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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.

SUBMITTER: Qi Y

PROVIDER: S-EPMC5516899 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Qi Yuchen Y Zhang Xin-Jun XJ Renier Nicolas N Wu Zhuhao Z Atkin Talia T Sun Ziyi Z Ozair M Zeeshan MZ Tchieu Jason J Zimmer Bastian B Fattahi Faranak F Ganat Yosif Y Azevedo Ricardo R Zeltner Nadja N Brivanlou Ali H AH Karayiorgou Maria M Gogos Joseph J Tomishima Mark M Tessier-Lavigne Marc M Shi Song-Hai SH Studer Lorenz L

Nature biotechnology 20170123 2

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 ...[more]

PMID: 28112759

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Project description:UnlabelledThe recapitulation of human neural development in a controlled, defined manner from pluripotent stem cells (PSCs) has considerable potential for studies of human neural development, circuit formation and function, and the construction of in vitro models of neurological diseases. The inhibition of Wnt signaling, often by the recombinant protein DKK1, is important for the induction of cortical neurons. Here, we report a novel differentiation method using a small-molecule WNT inhibitor, WNT-C59 (C59), to efficiently induce human anterior cortex. We compared two types of small molecules, C59 and XAV939 (XAV), as substitutes for DKK1 to induce cortical neurons from PSCs in serum-free embryoid body-like aggregate culture. DKK1 and XAV inhibited only the canonical pathway of Wnt signaling, whereas C59 inhibited both the canonical and noncanonical pathways. C59 efficiently induced CTIP2+/COUP-TF1- cells, which are characteristic of the cells found in the anterior cortex. In addition, when grafted into the cortex of adult mice, the C59-induced cells showed abundant axonal fiber extension toward the spinal cord. These results raise the possibility of C59 contributing to cell replacement therapy for motor neuron diseases or insults.SignificanceFor a cell therapy against damaged corticospinal tract caused by neurodegenerative diseases or insults, cortical motor neurons are needed. Currently, their induction from pluripotent stem cells is considered very promising; however, an efficient protocol to induce motor neurons is not available. For efficient induction of anterior cortex, where motor neurons are located, various WNT inhibitors were investigated. It was found that one of them could induce anterior cortical cells efficiently. In addition, when grafted into the cortex of adult mice, the induced cells showed more abundant axonal fiber extension toward spinal cord. These results raise the possibility that this inhibitor contributes to a cell-replacement therapy for motor neuron diseases or insults.

Dataset Information

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

Publications

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

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