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Nat Biotechnol. 2017 Feb;35(2):154-163. doi: 10.1038/nbt.3777. Epub 2017 Jan 23.

Combined small-molecule inhibition accelerates the derivation of functional cortical neurons from human pluripotent stem cells.

Author information

1
Developmental Biology, Sloan-Kettering Institute, New York, New York, USA.
2
Center of Stem Cell Biology, Sloan-Kettering Institute, New York, New York, USA.
3
Weill Cornell Graduate School, New York, New York, USA.
4
Laboratory of Brain Development and Repair, The Rockefeller University, New York, New York, USA.
5
Department of Physiology, Columbia University, New York, New York, USA.
6
Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, New York, USA.
7
Department of Physiology and Department of Neuroscience, Columbia University, New York, New York, USA.
8
SKI Stem Cell Core facility, Sloan-Kettering Institute, New York, New York, USA.

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.

PMID:
28112759
PMCID:
PMC5516899
DOI:
10.1038/nbt.3777
[Indexed for MEDLINE]
Free PMC Article

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