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

Gaia Colasante, Gabriele Lignani, Alicia Rubio, Lucian Medrihan, Latefa Yekhlef, Alessandro Sessa, Luca Massimino, Serena G. Giannelli, Silvio Sacchetti, Massimiliano Caiazzo, Damiana Leo, Dimitra Alexopoulou, Maria Teresa Dell'Anno, Ernesto Ciabatti, Marta Orlando, Michele Studer, Andreas Dahl, Raul R. Gainetdinov, Stefano Taverna, Fabio BenfenatiVania Broccoli

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)719-734
Number of pages16
JournalCell Stem Cell
Volume17
Issue number6
DOIs
Publication statusPublished - Dec 3 2015

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine
  • Genetics

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