The study, published Sept. 7 in Cell, suggests that therapeutics targeting these stem cells may lead to new treatment options for patients, including a class of drugs currently used to manage high blood pressure.

“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 co-corresponding author Dr. Matthew Greenblatt, the Rohr Family Research Scholar, associate professor of pathology and laboratory medicine at Weill Cornell and a pathologist at NewYork-Presbyterian/Weill Cornell Medical Center.

Once the researchers had identified the elusive stem cells, they explored whether the findings could address an unmet clinical need for alternatives to surgery to treat lumbar spinal stenosis.

“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.”

Search for a Master Tendon and Ligament Stem Cell

Dr. Greenblatt was well equipped to lead the search. In 2018, he and his colleagues located the stem cell that initiates fracture repair in the outer layer of bone. They went on to identify the stem cells that form the skull and spine.

Unlike bone, however, tendons and ligaments are relatively uniform tissues with fibroblast-like cells that are difficult to distinguish from one another. As a result, finding a bona fide tendon and ligament stem-cell population was a challenge.

“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,’” said Dr. Greenblatt. In other words, the rare cell population able to continually replenish itself and produce the mature cells needed to build and maintain these tissues. Studying mice, the researchers located the stem cells in a specialized anatomical niche within tendon and ligament tissue that serves as a reservoir for growth and repair.

Characterizing the mouse stem cell helped the researchers locate a human equivalent in ligament samples that Dr. Iyer had removed from patients during surgery with informed consent. The team—which included first author Dr. Lingling Hu, a postdoctoral fellow in Dr. Greenblatt’s and Dr. Iyer’s labs—confirmed that the human stem cells could both self-renew and produce ligament cells, demonstrating clinical relevance.

Furthermore, they determined that these stem cells are not relegated only to the spine. “We looked in the kneecap ligament; we looked at the Achilles tendon; and everywhere we looked, we found this cell,” said Dr. Greenblatt. “So, we think this is the universal stem cell for tendons and ligaments throughout the body.”

Potential Therapeutic Target for Spinal Stenosis

To find out if these cells are the culprits behind lumbar spinal stenosis, the researchers compared stem cells harvested from individuals with lumbar spinal stenosis to those isolated from spinal ligaments removed from people with herniated discs and no signs of stenosis. The patients provided informed consent pre-operatively.

The researchers detected higher stem cell numbers in the ligaments taken from people with stenosis. When these stenosis-derived cells were transplanted into mice, they produced more tendon cells than healthy stem cells did. “Though spinal stenosis is a complex condition, this really showed us that these cells are contributing to the pathology,” said Dr. Greenblatt, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell.

On a molecular level, the stenosis-associated stem cells showed higher levels of calcium signaling than their healthy counterparts. In fact, the researchers could trigger tissue overgrowth by increasing calcium signaling in stem cells from healthy ligaments using genetic manipulation.

Just as important, the team showed that curtailing calcium signaling blocked cell overgrowth in a mouse model of lumbar spinal stenosis. This may indicate that calcium channel blockers currently used to treat high blood pressure could be repurposed to treat spinal stenosis, but clinical studies will be needed to explore this direction.

“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 Dr. Iyer.

Beyond lumbar spinal stenosis, Dr. Greenblatt hopes to explore the role that these stem cells might play in other conditions, such as Marfan syndrome, a genetic disorder that affects the body’s connective tissues.

These findings could also eventually help researchers find treatments for tendons and ligaments that heal poorly after injuries, including rotator cuff tears, Achilles tendon injuries, ligament reconstruction and chronic tendon degeneration.

“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,” said Dr. Greenblatt.

