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

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

  • Nat Biotechnol. 2017 Feb;35(2):154-163. doi: 10.1038/nbt.3777.
Yuchen Qi 1 2 3,  Xin-Jun Zhang 1 2,  Nicolas Renier 4,  Zhuhao Wu 4,  Talia Atkin 5,  Ziyi Sun 5,  M Zeeshan Ozair 6,  Jason Tchieu 1 2,  Bastian Zimmer 1 2,  Faranak Fattahi 1 2 3,  Yosif Ganat 1 2,  Ricardo Azevedo 4,  Nadja Zeltner 1 2,  Ali H Brivanlou 6,  Maria Karayiorgou 5,  Joseph Gogos 7,  Mark Tomishima 1 2 8,  Marc Tessier-Lavigne 4,  Song-Hai Shi 1 2,  Lorenz Studer 1 2
Affiliations

Affiliations

  • 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.
PMID: 28112759 DOI: 10.1038/nbt.3777
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.

Figures
Products