Rapid single-step induction of functional neurons from human pluripotent stem cells
Open accessAbstract
Available methods for differentiating human embryonic stem cells (ESCs) and induced pluripotent cells (iPSCs) into neurons are often cumbersome, slow, and variable. Alternatively, human fibroblasts can be directly converted into induced neuronal (iN) cells. However, with present techniques conversion is inefficient, synapse formation is limited, and only small amounts of neurons can be generated. Here, we show that human ESCs and iPSCs can be converted into functional iN cells with nearly 100% yield and purity in less than 2 weeks by forced expression of a single transcription factor. The resulting ES-iN or iPS-iN cells exhibit quantitatively reproducible properties independent of the cell line of origin, form mature pre- and postsynaptic specializations, and integrate into existing synaptic networks when transplanted into mouse brain. As illustrated by selected examples, our approach enables large-scale studies of human neurons for questions such as analyses of human diseases, examination of human-specific genes, and drug screening.
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Endo-lysosomal dysfunction has recently emerged as a potential key driver of late-onset AD etiology.
“Endo-lysosomal dysfunction has recently emerged as a potential key driver of late-onset AD etiology, and recent evidence suggests that Aβ may accumulate intracellularly prior to extracellular plaque deposition85–87.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [87]
The Discussion discusses using induced neurons to study neurological diseases, while the Results focus on their functional properties and a Munc18-1 knockdown. Searches for endo-lysosomal dysfunction in late-onset Alzheimer’s disease and for intracellular Aβ accumulation before plaque deposition found no passage addressing either point; an Alzheimer’s disease study appears only in the References. Page numbers were not available in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredRecent evidence suggests that Aβ may accumulate intracellularly prior to extracellular plaque deposition.
“Endo-lysosomal dysfunction has recently emerged as a potential key driver of late-onset AD etiology, and recent evidence suggests that Aβ may accumulate intracellularly prior to extracellular plaque deposition85–87.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [87]
The Results section on applications to diseased human neurons describes synaptic signaling and Munc18-1 knockdown, not Aβ accumulation or plaque deposition (page unavailable). Searches for intracellular Aβ, amyloid beta, and plaque deposition found no passage addressing whether intracellular accumulation precedes extracellular plaques. (LLM, conf=0.76)
Experimental — accuracy not yet measuredNgn2-driven generation yields glutamatergic neurons.
“In addition to the Ngn2-driven generation of glutamatergic neurons (Fernandopulle et al., 2018; Wang et al., 2017; Zhang et al., 2013) used here”
From CRISPR Interference-Based Platform for Multimodal Genetic Screens in Human iPSC-Derived Neurons (2019) · cites this paper as Zhang et al., 2013
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- Authors
- Zhang, Y., Pak, C., Han, Y., Ahlenius, H., Zhang, Z., Chanda, S., Marro, S., Patzke, C., Acuna, C., Covy, J., Xu, W., Yang, N., Danko, T., Chen, L., Wernig, M., & Südhof, T. C.
- Affiliations
- Stanford Medicine (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Südhof, Thomas C.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 78
- Issue
- 5
- Pages
- 785-798
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3751803
- OpenAlex
- W2040027262
- Cited by
- 1,644
- References
- 58
- Citations by year
- 2026: 154 · 2025: 198 · 2024: 200 · 2023: 186 · 2022: 172 · 2021: 144 · 2020: 138 · 2019: 123 · 2018: 87 · 2017: 81 · 2016: 53 · 2015: 61 · 2014: 35 · 2013: 11
- FWCI
- 23.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Defense
- Ellison Medical Foundation
- California Institute for Regenerative Medicine (RT2-02061)
- Deutsche Forschungsgemeinschaft
- Svenska Sällskapet för Medicinsk Forskning
- Vetenskapsrådet
- National Institutes of Health (MH086403, AG010770-18A1, AG010770)
- National Institute on Aging (P50 AG010770-18A1, P01AG010770)
- National Institute of Mental Health (R01MH092931, R01MH091193, P50MH086403)
- National Institute of Neurological Disorders and Stroke (R01NS077906)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD078051)
- 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
- human embryonic stem cells, induced pluripotent stem cells, neuronal differentiation, forced gene expression, synaptogenesis, postsynaptic specialization, drug screening, human-specific genes
- MeSH terms
- Animals, Biophysics, Brain, Calcium, Cells, Cultured, Electric Stimulation, Fibroblasts, Gene Expression Regulation, Humans, Mutation, Nerve Tissue Proteins, Neurons, Rhodopsin, Synapses, Tetrodotoxin, Time Factors, Transfection, Epidermolysis Bullosa Dystrophica, Patch-Clamp Techniques, Microscopy, Confocal, Excitatory Amino Acid Antagonists, 6-Cyano-7-nitroquinoxaline-2,3-dione, Excitatory Postsynaptic Potentials, Collagen Type VII, Sodium Channel Blockers, RNA, Small Interfering, Pluripotent Stem Cells, Green Fluorescent Proteins, Mice, Munc18 Proteins, Biophysical Phenomena
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