Induction of human neuronal cells by defined transcription factors

By Z. Pang, Nan Yang, Thomas Vierbuchen, Austin Ostermeier, Daniel R Fuentes, Troy Q. Yang, A. Citri, V. Sebastiano, Samuele G. Marro, T. Sūdhof and 1 more. Nature, 2011

1,257 citations recorded by the source corpus.

Somatic cell nuclear transfer, cell fusion, or expression of lineage-specific factors have been shown to induce cell-fate changes in diverse somatic cell types. We recently observed that forced expression of a combination of three transcription factors, Brn2 (also known as Pou3f2), Ascl1 and Myt1l, can efficiently convert mouse fibroblasts into functional induced neuronal (iN) cells. Here we show that the same three factors can generate functional neurons from human pluripotent stem cells as early as 6 days after transgene activation. When combined with the basic helix–loop–helix transcription factor NeuroD1, these factors could also convert fetal and postnatal human fibroblasts into iN cells showing typical neuronal morphologies and expressing multiple neuronal markers, even after downregulation of the exogenous transcription factors. Importantly, the vast majority of human iN cells were able to generate action potentials and many matured to receive synaptic contacts when co-cultured with primary mouse cortical neurons. Our data demonstrate that non-neural human somatic cells, as well as pluripotent stem cells, can be converted directly into neurons by lineage-determining transcription factors. These methods may facilitate robust generation of patient-specific human neurons for in vitro disease modelling or future applications in regenerative medicine.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/28d373ac8a64d44fdd401db15dc74f9390003985

How researchers see this paper

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In Genetics

1. Aviv Regev
2. Fred H. Gage
3. J. Gonçalves
4. Bradley E. Bernstein
5. A. Shalek
6. Clifford J. Woolf

In Molecular Biology

1. Aviv Regev
2. Simon Kasif
3. Fred H. Gage
4. J. Gonçalves
5. D. Louis
6. Bradley E. Bernstein
7. A. Shalek
8. M. Hetzer

Citations in the corpus

• Transcriptional Regulation and its Misregulation in Disease (2013, neutral): “…expressed in various cell types (Buganim et al., 2012; Davis et al., 1987; Huang et al., 2011; Ieda et al., 2010; Kajimura et al., 2009; Marro et al., 2011; Pang et al., 2011; Sekiya and Suzuki, 2011; Takahashi and Yamanaka, 2006; Vierbuchen et al., 2010; Xie et al., 2004; Zhou et al., 2008).”
• Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects (2015, positive): “The direct transcription factor-based conversion of fibroblasts into induced neurons (iNs) represents an alternative avenue for generating human neurons in vitro (Pang et al., 2011; Vierbuchen et al., 2010).”
• Conversion of Mouse and Human Fibroblasts into Functional Spinal Motor Neurons (2011, background): “N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript conversion efficiency of human fibroblasts into iNs (Pang et al., 2011).”
• Reconstructing and reprogramming the tumor propagating potential of glioblastoma stem-like cells (2014, positive): “Notably, several TPC-specific TFs are components of cocktails that have been used to convert fibroblasts into neurons (Pang et al., 2011) or neural stem cells (Lujan et al.”
• In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model (2013, background): “Many studies have since demonstrated transdifferentiation across different cell lineages, including reprogramming mouse or human fibroblasts directly into neurons (Ambasudhan et al., 2011; Caiazzo et al., 2011; Kim et al., 2011; Ladewig et al., 2012; Liu et al., 2012, 2013; Meng et al., 2012; Pang e”