For a long time, physicians believed all bones formed in the same way – through a universal process of ossification. However, this study, led by primary investigator Matthew Greenblatt, MD, PhD, associate professor of pathology and laboratory medicine at Weill Cornell Medicine and assistant scientist in the HSS research division, alongside clinical collaborator Sravisht Iyer MD, spine surgeon at HSS, illuminated that certain vertebral skeletal stem cells play a unique and formative role in the development and life cycle of spinal vertebrae. Specifically, the investigators identified a stem cell that is responsible for bone formation in the vertebrae. Their research was made possible by support from a Pershing Square Foundation Cancer Research Prize and a special program established by the Anna-Maria and Stephen Kellen Foundation and Marina Kellen French, Vice President of the Foundation and an HSS trustee, that provides support for clinicians pursuing research as a significant component of their careers.

This significant finding carries profound implications for the field of spine health, including spinal healing, degeneration, treatment approaches, comprehension of degenerative spine disorders – and the potential to lead to breakthroughs in the prevention and treatment of vertebral osteoporosis and cancer metastasis.

“Understanding how vertebrae develop will help us more effectively treat patients, screen them before surgical intervention, and will ultimately lead to more effective preventive care and optimized bone health,” said Dr. Iyer. “The identification of this unique stem cell in the spine has the potential to significantly enhance our patients' outcomes in spine fusion surgery–a procedure performed hundreds of thousands of times in the United States each year–because it may allow for us to screen for problems ahead of time,” he continued. “The findings may also advance care for people with osteoporosis and, specifically, the 30 to 50 percent of the global population who suffer a vertebral fracture at some point in their lives.”

By manipulating bone-like “organoids” made from vertebral stem cells, this study also explored the disparities in metastasis rates between spinal bones and long bones, which include bones of the thigh, leg, arm and forearm. "Traditionally, it was believed that cancer cells were attracted to the spine due to directed blood flow. However, our discovery of this vertebral stem cell provides a likely explanation of why some cancers most often spread to the spine,” stated Dr. Greenblatt. “We predict this discovery will lead to the targeting of these cells to disrupt the function and ultimately reduce the spread of cancer to the spine."

The research team for this study included Jun Sun, PhD, first author and a postdoctoral associate at Weill Cornell; Kyle Morse, MD, an orthopedic surgery resident at HSS; and Lingling Hu, PhD, researcher at HSS, and has implications extending far beyond the laboratory and has the potential to impact patient care worldwide. Armed with insights into spine development and evolution, physicians will be able to tailor treatments and surgical intervention with more precision, with hope for improved patient outcomes across the board.

What follows are some highlights from the meeting:

Intravenous versus Oral Administration of Acetaminophen Perioperative to Instrumented Lumbar Fusion: A Single-Center, Randomized Controlled Trial

In patients undergoing certain orthopedic surgeries, giving intravenous (IV) acetaminophen for pain relief has been shown to have fewer side effects and potentially lower risk than opioids but is associated with higher costs than oral acetaminophen. In this single-center, randomized controlled trial, investigators led by Darren R. Lebl, MD, MBA, and Celeste Abjornson, PhD, prospectively evaluated clinical outcomes of IV versus oral acetaminophen after circumferential lumbar fusion. One hundred patients between the ages of 18-85 were randomly assigned to one of the two groups (50 in each) and were included in the study. There was a specific dosing regimen that started within the three hours prior to surgery and continued for the next 48 hours. Patients were able to access supplemental opioid analgesics as needed. The researchers found that morphine consumption was significantly lower for the IV acetaminophen group compared with the oral acetaminophen group within the first 48 hours post-operatively. The average daily morphine usage after 48 hours for those who received the IV acetaminophen regimen was also significantly lower. The research suggests that IV acetaminophen is a safe and effective supplement to opioid-based pain management after surgery, and that it provides a promising option for pain control.

