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Small molecules enable highly efficient neuronal conversion of human fibroblasts

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Abstract

Forced expression of proneural transcription factors has been shown to direct neuronal conversion of fibroblasts. Because neurons are postmitotic, conversion efficiencies are an important parameter for this process. We present a minimalist approach combining two-factor neuronal programming with small molecule–based inhibition of glycogen synthase kinase-3β and SMAD signaling, which converts postnatal human fibroblasts into functional neuron-like cells with yields up to >200% and neuronal purities up to >80%.

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Figure 1: Highly efficient conversion of HPF into βIII-tub+ cells.
Figure 2: Characterization of trans-differentiated cells derived from HPF-AN lines.

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Acknowledgements

We thank D. Kühne for technical support, J. Itskovitz-Eldor (Technion, Israel Institute of Technology, Haifa, Israel) and W.S. Kunz (University of Bonn, Germany) for providing HPF, and M. Emond for fruitful discussions. This work was supported by grants from the Federal Ministry of Education and Research (01GN1009B and 01GN1008C to O.B. and 01GN1008A to P.W. and G.K.), the German Research Foundation (SFB-TR3 D2 to O.B.), the European Union (FP7-HEALTH-2007-B-22943-NeuroStemcell and HEALTH-F5-2010-266753-SCR&Tox to O.B.), the Stem Cell Network North Rhine Westphalia (L-072.0058 to J.L.), the Else Kröner-Fresenius-Stiftung Fellowship (F.-J.M.) and the Hertie Foundation (O.B.).

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Author notes

  1. Jerome Mertens and Jaideep Kesavan: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Reconstructive Neurobiology, LIFE & BRAIN Center, University of Bonn and Hertie Foundation, Bonn, Germany

    Julia Ladewig, Jerome Mertens, Jaideep Kesavan, Jonas Doerr, Daniel Poppe, Finnja Glaue, Philipp Koch & Oliver Brüstle

  2. Institute of Human Genetics, LIFE & BRAIN Center, University of Bonn, Bonn, Germany

    Stefan Herms

  3. Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University Medical Centre, Düsseldorf, Germany

    Peter Wernet & Gesine Kögler

  4. Department of Psychiatry and Psychotherapy, Centre for Integrative Psychiatry ZIP-Kiel, University Hospital Schleswig Holstein, Kiel, Germany

    Franz-Josef Müller

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  1. Julia Ladewig
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  2. Jerome Mertens
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  3. Jaideep Kesavan
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  4. Jonas Doerr
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  5. Daniel Poppe
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  7. Stefan Herms
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  8. Peter Wernet
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  10. Franz-Josef Müller
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  11. Philipp Koch
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Contributions

J.L. conceived and designed the study, performed experiments, assembled, analyzed and interpreted data and helped write the manuscript; J.M., J.D., D.P., J.K. and F.G. performed experiments and analyzed and interpreted data; F.-J.M. and S.H. analyzed and interpreted data; P.W. and G.K. provided materials; P.K. and O.B. conceived and designed study, assembled, analyzed and interpreted data and helped write the manuscript.

Corresponding authors

Correspondence to Philipp Koch or Oliver Brüstle.

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Competing interests

O.B. declares a competing financial interest as a co-founder of and stockholder in LIFE & BRAIN GmbH.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9, Supplementary Note (PDF 9322 kb)

Supplementary Table 1

Gene expression profile of the converted HPFs (XLSX 19 kb)

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Ladewig, J., Mertens, J., Kesavan, J. et al. Small molecules enable highly efficient neuronal conversion of human fibroblasts. Nat Methods 9, 575–578 (2012). https://doi.org/10.1038/nmeth.1972

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  • DOI: https://doi.org/10.1038/nmeth.1972

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