Direct Induction and Functional Maturation of Forebrain GABAergic Neurons from Human Pluripotent Stem Cells

• DOI: 10.1016/j.celrep.2016.07.035
• Publication Date: 2016-08-05T12:34:47Z
• Authors: Alfred Xuyang Sun; Qiang Yuan; Shawn Tan; Yixin Xiao; Danlei Wang; Audrey Tze Ting Khoo; Levena Sani; Hoang-Dai Tran; Paul Kim; Yong Seng Chiew; Kea Joo Lee; Yi-Chun Yen; Huck Hui Ng; Bing Lim; Hyunsoo Shawn Je
• Keywords: QH301-705.5; LIM-Homeodomain Proteins; Gene Expression; Nerve Tissue Proteins; interneuron; Mice, SCID; Cell Line; GABA; Mice; 03 medical and health sciences; Neural Stem Cells; synapse; Interneurons; Mice, Inbred NOD; Basic Helix-Loop-Helix Transcription Factors; Animals; Humans; direct conversion; human pluripotent stem cells; Biology (General); GABAergic Neurons; Cerebral Cortex; Homeodomain Proteins; 0303 health sciences; Nuclear Proteins; Cell Differentiation; Coculture Techniques; 3. Good health; Neuroglia; Biomarkers

Gamma-aminobutyric acid (GABA)-releasing interneurons play an important modulatory role in the cortex and have been implicated in multiple neurological disorders. Patient-derived interneurons could provide a foundation for studying the pathogenesis of these diseases as well as for identifying potential therapeutic targets. Here, we identified a set of genetic factors that could robustly induce human pluripotent stem cells (hPSCs) into GABAergic neurons (iGNs) with high efficiency. We demonstrated that the human iGNs express neurochemical markers and exhibit mature electrophysiological properties within 6-8 weeks. Furthermore, in vitro, iGNs could form functional synapses with other iGNs or with human-induced glutamatergic neurons (iENs). Upon transplantation into immunodeficient mice, human iGNs underwent synaptic maturation and integration into host neural circuits. Taken together, our rapid and highly efficient single-step protocol to generate iGNs may be useful to both mechanistic and translational studies of human interneurons.