Small molecules enable neurogenin 2 to efficiently convert human fibroblasts into cholinergic neurons
Open accessAbstract
Cell fate can be reprogrammed by modifying intrinsic and extrinsic cues. Here we show that two small molecules (forskolin and dorsomorphin) enable the transcription factor Neurogenin 2 (NGN2) to convert human fetal lung fibroblasts into cholinergic neurons with high purity (>90%) and efficiency (up to 99% of NGN2-expressing cells). The conversion is direct without passing through a proliferative progenitor state. These human induced cholinergic neurons (hiCN) show mature electrophysiological properties and exhibit motor neuron-like features, including morphology, gene expression and the formation of functional neuromuscular junctions. Inclusion of an additional transcription factor, SOX11, also efficiently converts postnatal and adult skin fibroblasts from healthy and diseased human patients to cholinergic neurons. Taken together, this study identifies a simple and highly efficient strategy for reprogramming human fibroblasts to subtype-specific neurons. These findings offer a unique venue for investigating the molecular mechanisms underlying cellular plasticity and human neurodegenerative diseases.
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Direct conversion of human fibroblasts into iNs bypasses the embryo-like state and directly results in postmitotic neurons with mature marker expression and functionality.
“In contrast, direct conversion of human fibroblasts into induced neurons (iNs) bypasses the embryo-like state and directly results in postmitotic neurons with mature marker expression and functionality (Liu et al., 2013; Pang et al., 2011).”
From Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients (2021) · cites this paper as Liu et al., 2013
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- Authors
- Liu, M.-L., Zang, T., Zou, Y., Chang, J. C., Gibson, J. R., Huber, K. M., & Zhang, C.-L.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Zhang, Chun-Li
- Venue
- Nature Communications
- Published
- 2013-07-22
- Volume
- 4
- Issue
- 1
- Pages
- 2183-2183
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC3843951
- OpenAlex
- W2093314050
- Cited by
- 343
- References
- 47
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 15 · 2023: 23 · 2022: 19 · 2021: 36 · 2020: 37 · 2019: 31 · 2018: 26 · 2017: 37 · 2016: 37 · 2015: 36 · 2014: 18 · 2013: 3
- FWCI
- 14.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Ellison Medical Foundation (AG-NS-0753-11)
- Welch Foundation (I‐1724)
- Whitehall Foundation (2009-12-05)
- National Institutes of Health (1dp2od006484-01)
- National Institute of Neurological Disorders and Stroke (R01NS111776, R01NS070981)
- 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
- Neurogenin2, cholinergic neurons, fibroblast-to-neuron conversion, small molecule reprogramming, forskolin, compound C, SOX11, motor neuron-like cells, neuromuscular junction formation, cellular plasticity, neurodegenerative diseases
- MeSH terms
- Action Potentials, Adult, Cell Differentiation, Fetus, Fibroblasts, Colforsin, Humans, Lung, Nerve Tissue Proteins, Neuromuscular Junction, Pyrazoles, Pyrimidines, Time Factors, Gene Expression, Genes, Reporter, Green Fluorescent Proteins, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, SOXC Transcription Factors, Cholinergic Neurons, Primary Cell Culture
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