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Cell Stem Cell. 2015 Dec 3;17(6):719-734. doi: 10.1016/j.stem.2015.09.002. Epub 2015 Oct 29.

Rapid Conversion of Fibroblasts into Functional Forebrain GABAergic Interneurons by Direct Genetic Reprogramming.

Author information

1
Division of Neuroscience, Ospedale San Raffaele, 20132 Milan, Italy.
2
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy.
3
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.
4
Deep Sequencing Group, Biotechnology Center TU Dresden, Fetscherstrasse 105, 01307 Dresden, Germany.
5
University of Nice-Sophia Antipolis, 06108 Nice, France; INSERM, iBV, UMR 1091, 06108 Nice, France.
6
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.
7
Division of Neuroscience, Ospedale San Raffaele, 20132 Milan, Italy; CNR Institute of Neuroscience, 20129 Milan, Italy. Electronic address: broccoli.vania@hsr.it.

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.

PMID:
26526726
DOI:
10.1016/j.stem.2015.09.002
[Indexed for MEDLINE]
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