The team then searched for the same cells in humans, using ligament samples removed by spine surgeon Dr. Sravisht Iyer during operations on patients who had given informed consent. First author Dr. Lingling Hu, a postdoctoral fellow in Greenblatt's and Iyer's labs, confirmed that the human cells could both renew themselves and generate ligament cells.

The cells turned up well beyond the spine. "We looked in the kneecap ligament; we looked at the Achilles tendon; and everywhere we looked, we found this cell," Greenblatt said. "So, we think this is the universal stem cell for tendons and ligaments throughout the body."

A link to spinal stenosis

The researchers next asked whether these cells play a role in lumbar spinal stenosis, a condition affecting an estimated 103 million people worldwide. It develops when thickened ligaments narrow the space inside the spinal canal, putting pressure on nerves. Patients whose condition becomes severe often have few options beyond surgery to relieve the compression.

The comparison was direct. Ligaments from stenosis patients contained more of the newly identified stem cells than ligaments from people without the condition, taken from surgeries for herniated discs. When the researchers transplanted the stenosis patients' cells into mice, those cells produced more tendon cells than cells from people without stenosis.

"Though spinal stenosis is a complex condition, this really showed us that these cells are contributing to the pathology," said Greenblatt, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell.

Calcium signaling as a suspect

Looking inside the cells, the researchers found that stem cells associated with stenosis showed greater calcium signaling than healthy cells. Calcium signaling is one of the ways cells communicate internally and regulate processes such as growth and activity. To test cause rather than correlation, the scientists genetically increased calcium signaling in stem cells from healthy ligaments — and triggered excessive tissue growth.

The reverse experiment delivered the more clinically interesting result. When the researchers reduced calcium signaling in a mouse model of lumbar spinal stenosis, the abnormal cell growth was blocked.

"This is probably the first work that's shown a potential therapeutic target for one of the most common spine conditions in the world," said Iyer, an associate professor of orthopedics at Weill Cornell and a spine surgeon at Hospital for Special Surgery.

"Identifying these specialized stem cells unlocks a new area of research that allows us to address this disease much more mechanistically, rather than just waiting until a patient's condition worsens and requires surgery to relieve the nerve compression," Iyer said. "The findings are exciting for their potential to change the way we deliver spinal care."

What comes next

The implications may reach beyond the spine. Greenblatt plans to investigate whether the same stem cells are involved in other connective tissue conditions, including Marfan syndrome, a genetic disorder that affects connective tissues throughout the body. The discovery could also help researchers understand why some tendon and ligament injuries — rotator cuff tears, Achilles tendon injuries, ligament reconstruction, and chronic tendon degeneration — are so difficult to heal.

"Given that this cell appears to be the ultimate origin of all tendon and ligament cells, defects in this cell are likely at the heart of a wide range of tendon and ligament disorders," Greenblatt said.

The findings remain preliminary in key respects. The transplantation and calcium-signaling experiments were conducted in mice, and any drug-based approach for patients would need to clear clinical trials before it could reach the clinic. Still, for a condition long managed mainly by surgery, the work opens a mechanistic path that did not exist before.

The research was supported by, among others, the Marfan Foundation, the Children's Tumor Foundation, the Arthritis National Research Foundation, the National Institutes of Health, the Pershing Square Foundation, and a Burroughs Wellcome Career Award for Medical Scientists.