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Nat Neurosci. 2015 Jan;18(1):17-24. doi: 10.1038/nn.3886. Epub 2014 Nov 24.

Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts.

Author information

1
1] F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. [2] Department of Anesthesia, Critical Care and Pain Medicine and Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
2
1] F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. [2] Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
3
1] F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. [2] Laboratório de Neurodegeneração e Reparo, Departamento de Patologia, Faculdade de Medicina, Universidade Federal Do Rio De Janeiro, Rio de Janeiro, Brazil.
4
F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
5
1] Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, California, USA.
6
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
7
1] Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] The Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts, USA.

Abstract

Reprogramming somatic cells from one cell fate to another can generate specific neurons suitable for disease modeling. To maximize the utility of patient-derived neurons, they must model not only disease-relevant cell classes, but also the diversity of neuronal subtypes found in vivo and the pathophysiological changes that underlie specific clinical diseases. We identified five transcription factors that reprogram mouse and human fibroblasts into noxious stimulus-detecting (nociceptor) neurons. These recapitulated the expression of quintessential nociceptor-specific functional receptors and channels found in adult mouse nociceptor neurons, as well as native subtype diversity. Moreover, the derived nociceptor neurons exhibited TrpV1 sensitization to the inflammatory mediator prostaglandin E2 and the chemotherapeutic drug oxaliplatin, modeling the inherent mechanisms underlying inflammatory pain hypersensitivity and painful chemotherapy-induced neuropathy. Using fibroblasts from patients with familial dysautonomia (hereditary sensory and autonomic neuropathy type III), we found that the technique was able to reveal previously unknown aspects of human disease phenotypes in vitro.

PMID:
25420066
PMCID:
PMC4429606
DOI:
10.1038/nn.3886
[Indexed for MEDLINE]
Free PMC Article

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