Researchers at Weill Cornell Medicine and Hospital for Special Surgery have identified a previously elusive population of stem cells that appears to produce the body’s tendons and ligaments, the connective tissues that join muscles and bones.
Scientists also found evidence that these cells can become overactive in the lower spine, where they may contribute to lumbar spinal stenosis. The condition affects approximately 103 million people worldwide and develops when thickened ligaments reduce the space within the spinal canal. This narrowing can put pressure on the nerves and cause pain, numbness, and difficulty walking.
The study, published September 7 in Cellraises the possibility that targeting these stem cells could eventually lead to new treatments for spinal stenosis. One possible approach could involve medications already used to control high blood pressure.
“While previous studies have proposed several candidate stem cells, none have definitively demonstrated that a single population of cells can self-renew and generate the full spectrum of tendon and ligament cell types,” said co-corresponding author Dr. Matthew Greenblatt, a Rohr Family Research Scholar, associate professor of pathology and laboratory medicine at Weill Cornell and pathologist at NewYork-Presbyterian/Weill Cornell Medical Center.
After identifying the cells, the team investigated whether they could offer clues to treating lumbar spinal stenosis, particularly for patients who currently have few options other than surgery once the condition becomes severe.
“The identification of these specialized stem cells opens up a new area of research that allows us to approach this disease much more mechanistically, rather than simply waiting until the patient’s condition worsens and requires surgery to relieve nerve compression,” said study co-corresponding author Dr. Sravisht Iyer, associate professor of orthopedics at Weill Cornell and spine surgeon at the Hospital for Special Surgery (HSS). “The findings are exciting because of their potential to change the way we provide spine care.”
Finding the stem cells that form tendons and ligaments
Dr. Greenblatt and his colleagues had previously tracked several important populations of skeletal stem cells. In 2018, the group identified the stem cell that initiates fracture repair in the outer layer of bone. They later discovered stem cells involved in the formation of the skull and spine.
Finding an equivalent cell for tendons and ligaments proved more difficult. Unlike bone, these tissues contain many fibroblast-like cells that look similar, making it difficult to distinguish one population of cells from another.
“We analyzed thousands of individual cells and classified them into individual cell types. We then identified which ones had the properties we associate with ‘stemness,'” Dr. Greenblatt said.
In this case, “stem” refers to the ability of a population of rare cells to continually renew itself while producing the mature cells necessary to form and maintain tendon and ligament tissue. In mice, the researchers found that these cells live in a specialized region within tendons and ligaments that appears to act as a reservoir for tissue growth and repair.
The team then used what they had learned from the mice to look for similar cells in people. The human ligament samples came from tissue removed by Dr. Iyer during surgery from patients who had given informed consent.
The researchers, including first author Dr. Lingling Hu, a postdoctoral fellow in the laboratories of Dr. Greenblatt and Dr. Iyer, confirmed that human cells could renew themselves and generate ligament cells.
The cells also seemed to exist far beyond the column.
“We looked at the patella ligament; we looked at the Achilles tendon; and everywhere we looked, we found this cell,” Dr. Greenblatt said. “Therefore, we believe that this is the universal stem cell for tendons and ligaments throughout the body.”
How stem cells may contribute to spinal stenosis
The researchers next examined whether these cells could be involved in lumbar spinal stenosis.
They compared stem cells taken from patients with spinal stenosis with cells taken from spinal ligaments taken from people who had herniated discs but showed no signs of stenosis. Patients gave informed consent before surgery.
The ligaments of people with stenosis contained more of the newly identified stem cells. When the researchers transplanted those cells into mice, they produced more tendon cells than stem cells taken from people without stenosis.
“Although spinal stenosis is a complex condition, this really showed us that these cells contribute to the pathology,” said Dr. Greenblatt, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell.
The researchers then took a closer look at what was happening inside the cells. Stem cells associated with stenosis showed greater calcium signaling than healthy cells.
Calcium signaling is one of the ways cells communicate internally and control processes such as growth and activity. When scientists genetically increased calcium signaling in healthy ligament stem cells, they were able to trigger excessive tissue growth.
A possible drug target for spinal stenosis
The opposite effect was also important. When researchers reduced calcium signaling in a mouse model of lumbar spinal stenosis, abnormal cell growth was blocked.
That finding suggests that calcium signaling could become a therapeutic target. It also raises the possibility that calcium channel blockers, a class of drugs already widely used to treat high blood pressure, could one day be studied as a treatment for spinal stenosis. Clinical trials will be needed before researchers can determine whether this approach is safe or effective in patients.
“This is probably the first work to show a potential therapeutic target for one of the most common spinal conditions in the world,” Dr. Iyer said.
The implications may extend beyond spinal stenosis. Dr. 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 better understand why some tendon and ligament injuries are so difficult to heal. Potential areas of future study include rotator cuff tears, Achilles tendon injuries, ligament reconstruction, and chronic tendon degeneration.
“Since this cell appears to be the ultimate origin of all tendon and ligament cells, it is likely that defects in this cell are at the heart of a wide range of tendon and ligament disorders,” Dr. Greenblatt said.
This work was supported in part by the Victor A. McKusick Fellowship from the Marfan Foundation, a Kellen Scholars Award, the Children’s Tumor Foundation (CTF-2023-01-005), the Arthritis National Research Foundation (1065843), a Weill Cornell Jumpstart Award, 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 Pershing Square Foundation MIND Award, a Mary Kay Ash Foundation Award, a Marfan Foundation Innovation Award, and a Burroughs Wellcome Career Award for Medical Scientists.