TY - JOUR

T1 - Rapid Conversion of Fibroblasts into Functional Forebrain GABAergic Interneurons by Direct Genetic Reprogramming

AU - Colasante, Gaia

AU - Lignani, Gabriele

AU - Rubio, Alicia

AU - Medrihan, Lucian

AU - Yekhlef, Latefa

AU - Sessa, Alessandro

AU - Massimino, Luca

AU - Giannelli, Serena G.

AU - Sacchetti, Silvio

AU - Caiazzo, Massimiliano

AU - Leo, Damiana

AU - Alexopoulou, Dimitra

AU - Dell'Anno, Maria Teresa

AU - Ciabatti, Ernesto

AU - Orlando, Marta

AU - Studer, Michele

AU - Dahl, Andreas

AU - Gainetdinov, Raul R.

AU - Taverna, Stefano

AU - Benfenati, Fabio

AU - Broccoli, Vania

N1 - Publisher Copyright: © 2015 Elsevier Inc.

PY - 2015/12/3

Y1 - 2015/12/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84952638827&partnerID=8YFLogxK

U2 - 10.1016/j.stem.2015.09.002

DO - 10.1016/j.stem.2015.09.002

M3 - Article

C2 - 26526726

AN - SCOPUS:84952638827

VL - 17

SP - 719

EP - 734

JO - Cell Stem Cell

JF - Cell Stem Cell

SN - 1934-5909

IS - 6

ER -