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Nat Neurosci DOI:10.1038/nn.3886

Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts.

Publication TypeJournal Article
Year of Publication2015
AuthorsWainger, BJ, Buttermore, ED, Oliveira, JT, Mellin, C, Lee, S, Saber, WAfshar, Wang, AJ, Ichida, JK, Chiu, IM, Barrett, L, Huebner, EA, Bilgin, C, Tsujimoto, N, Brenneis, C, Kapur, K, Rubin, LL, Eggan, K, Woolf, CJ
JournalNat Neurosci
Date Published2015 Jan
KeywordsAnimals, Dysautonomia, Familial, Electrophysiological Phenomena, Fibroblasts, Humans, Inflammation, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Models, Neurological, Nociceptors, Pain, Peripheral Nervous System Diseases, Sensory Receptor Cells, Transcription Factors

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.


Alternate JournalNat. Neurosci.
PubMed ID25420066
PubMed Central IDPMC4429606
Grant List1K08-NS082364 / NS / NINDS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
NS038253 / NS / NINDS NIH HHS / United States
R01 NS038253 / NS / NINDS NIH HHS / United States
K08 NS082364 / NS / NINDS NIH HHS / United States
T32 GM07592 / GM / NIGMS NIH HHS / United States
R00 NS077435 / NS / NINDS NIH HHS / United States