Massimino
authors.affiliation: Division of Neuroscience, Ospedale San Raffaele, 20132 Milan, Italy.
authors.forename: Serena G
authors.initials: SG
authors.lastname: Giannelli
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Sacchetti
authors.affiliation: Division of Neuroscience, Ospedale San Raffaele, 20132 Milan, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Caiazzo
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy.
authors.forename: Damiana
authors.initials: D
authors.lastname: Leo
authors.affiliation: Deep Sequencing Group, Biotechnology Center TU Dresden, Fetscherstrasse 105, 01307 Dresden, Germany.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Alexopoulou
authors.affiliation: Division of Neuroscience, Ospedale San Raffaele, 20132 Milan, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Dell'Anno
authors.affiliation: Division of Neuroscience, Ospedale San Raffaele, 20132 Milan, Italy.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Ciabatti
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Orlando
authors.affiliation: University of Nice-Sophia Antipolis, 06108 Nice, France; INSERM, iBV, UMR 1091, 06108 Nice, France.
authors.forename: Michele
authors.initials: M
authors.lastname: Studer
authors.affiliation: Deep Sequencing Group, Biotechnology Center TU Dresden, Fetscherstrasse 105, 01307 Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Dahl
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy; Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia.
authors.forename: Raul R
authors.initials: RR
authors.lastname: Gainetdinov
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy; Neuroimmunology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Taverna
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Benfenati
authors.affiliation: Division of Neuroscience, Ospedale San Raffaele, 20132 Milan, Italy; CNR Institute of Neuroscience, 20129 Milan, Italy. Electronic address: broccoli.vania@hsr.it.
authors.forename: Vania
authors.initials: V
authors.lastname: Broccoli
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D065150:Cellular Reprogramming; D018920:Coculture Techniques; D053595:Embryonic Stem Cells / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007395:Interneurons / Q000166:cytology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D016548:Prosencephalon / Q000166:cytology*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D013687:Telencephalon / Q000166:cytology; D014158:Transcription, Genetic; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D055748:SOXB1 Transcription Factors; D005680:gamma-Aminobutyric Acid; C499317:Ascl1 protein, mouse; C489565:Foxg1 protein, mouse; C527783:Sox2 protein, mouse