Efficient Specification of Interneurons from Human Pluripotent Stem Cells by Dorsoventral and Rostrocaudal Modulation

Authors

  • Tae-Gon Kim,

    1. Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
    2. Harvard Stem Cell Institute, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
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  • Ruiqin Yao,

    1. Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
    2. Harvard Stem Cell Institute, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
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  • Travis Monnell,

    1. Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
    2. Harvard Stem Cell Institute, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
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  • Jun-Hyeong Cho,

    1. Cellular Neurobiology Laboratory, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
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  • Anju Vasudevan,

    1. Angiogenesis & Brain Development Laboratory, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
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  • Alice Koh,

    1. Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
    2. Harvard Stem Cell Institute, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
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  • Peeyush Kumar T.,

    1. Angiogenesis & Brain Development Laboratory, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
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  • Minho Moon,

    1. Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
    2. Harvard Stem Cell Institute, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
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  • Debkanya Datta,

    1. Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
    2. Harvard Stem Cell Institute, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
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  • Vadim Y. Bolshakov,

    1. Cellular Neurobiology Laboratory, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
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  • Kwang-Soo Kim,

    Corresponding author
    1. Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
    2. Harvard Stem Cell Institute, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
    • Correspondence: Kwang-Soo Kim, Ph.D., McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02178, USA. Telephone: 617-855-2024; Fax: 617-855-3479; e-mail: kskim@mclean.harvard.edu; or Sangmi Chung, Ph.D., McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02178, USA. Telephone: 617-855-3478; Fax: 617-855-2020; e-mail: schung@mclean.harvard.edu.

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  • Sangmi Chung

    Corresponding author
    1. Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
    2. Harvard Stem Cell Institute, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
    • Correspondence: Kwang-Soo Kim, Ph.D., McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02178, USA. Telephone: 617-855-2024; Fax: 617-855-3479; e-mail: kskim@mclean.harvard.edu; or Sangmi Chung, Ph.D., McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02178, USA. Telephone: 617-855-3478; Fax: 617-855-2020; e-mail: schung@mclean.harvard.edu.

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Abstract

GABAergic interneurons regulate cortical neural networks by providing inhibitory inputs, and their malfunction, resulting in failure to intricately regulate neural circuit balance, is implicated in brain diseases such as Schizophrenia, Autism, and Epilepsy. During early development, GABAergic interneuron progenitors arise from the ventral telencephalic area such as medial ganglionic eminence (MGE) and caudal ganglionic eminence (CGE) by the actions of secreted signaling molecules from nearby organizers, and migrate to their target sites where they form local synaptic connections. In this study, using combinatorial and temporal modulation of developmentally relevant dorsoventral and rostrocaudal signaling pathways (SHH, Wnt, and FGF8), we efficiently generated MGE cells from multiple human pluripotent stem cells. Most importantly, modulation of FGF8/FGF19 signaling efficiently directed MGE versus CGE differentiation. Human MGE cells spontaneously differentiated into Lhx6-expressing GABAergic interneurons and showed migratory properties. These human MGE-derived neurons generated GABA, fired action potentials, and displayed robust GABAergic postsynaptic activity. Transplantation into rodent brains results in well-contained neural grafts enriched with GABAergic interneurons that migrate in the host and mature to express somatostatin or parvalbumin. Thus, we propose that signaling modulation recapitulating normal developmental patterns efficiently generate human GABAergic interneurons. This strategy represents a novel tool in regenerative medicine, developmental studies, disease modeling, bioassay, and drug screening. Stem Cells 2014;32:1789–1804

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