Combined small-molecule inhibition accelerates the derivation of functional cortical neurons from human pluripotent stem cells
Open accessAbstract
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.
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Differentiation of induced pluripotent stem cells into neural cells recapitulates many neurodevelopmental features observed in prenatal human tissue and occurs in a temporal sequence that roughly corresponds to in vivo corticogenesis.
“Although these models come with their own limitations, including variability and limited functional maturation (Box 1), the differentiation of iPSCs into neural cells recapitulates many of the neurodevelopmental features observed in prenatal human tissue and occurs in a temporal sequence that roughly corresponds to in vivo corticogenesis29–31.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [30]
The Phenotypic analysis of CNS and cortical neuron identity section (page unavailable) reports successive waves of cell birth and a temporal order of cortical-layer marker expression consistent with in vivo corticogenesis. It does not establish the broader claim that the cultures recapitulate many features observed in prenatal human tissue. (LLM, conf=0.84)
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- Authors
- Qi, Y., Zhang, X.-J., Renier, N., Wu, Z., Atkin, T., Sun, Z., Ozair, M. Z., Tchieu, J., Zimmer, B., Fattahi, F., Ganat, Y., Azevedo, R., Zeltner, N., Brivanlou, A. H., Karayiorgou, M., Gogos, J., Tomishima, M., Tessier-Lavigne, M., Shi, S.-H., & Studer, L.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Rockefeller University (US)
- Columbia University (US)
- Corresponding author
- Studer, Lorenz
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2017-01-23
- Volume
- 35
- Issue
- 2
- Pages
- 154-163
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC5516899
- OpenAlex
- W2582868206
- Cited by
- 248
- References
- 31
- Citations by year
- 2026: 18 · 2025: 30 · 2024: 23 · 2023: 29 · 2022: 29 · 2021: 34 · 2020: 25 · 2019: 31 · 2018: 17 · 2017: 11
- FWCI
- 9.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Memorial Sloan-Kettering Cancer Center (CA008748, P30 CA008748)
- Starr Foundation (P30CA008748)
- New York State Stem Cell Science (C028128, C026879, C029153)
- National Institutes of Health (CA008748)
- National Institute of Mental Health (R01MH097879, R01MH101382)
- National Institute on Drug Abuse (R01DA024681)
- National Cancer Institute (P30CA008748)
- National Institute of Neurological Disorders and Stroke (R01NS072381, R21NS084334)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- cortical neuron differentiation, human pluripotent stem cells, small molecule inhibitors, neuronal maturation, electrophysiological maturation, peripheral sensory neurons, neural transplantation, disease modeling, regenerative medicine
- MeSH terms
- Cell Differentiation, Cells, Cultured, Central Nervous System Agents, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Humans, Neurons, Pluripotent Stem Cells, Neurogenesis, Batch Cell Culture Techniques
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