title: Combined small-molecule inhibition accelerates the derivation of functional cortical neurons from human pluripotent stem cells.
abstract: Considerable progress has been made in converting human pluripotent stem cells (hPSCs) into functional neurons. However, the protracted timing of human neuron specification and functional maturation remains a key challenge that hampers the routine application of hPSC-derived lineages in disease modeling and regenerative medicine. Using a combinatorial small-molecule screen, we previously identified conditions to rapidly differentiate hPSCs into peripheral sensory neurons. Here we generalize the approach to central nervous system (CNS) fates by developing a small-molecule approach for accelerated induction of early-born cortical neurons. Combinatorial application of six pathway inhibitors induces post-mitotic cortical neurons with functional electrophysiological properties by day 16 of differentiation, in the absence of glial cell co-culture. The resulting neurons, transplanted at 8 d of differentiation into the postnatal mouse cortex, are functional and establish long-distance projections, as shown using iDISCO whole-brain imaging. Accelerated differentiation into cortical neuron fates should facilitate hPSC-based strategies for disease modeling and cell therapy in CNS disorders.
authors.affiliation: Developmental Biology, Sloan-Kettering Institute, New York, New York, USA.|Center of Stem Cell Biology, Sloan-Kettering Institute, New York, New York, USA.|Weill Cornell Graduate School, New York, New York, USA.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Developmental Biology, Sloan-Kettering Institute, New York, New York, USA.|Center of Stem Cell Biology, Sloan-Kettering Institute, New York, New York, USA.
authors.forename: Xin-Jun
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: Laboratory of Brain Development and Repair, The Rockefeller University, New York, New York, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Renier
authors.affiliation: Laboratory of Brain Development and Repair, The Rockefeller University, New York, New York, USA.
authors.forename: Zhuhao
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Physiology, Columbia University, New York, New York, USA.
authors.forename: Talia
authors.initials: T
authors.lastname: Atkin
authors.affiliation: Department of Physiology, Columbia University, New York, New York, USA.
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, New York, USA.
authors.forename: M Zeeshan
authors.initials: MZ
authors.lastname: Ozair
authors.affiliation: Developmental Biology, Sloan-Kettering Institute, New York, New York, USA.|Center of Stem Cell Biology, Sloan-Kettering Institute, New York, New York, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Tchieu
authors.affiliation: Developmental Biology, Sloan-Kettering Institute, New York, New York, USA.|Center of Stem Cell Biology, Sloan-Kettering Institute, New York, New York, USA.
authors.forename: Bastian
authors.initials: B
authors.lastname: Zimmer
authors.affiliation: Developmental Biology, Sloan-Kettering Institute, New York, New York, USA.|Center of Stem Cell Biology, Sloan-Kettering Institute, New York, New York, USA.|Weill Cornell Graduate School, New York, New York, USA.
authors.forename: Faranak
authors.initials: F
authors.lastname: Fattahi
authors.affiliation: Developmental Biology, Sloan-Kettering Institute, New York, New York, USA.|Center of Stem Cell Biology, Sloan-Kettering Institute, New York, New York, USA.
authors.forename: Yosif
authors.initials: Y
authors.lastname: Ganat
authors.affiliation: Laboratory of Brain Development and Repair, The Rockefeller University, New York, New York, USA.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Azevedo
authors.affiliation: Developmental Biology, Sloan-Kettering Institute, New York, New York, USA.|Center of Stem Cell Biology, Sloan-Kettering Institute, New York, New York, USA.
authors.forename: Nadja
authors.initials: N
authors.lastname: Zeltner
authors.affiliation: Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, New York, USA.
authors.forename: Ali H
authors.initials: AH
authors.lastname: Brivanlou
authors.affiliation: Department of Physiology, Columbia University, New York, New York, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Karayiorgou
authors.affiliation: Department of Physiology and Department of Neuroscience, Columbia University, New York, New York, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Gogos
authors.affiliation: Developmental Biology, Sloan-Kettering Institute, New York, New York, USA.|Center of Stem Cell Biology, Sloan-Kettering Institute, New York, New York, USA.|SKI Stem Cell Core facility, Sloan-Kettering Institute, New York, New York, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Tomishima
authors.affiliation: Laboratory of Brain Development and Repair, The Rockefeller University, New York, New York, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Tessier-Lavigne
authors.affiliation: Developmental Biology, Sloan-Kettering Institute, New York, New York, USA.|Center of Stem Cell Biology, Sloan-Kettering Institute, New York, New York, USA.
authors.forename: Song-Hai
authors.initials: SH
authors.lastname: Shi
authors.affiliation: Developmental Biology, Sloan-Kettering Institute, New York, New York, USA.|Center of Stem Cell Biology, Sloan-Kettering Institute, New York, New York, USA.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Studer
mesh_terms: D061249:Batch Cell Culture Techniques / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002491:Central Nervous System Agents / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*
chemical_list: D002491:Central Nervous System Agents