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

Yuchen Qi, Xin Jun Zhang, Nicolas Renier, Zhuhao Wu, Talia Atkin, Ziyi Sun, M. Zeeshan Ozair, Jason Tchieu, Bastian Zimmer, Faranak Fattahi, Yosif Ganat, Ricardo Azevedo, Nadja Zeltner, Ali H. Brivanlou, Maria Karayiorgou, Joseph Gogos, Mark Tomishima, Marc Tessier-Lavigne, Song Hai Shi, Lorenz Studer

Research output: Contribution to journalArticlepeer-review

124 Scopus citations

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.

Original languageEnglish
Pages (from-to)154-163
Number of pages10
JournalNature Biotechnology
Volume35
Issue number2
DOIs
StatePublished - 1 Feb 2017
Externally publishedYes

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