After more than six years of intensive effort, a team of Harvard researchers has successfully converted mouse and human skin cells into pain-sensing neurons that respond to a number of stimuli that cause acute and inflammatory pain.
The ‘disease in a dish’ model of pain reception may advance the understanding of why individuals differ in their pain responses or risk of developing chronic pain, and make possible the development of improved drugs to treat pain.
Clifford Woolf, co-director of Harvard Stem Cell Institute (HSCI)’s nervous systems diseases programme led the research effort, with collaborators including postdoctoral fellows Brian Wainger and Liz Buttermore, as well as Lee Rubin and Kevin Eggan, both professors in Harvard’s department of stem cell and regenerative biology.
The pain-sensing neurons created by Woolf and his team are reported to respond to both the kind of intense stimuli triggered by a physical injury and that causing ‘ouch’ pain, as well as to the more subtle stimuli triggered by inflammation, which results in pain tenderness, and even by some forms of cancer chemotherapy. The fact that the pain-sensing neurons respond to both the gross and fine forms of stimulation that produce distinct pains in humans provides confirmation that the neurons are functioning as naturally developed neurons would, said Woolf.
The project is the result of an ongoing collaboration between HSCI researchers and pharmaceutical giant Glaxo SmithKline. “For the first three years we had nothing to show for all our efforts but [Glaxo SmithKline], like us, were in it for the long haul.”
Although the early days of the project were like “hitting our head against a brick wall”, once the team began attempting to create the neurons directly from mouse and human skin cells, everything began to fall into place, said Woolf.
“We took mature pain-sensing neurons from mice, and found transcription factors that hadn’t been described in them before,” he added. Then, using a total of five factors – including three that were previously undescribed – the team was able to transform skin cells directly into the pain-sensing neurons.
Woolf notes that the neurons his team has developed “beautifully model” neuropathies and hypersensitivity to pain experienced by some of the patients who donated skin cells to the project. “Many pain conditions are due to genetic mutations, and we can now model these.”
Wainger, B.J., Buttermore, E.D., Oliveira, J.T., et al. (2014) Nat. Neurosci. doi: 10.1038/nn.3886