title: Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts.
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.
authors.affiliation: 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.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Wainger
authors.affiliation: 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.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Buttermore
authors.affiliation: 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.
authors.forename: Julia T
authors.initials: JT
authors.lastname: Oliveira
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
authors.forename: Cassidy
authors.initials: C
authors.lastname: Mellin
authors.affiliation: 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.
authors.forename: Seungkyu
authors.identifier: 0000000219293320
authors.initials: S
authors.lastname: Lee
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
authors.forename: Wardiya Afshar
authors.initials: WA
authors.lastname: Saber
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Justin K
authors.initials: JK
authors.lastname: Ichida
authors.affiliation: 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.
authors.forename: Isaac M
authors.initials: IM
authors.lastname: Chiu
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Barrett
authors.affiliation: 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.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Huebner
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
authors.forename: Canan
authors.initials: C
authors.lastname: Bilgin
authors.affiliation: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Tsujimoto
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Brenneis
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
authors.forename: Kush
authors.identifier: 000000019022913X
authors.initials: K
authors.lastname: Kapur
authors.affiliation: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Lee L
authors.initials: LL
authors.lastname: Rubin
authors.affiliation: 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.
authors.forename: Kevin
authors.initials: K
authors.lastname: Eggan
authors.affiliation: 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.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
mesh_terms: D000818:Animals; D004402:Dysautonomia, Familial / Q000473:pathology; D055724:Electrophysiological Phenomena / Q000502:physiology; D005347:Fibroblasts; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008959:Models, Neurological; D009619:Nociceptors; D010146:Pain / Q000503:physiopathology*; D010523:Peripheral Nervous System Diseases / Q000473:pathology; D011984:Sensory Receptor Cells; D014157:Transcription Factors
chemical_list: D014157:Transcription Factors