An investigation into the difference between human nerve cells and animal cells has provided researchers at the Center for Advanced Pain Studies (CAPS) at the University of Texas at Dallas with important clues in the search for more effective treatments for chronic pain.
Dr. Ted Price BS’97, Ashbel Smith Professor of Neuroscience at the School of Behavioral and Brain Sciences (BBS) and Director of CAPS, leads a team analyzing the origins of how pain is generated by nociceptors – pain-sensing nerve cells – in human dorsal root ganglia (DRG) neurons. Price is co-corresponding author of a study, featured on the cover of the February 16 issue of Scientific Translational Medicine, which traces the full range of messenger RNA (mRNA) strands – a grouping called the transcriptome – produced in these cells.
Since mRNA is a single-stranded copy of a gene that can be translated into protein, the results allow neuroscientists to better understand which genes are expressed in DRG neurons. The study also reinforces the value of studying human tissue — as opposed to animal cells — in the search for pain treatments.
DRG neurons are specialized nerve cells clustered near the base of the spine. Very little work has been done before with these human cells due to the scarcity of their availability for research.
“We are one of the few groups in the country that has access to DRG tissue from human donors acquired specifically for research,” said Stephanie Shiers PhD’19, a neuroscientist and co-author of the paper.
Demonstrate the differences
Shiers’ previous research has demonstrated in general terms that there are significant differences between nociceptors in mice and humans. This work explained why proposed pain treatments that work in mice fail in humans.
“This paper is the next step, clearly demonstrating the profound magnitude of these differences,” Price said. “A whole set of nociceptors that many people study in mice just don’t end up in humans. There are subtypes in humans that don’t even exist in non-human primates.
“It’s not that we should abandon all existing non-human pain models. But some are really good, while others are not, depending on what you want to study. When it comes to this aspect of pain, our work shows which is which.
“We are now able to approach the development of pain therapies in a more specific way and to think about how chronic pain arises in people in a different way. I hope our discoveries can change the way people do research in our field.
Dr. Ted Price BS’97, Ashbel Smith Professor of Neuroscience in the School of Behavioral and Brain Sciences
To profile all of the gene activity in a sample of DRG tissue, the research team used an advanced technique called spatial transcriptomics, which has improved capabilities over single-cell RNA sequencing.
“It’s rare to have access to both the human tissues we used and the technology,” said Dr. Diana Tavares-Ferreira, also the study’s co-first and co-corresponding author and CAPS fellow. “Spatial transcriptomics makes it possible to overcome the large size of these neurons and to see with some certainty where and how a gene is expressed in human nociceptors.
“Our primary goal was to completely characterize the entire transcriptome of human DRG neurons, as much of the work that has been done to find new therapeutic targets for pain has been done in mice. Our findings help clarify why these efforts struggle to produce results.
Better physiological image
By describing the types of neurons present in human DRGs and detailing their gene expression, the team has a much better picture of each gene’s physiological functions, Price said.
“With this knowledge, not only can anyone use our data to search for drug targets they couldn’t have searched for before, but in some cases we don’t need to use the mice at all now. . We can use human information,” he said.
Price called the removal of this reliance on animal models a “fundamental shift” because it allows scientists to explore how any type of cell could interact with any neuron in the human peripheral nervous system. .
“We are now able to approach the development of pain therapies in a more specific way and to think about how chronic pain arises in people in a different way,” Price said. “I hope our discoveries can change the way people do research in our field. It is a roadmap that we will use and that others are invited to follow.
Reference: Tavares-Ferreira D, Shiers S, Ray PR, et al. Spatial transcriptomics of dorsal root ganglia identifies molecular signatures of human nociceptors. Sci Transl Med. 2022.14(632):eabj8186. doi: 10.1126/scitranslmed.abj8186
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