Migraine and related headaches are caused by activity in a part of the nervous system known as the trigeminal ganglion (TG). However, it remains unclear which genes and cell types of the TG are involved. Now, by analyzing mouse and human TG, researchers from Brigham and Women’s Hospital and Massachusetts General Hospital profiled, at single-cell resolution, the genes expressed in each TG cell type. Their atlas may lead to the development of more effective treatments.
Their findings are published in the journal Neuron, in a paper titled, “Human and mouse trigeminal ganglia cell atlas implicates multiple cell types in migraine.”
“Sensitization of trigeminal ganglion neurons contributes to primary headache disorders such as migraine, but the specific neuronal and non-neuronal trigeminal subtypes that are involved remain unclear,” the researchers wrote. “We thus developed a cell atlas in which human and mouse trigeminal ganglia are transcriptionally and epigenomically profiled at single-cell resolution.”
“Very few pain therapeutics have made it to the clinic, despite strong efficacy in animal models, so our goal was to analyze human tissue to look for new targets for headache and facial pain treatment,” said William Renthal, MD, PhD, director of research, John R. Graham Headache Center, department of neurology, Brigham and Women’s Hospital. “We now have an atlas of the genes that are expressed in each of the cell types in the TG, the key relay center for migraine and facial pain, and we are now using this tool to identify potential therapeutic targets that are selectively expressed in cell types that drive head pain. We believe this will lead to more precise medicines without as many side effects.”
In addition to analyzing the TG of four human donors, the researchers studied two mouse models of headache. Importantly, they found that while cell types between mice and humans are largely conserved, some of the genes known to be involved in pain are expressed in different subsets of cells in mice versus humans. This gave the researchers new ideas about which cells to study further.
“A major value of this study is that it wasn’t limited to one specific cell type or branch of the trigeminal ganglion,“ said Jochen K. Lennerz, MD, PhD, medical director of the Center for Integrated Diagnostics in the department of pathology at MGH. Lennerz’s lab performed the complex tissue-harvesting procedures required to extract the TG, which is located inside the cranium but has neurons that enervate the teeth, eyes, and other facial structures. “We included all of the cells that make up the TG,” he said. “This was a very holistic approach which has resulted in an amazing compendium that researchers can look at from all perspectives and specialties. It may not only be neurons we are looking for when identifying biomolecules as therapeutic targets.”
The new findings may pave the way for treatments beyond migraine headaches, including post-concussive headaches or cluster headaches. The researchers are looking forward to improving upon their current atlas by sequencing additional human tissues.
“We have a resource now that allows an individual to go online, look up a gene of interest, find out where it’s expressed and how it’s regulated, and then use this information to inspire new experiments,” Renthal said. “This atlas is only a first draft, and we need to expand the number of donors to build a more complete one. That’s a current limitation but also a future direction for our work.”
“This trigeminal ganglion cell atlas improves our understanding of the cell types, genes, and epigenomic features involved in headache pathophysiology and establishes a rich resource of cell-type-specific molecular features to guide the development of more selective treatments for headache and facial pain,” concluded the researchers.