title: Efficient specification of interneurons from human pluripotent stem cells by dorsoventral and rostrocaudal modulation.
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.
authors.affiliation: Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA; Harvard Stem Cell Institute, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA.
authors.forename: Tae-Gon
authors.initials: TG
authors.lastname: Kim
authors.forename: Ruiqin
authors.initials: R
authors.lastname: Yao
authors.forename: Travis
authors.initials: T
authors.lastname: Monnell
authors.forename: Jun-Hyeong
authors.initials: JH
authors.lastname: Cho
authors.forename: Anju
authors.initials: A
authors.lastname: Vasudevan
authors.forename: Alice
authors.initials: A
authors.lastname: Koh
authors.forename: Kumar T
authors.initials: KT
authors.lastname: Peeyush
authors.forename: Minho
authors.initials: M
authors.lastname: Moon
authors.forename: Debkanya
authors.initials: D
authors.lastname: Datta
authors.forename: Vadim Y
authors.initials: VY
authors.lastname: Bolshakov
authors.forename: Kwang-Soo
authors.initials: KS
authors.lastname: Kim
authors.forename: Sangmi
authors.initials: S
authors.lastname: Chung
mesh_terms: D000818:Animals; D019521:Body Patterning; D001921:Brain / Q000166:cytology* / Q000196:embryology; D002460:Cell Line; D005346:Fibroblast Growth Factors / Q000502:physiology; D059330:GABAergic Neurons / Q000502:physiology; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D007395:Interneurons / Q000502:physiology* / Q000637:transplantation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058953:Neural Stem Cells / Q000502:physiology; D039904:Pluripotent Stem Cells / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; C509239:SHH protein, human; D005346:Fibroblast Growth Factors
keywords: Differentiation; Interneurons; Medial ganglionic eminence; Pluripotent stem cells