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Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts

2014; Nature Portfolio; Volume: 18; Issue: 1 Linguagem: Inglês

10.1038/nn.3886

1546-1726

Brian J. Wainger, Elizabeth D. Buttermore, Júlia Teixeira Oliveira, Cassidy Mellin, Seungkyu Lee, Wardiya Afshar Saber, Amy J. Wang, Justin K. Ichida, Isaac M. Chiu, Lee Barrett, Eric A. Huebner, Canan Bilgin, Naomi Tsujimoto, Christian Brenneis, Kush Kapur, Lee L. Rubin, Kevin Eggan, Clifford J. Woolf,

Ion channel regulation and function

In this study, the authors show that they can induce the direct conversion of fibroblasts into nociceptor neurons via the expression of only five key transcription factors. They further confirm that these induced neurons are bona fide nociceptors by demonstrating that their expression profiles resemble that of their endogenous counterparts and show that they are responsive to common nociceptor agonists. 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.