Newly identified stem cells help explain ligament overgrowth in lumbar spinal stenosis, with mouse experiments pointing to calcium signaling as a possible treatment target.
When ligaments in the lower back grow too thick, they can press on spinal nerves, causing pain, numbness, and difficulty walking. This narrowing of the spinal canal, called lumbar spinal stenosis, affects an estimated 103 million people worldwide. Researchers are now investigating whether controlling the cells that produce ligament tissue could help treat the condition before surgery becomes necessary.
A team at Weill Cornell Medicine and Hospital for Special Surgery has identified stem cells that generate tendons and ligaments. Tendons connect muscles to bones, while ligaments connect bones to one another. The researchers found that these stem cells become unusually numerous and active in spinal ligaments affected by stenosis. In mice, they also found a way to block the resulting tissue overgrowth.
The study, published in the journal Cell, points to a possible treatment strategy involving calcium signaling, a system cells use to control their activity.
“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,” said study co-corresponding author Dr. Sravisht Iyer, an associate professor of orthopedics at Weill Cornell and a spine surgeon at Hospital for Special Surgery (HSS). “The findings are exciting for their potential to change the way we deliver spinal care.”
Calcium signaling offers a treatment target
To investigate the cells’ involvement in stenosis, the team compared spinal ligament samples from patients with the condition against samples from patients who had herniated discs but no signs of stenosis. All patients provided informed consent before surgery.
Ligaments from patients with stenosis contained more of the stem cells. When transplanted into mice, those cells also produced more tendon cells than stem cells from ligaments without stenosis.
“Though spinal stenosis is a complex condition, this really showed us that these cells are contributing to the pathology,” said co-corresponding author Dr. Matthew Greenblatt, an associate professor of pathology and laboratory medicine at Weill Cornell and a pathologist at NewYork-Presbyterian/Weill Cornell Medical Center.
The researchers then examined what was different about the cells’ activity. Stem cells associated with stenosis had higher levels of calcium signaling than their healthy counterparts. Genetically increasing that signaling in stem cells from healthy ligaments triggered tissue overgrowth. Reducing it in a mouse model of lumbar spinal stenosis blocked cell overgrowth.
That result raises the possibility of repurposing calcium channel blockers, a class of drugs already used to treat high blood pressure. Clinical studies are still needed to determine whether these drugs could treat spinal stenosis.
“This is probably the first work that’s shown a potential therapeutic target for one of the most common spine conditions in the world,” Iyer said.
Ligament stem cells resemble their neighbors
Before the team could investigate this connection to disease, it had to establish which cells were responsible for making and maintaining tendons and ligaments. Greenblatt and his colleagues had previously identified several stem cell populations in bone. In 2018, they found a stem cell in the outer layer of bone that initiates fracture repair. Later work identified stem cells that form the skull and spine.
Tendons and ligaments presented a different challenge. Their cells look much alike, resembling fibroblasts, the cells that produce the supporting material in connective tissue. Appearance alone offered little help in distinguishing a stem cell from its neighbors.
“While previous studies had proposed several candidate stem cells, none had definitively shown that a single cell population could both self-renew and generate the full spectrum of tendon and ligament cell types,” said Greenblatt, the Rohr Family Research Scholar and a member of Weill Cornell’s Sandra and Edward Meyer Cancer Center.
“We analyzed thousands of individual cells and sorted them into individual cell types. Then we identified which one had the properties we associate with ‘stemness,’” Greenblatt said.
These cells could replenish their own population and produce the mature cells that build and maintain tendons and ligaments.
In mice, the researchers located this rare population in a distinct region within tendon and ligament tissue that acts as a reservoir for growth and repair. Characterizing those cells gave them a way to look for a human equivalent in ligament samples Iyer had removed during surgery with patients’ informed consent.
The team, including 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 produce ligament cells.
From spinal stenosis to tendon injuries
“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.”
That possible wider role gives researchers several other conditions to investigate. Greenblatt hopes to study whether the cells contribute to Marfan syndrome, a genetic disorder affecting connective tissue.
“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.
Reference: “Identification of the tendon/ligament stem cell in mice and humans” by Lingling Hu, Jun Sun, Kyle W. Morse, Seoyeon Bok, Yimin Zheng, Un In Chan, Han Choi, Eugenie Macfarlane, Alisha R. Yallowitz, Michelle Cung, Ting Cong, Peyton Lee Carpen, Federico La Manna, Shawon Debnath, Haiyin Li, Tim Xu, Lipeng Wang, Yangkang Zheng, Takeshi Hirose, Ryan N. Serio, Billy Lu, Ryan J. Chaffee, Armin Scheben, Ling J. Zheng, Jason McCormick, Daniel Shinn, Anthony Pajak, Kasra Araghi, Eric Zhao, Anna Yemelyanova, Chike Cao, Geoffrey S. Pitt, Scott A. Rodeo, Dawid G. Nowak, Sravisht Iyer and Matthew B. Greenblatt, 7 September 2026, Cell.
DOI: 10.1016/j.cell.2026.08.018
This work was supported in part by the Marfan Foundation’s Victor A. McKusick Fellowship, a Kellen Scholars Award, the Children’s Tumor Foundation (CTF-2023-01-005), the Arthritis National Research Foundation (1065843), a Jumpstart award from Weill Cornell, a National Research Foundation of Korea (NRF) award funded by the Ministry of Education (NRF-2021R1A6A3A14038667), the National Institutes of Health (grants T32-AR078751 and T32-AR071302-07), a MIND Prize from the Pershing Square Foundation, a Mary Kay Ash Foundation Award, an Innovator Award from the Marfan Foundation and a Burroughs Wellcome Career Award for Medical Scientists.
Never miss a breakthrough: Join the SciTechDaily newsletter.
Follow us on Google and Google News.