Direct conversion of fibroblasts to functional neurons by defined factors
Open accessAbstract
Cellular differentiation and lineage commitment are considered to be robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. This raised the question of whether transcription factors could directly induce other defined somatic cell fates, and not only an undifferentiated state. We hypothesized that combinatorial expression of neural-lineage-specific transcription factors could directly convert fibroblasts into neurons. Starting from a pool of nineteen candidate genes, we identified a combination of only three factors, Ascl1, Brn2 (also called Pou3f2) and Myt1l, that suffice to rapidly and efficiently convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro. These induced neuronal (iN) cells express multiple neuron-specific proteins, generate action potentials and form functional synapses. Generation of iN cells from non-neural lineages could have important implications for studies of neural development, neurological disease modelling and regenerative medicine.
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Viral screens using focused overexpression libraries can identify putative reprogramming factors, for example, by identifying a defined set of transcription factors that are selectively required to induce pluripotent stem cells or trans-differentiate from mature somatic cell into another mature somatic cell.
“Viral screens using focused overexpression libraries can identify putative reprogramming factors, for example, by identifying a defined set of transcription factors that are selectively required to induce pluripotent stem cells (2–4,7) or trans-differentiate from mature somatic cell into another mature somatic cell (1,8–11).”
From Establishment of single-cell screening system for the rapid identification of transcriptional modulators involved in direct cell reprogramming (2012) · cites this paper as [10]
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Experimental — accuracy not yet measuredPooled screens for cell reprogramming have generally adopted a one-by-one elimination approach or testing for exhaustive combinations and interrogating phenotypes in cell culture from transgenic mice and/or aberrantly cloned cell lines.
“Despite the power of viral technologies, pooled screens for cell reprogramming have generally adopted a one-by-one elimination approach or testing for exhaustive combinations and interrogating phenotypes in cell culture from transgenic mice (1,3,10) and/or aberrantly cloned cell lines (12).”
From Establishment of single-cell screening system for the rapid identification of transcriptional modulators involved in direct cell reprogramming (2012) · cites this paper as [10]
iPSC-derived cells from different lineages can be combined into defined three-dimensional cultures called assembloids.
“Furthermore, iPSC-derived cell types from different lineages can be combined into defined three-dimensional cultures, termed assembloids9,94–98.”
From CRISPR-based functional genomics for neurological disease (2020) · cites this paper as [98]
MYT1L is a myelin transcription factor required to convert mouse embryonic and postnatal fibroblasts into functional neurons.
“MYT1L is a myelin transcription factor required to convert mouse embryonic and postnatal fibroblasts into functional neurons [68].”
From Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders (2012) · cites this paper as [68]
Functional induced neurons (iN) can be generated directly from fibroblasts by forced expression of neural specific transcription factors, a process called transdifferentiation.
“Functional induced neurons (iN) can be generated directly from fibroblasts by forced expression of neural specific transcription factors, a process also called transdifferentiation (Vierbuchen et al., 2010).”
From Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation (2016) · cites this paper as Vierbuchen et al., 2010
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Self-citation
- Authors
- Vierbuchen, T., Ostermeier, A., Pang, Z. P., Kokubu, Y., Südhof, T. C., & Wernig, M.
- Affiliations
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Wernig, Marius
- Venue
- Nature
- Published
- 2010-01-27
- Volume
- 463
- Issue
- 7284
- Pages
- 1035-1041
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2829121
- OpenAlex
- W2136541538
- Cited by
- 3,017
- References
- 38
- Citations by year
- 2026: 84 · 2025: 97 · 2024: 87 · 2023: 135 · 2022: 140 · 2021: 148 · 2020: 148 · 2019: 165 · 2018: 192 · 2017: 211 · 2016: 224 · 2015: 232 · 2014: 231 · 2013: 272 · 2012: 253
- FWCI
- 119.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5t32ns007280-35)
- U.S. Public Health Service (1018438-142-PABCA)
- National Heart, Lung, and Blood Institute (U01HL100397)
- National Cancer Institute (T32CA009302)
- National Institute of Neurological Disorders and Stroke (T32NS-007280, 5T32NS007280)
- 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
- ASCL1, Brn2, MYT1L, action potential, induced pluripotent stem cells, regenerative medicine
- MeSH terms
- Oligodendrocyte Transcription Factor 2, Action Potentials, Animals, Cell Line, Cells, Cultured, Embryo, Mammalian, Fibroblasts, Nerve Tissue Proteins, Neurons, Synapses, Tail, Time Factors, Transcription Factors, Biomarkers, Cell Lineage, Regenerative Medicine, POU Domain Factors, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Cell Transdifferentiation
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