Article | Published:

Selective conversion of fibroblasts into peripheral sensory neurons

Nature Neuroscience volume 18, pages 2535 (2015) | Download Citation

Abstract

Humans and mice detect pain, itch, temperature, pressure, stretch and limb position via signaling from peripheral sensory neurons. These neurons are divided into three functional classes (nociceptors/pruritoceptors, mechanoreceptors and proprioceptors) that are distinguished by their selective expression of TrkA, TrkB or TrkC receptors, respectively. We found that transiently coexpressing Brn3a with either Ngn1 or Ngn2 selectively reprogrammed human and mouse fibroblasts to acquire key properties of these three classes of sensory neurons. These induced sensory neurons (iSNs) were electrically active, exhibited distinct sensory neuron morphologies and matched the characteristic gene expression patterns of endogenous sensory neurons, including selective expression of Trk receptors. In addition, we found that calcium-imaging assays could identify subsets of iSNs that selectively responded to diverse ligands known to activate itch- and pain-sensing neurons. These results offer a simple and rapid means for producing genetically diverse human sensory neurons suitable for drug screening and mechanistic studies.

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Acknowledgements

We would like to thank M. Talantova and D. Zhang for assistance with mouse electrophysiology, K. Spencer for assistance with microscopy, A. Patapoutian, S. Murthy, A. Dubin, S. Ranade and J. Mathur for helpful discussions, and W. Ferguson for technical assistance. This research was supported by the National Institute on Drug Abuse (DA031566 to P.S.), the National Institute on Deafness and other Communication Disorders (DC012592 to K.K.B.), the National Institute of Mental Health (MH102698 to K.K.B.), the California Institute for Regenerative Medicine (RB3-02186 to K.K.B.), the Baxter Family, Norris and Del Webb Foundations (K.K.B.), by Las Patronas and the Dorris Neuroscience Center (K.K.B.), a pre-doctoral fellowship from the California Institute of Regenerative Medicine (J.W.B. and R.K.T.), an NSF Predoctoral Fellowship (R.K.T.), the Andrea Elizabeth Vogt Memorial Award (J.W.B.) and the Scripps Stem Cell Postdoctoral Fellowship (V.L.S.).

Author information

Author notes

    • Joel W Blanchard
    •  & Kevin T Eade

    These authors contributed equally to this work.

Affiliations

  1. Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California, USA.

    • Joel W Blanchard
    • , Kevin T Eade
    • , Valentina Lo Sardo
    • , Rachel K Tsunemoto
    • , Daniel Williams
    •  & Kristin K Baldwin
  2. BioCircuits Institute, University of California San Diego, La Jolla, California, USA.

    • Attila Szűcs
  3. Balaton Limnological Institute of the Hungarian Academy of Sciences, Tihany, Hungary.

    • Attila Szűcs
  4. Neuroscience Graduate Program, University of California San Diego, La Jolla, California, USA.

    • Rachel K Tsunemoto
    •  & Kristin K Baldwin
  5. Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California, USA.

    • Pietro Paolo Sanna

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Contributions

K.K.B., J.W.B. and K.T.E. designed and conceived the experiments. K.T.E., J.W.B., V.L.S., R.K.T. and D.W. performed the experiments. A.S. and P.P.S. performed electrophysiology. K.K.B., J.W.B. and K.T.E. wrote and revised the manuscript and all of the authors edited the final drafts.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Kristin K Baldwin.

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DOI

https://doi.org/10.1038/nn.3887

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