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RESEARCH HIGHLIGHTS SENSORY NEURONS The sense in reprogramming maxstock / Alamy The overexpression of certain Interestingly, most of the mouse and Peripheral sensitization of nocicep- transcription factors in fibroblasts human induced neurons expressed tors can underlie low-threshold clini- these studies has the potential to rapidly generate one of these three receptors. cal pain hypersensitivity. Interestingly, reveal various classes of neurons in vitro, Moreover, calcium assays revealed sub- pretreatment of tdTomato-expressing which could prove beneficial for populations of the mouse and human cells with prostaglandin E2, which techniques mechanistic studies of disease and cells that were selectively responsive sensitizes TRPV1, increased the for generating drug screening. Two new studies to known pain- and itch-inducing responsiveness of these cells to low functional now show that mouse and human ligands. Thus, these data indicate that doses of caspaicin, suggesting that peripheral fibroblasts can be reprogrammed to functional sensory neurons can be induced nociceptors can be used to become peripheral sensory neurons generated in vitro from embryonic model inflammatory sensitization. sensory through this approach. fibroblasts through the expression of Finally, the authors simultane- neurons Peripheral sensory neurons two transcription factors. ously expressed the five identified from mouse are derived from precursors that In their study, Woolf and col- transcription factors in human fibro- express the transcription factors leagues aimed to specifically generate blasts and were again able to generate and human neurogenin 1 (NGN1) and/or NGN2. nociceptors (as opposed to sensory cells that expressed neuronal markers fibroblasts These proteins are not expressed neurons more broadly) from fibro- and that had electrophysiological in vitro in mature sensory neurons, which blasts. To do so, they first generated properties resembling those of instead have been shown to express mice in which expression of the nociceptors. Furthermore, they were the transcription factor BRN3A (also reporter tdTomato was dependent on able to generate nociceptors from known as POU4F1). expression of TRPV1, a cation chan- fibroblasts taken from individuals Baldwin and colleagues transiently nel that is found in nociceptors and with familial dysautonomia. These expressed BRN3A and NGN1 or responds to caspaicin and noxious neurons show impaired neurite BRN3A and NGN2 in mouse and heat. They isolated embryonic fibro- growth and a reduced number of human embryonic fibroblasts to see blasts from this line and expressed branches per cell, compared with whether they could generate cells with different combinations of transcrip- induced nociceptors from healthy the characteristic features of sensory tion factors in these cells to induce controls, indicating that induced neurons. Following the expression of tdTomato expression. nociceptors may provide insights into either combination of factors, most This screening approach revealed disease pathophysiology. of the mouse and human cells showed that the simultaneous expression of Together, these studies reveal a neuron-like morphology. In addi- five transcription factors — ASC1, techniques for generating functional tion, the large majority of these cells MYT1L, NGN1, ISL2 and KLF7 peripheral sensory neurons from expressed multiple neuronal markers — could induce the expression mouse and human fibroblasts and exhibited electrophysiological of tdTomato and hence TRPV1. in vitro and highlight the potential properties consistent with functional Immunohistochemistry and RT-PCR for use of such cells in the modelling neurons, indicating that they could be analyses revealed that these cells of pathological conditions. considered induced neurons. also expressed neuronal and other Darran Yates Nociceptors and puritoceptors, nociceptor markers. Moreover, cas- ORIGINAL RESEARCH PAPERS Blanchard, J. W. mechanoceptors, and propriocep- paicin activated ~40% of these cells, et al. Selective conversion of fibroblasts into tors — the three functional subgroups as revealed by calcium imaging and peripheral sensory neurons. Nature Neurosci. http://dx.doi.org/10.1038/nn.3887 (2014) | of peripheral sensory neurons — extracellular recordings. Together, Wainger, B. J. et al. Modeling pain in vitro using selectively express different types of these data indicate that the fibroblasts nociceptor neurons reprogrammed from tropomyosin-related kinase (TRKA, were reprogrammed to generate fibroblasts. Nature Neurosci. http://dx.doi. org/10.1038/nn.3886 (2014) TRKB and TRKC, respectively). functional nociceptors. NATURE REVIEWS | NEUROSCIENCE VOLUME 16 | JANUARY 2015 © 2014 Macmillan Publishers Limited. All rights reserved.
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