Authors: Gregory Paschal; Fedan Avrumova; Philip Paschal; Ellen M. Soffin, MD, PhD; Joseph Nguyen; Federico P. Girardi, MD; Andrew A. Sama, MD; Frank P. Cammisa Jr., MD; Darren R. Lebl, MD, MBA; Celeste Abjornson, PhD, (HSS)

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Racial Disparities in Outpatient Anterior Cervical Discectomy and Fusion and Cervical Disc Replacement

Recent reports have suggested disparities within cervical spine surgery, including lower utilization rates and worse perioperative outcomes for Black patients. In this retrospective cohort study, a team led by HSS resident Troy B. Amen sought to assess whether these disparities also exist for outpatient cervical spine surgery. Using data collected by the American College of Surgeons National Surgical Quality Improvement Program between 2010 and 2019, the team looked at patients who underwent primary anterior cervical discectomy and fusion (ACDF) or cervical disc replacement (CDR) and stratified them by race and ethnicity. They categorized procedures as inpatient or outpatient based on length of stay. They found that, overall, Black patients were significantly less likely to undergo ACDF (5.9%, vs. 10.6% of white patients) as well as CDR (19.9%, vs. 26.1% of white patients) as outpatients. Between 2010 and 2019, these disparities increased, even when adjusting for other factors. The findings highlight the need for renewed intervention by orthopedic surgeons and policymakers to address inequalities in outpatient care.

Authors: Troy B. Amen; Patawut Bovonratwet, (HSS); Samuel S. Rudisill (Rush Medical College); Lauren Barber; Yusef Jordan, (HSS); Abhinaba Chatterjee (Weill Cornell Medicine); Jung Kee Mok (UNC Chapel Hill); Nathan Varady; Sheeraz Qureshi, MD, MBA (HSS)

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Improving Racial and Ethnic Disparities in Ambulatory Surgical Center Utilization for Anterior Cervical Discectomy and Fusion

Although racial and ethnic disparities within the field of spine surgery have been documented, the link between the recent emergence of ambulatory surgical centers and access to these procedures in the outpatient setting isn’t known. A study led by HSS resident Troy B. Amen sought to assess disparities in the use of these outpatient surgical centers among white, Black, and Hispanic patients having spine surgery. The investigators also looked at how racial differences have changed between 2015 and 2018. Using data from the Healthcare Cost and Utilization Project New York State Ambulatory Database, the researchers looked at differences in same-day discharges in patients having anterior cervical discectomy and fusion (ACDF). They found that during this time, Black and Hispanic patients were significantly less likely to undergo ACDF surgery at an ambulatory center compared with white patients, but that these disparities lessened over time. They note that these improvements are encouraging and may help counteract previously documented disparities in spine surgery in the inpatient setting, although additional research is needed to confirm that.

Authors: Troy B. Amen, (HSS); Abhinaba Chatterjee (Weill Cornell Medicine); Sheeraz Qureshi, MD, MBA (HSS)

Predictors of Non-improvement After Minimally Invasive Lumbar Spine Surgery

Minimally invasive surgery of the lumbar spine is associated with good clinical outcomes, but a small number of patients may not improve, or may even worsen, after this surgery. A study led by HSS research fellow Junho Song sought to identify predictors of patients who are not likely to improve. The study included 448 patients who underwent minimally invasive transforaminal interbody fusion, laminectomy, or microdiscectomy at HSS between 2017 and 2021. At follow-up of at least six months after surgery, the patients were categorized as better, the same, or worse. A total of 66 patients reported no significant improvement; among these, 35 patients reported worsening after surgery, and the rest reported no change. Patients who did not fare as well were more likely to be older or obese. The researchers found that smoking was also a factor for those who didn’t do as well, likely due to changes in metabolic systems and local vasculature caused by tobacco use. The investigators say these findings provide valuable evidence that may be useful for improving the selection of patients to undergo minimally invasive spine surgery. They may also help to establish clearer patient expectations for those undergoing this procedure.

Authors: Junho Song; Pratyush Shahi; Kasra Araghi; Robert Kamil; Dimitra Melissaridou; Sidhant Singh Dalal (University of Arkansas for Medical Sciences); Daniel Shinn; Sheeraz Qureshi, MD, MBA; Sravisht Iyer, MD (HSS)

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Robotics Reduces Radiation Exposure in Minimally Invasive Lumbar Fusion Compared to Navigation

For minimally invasive spine surgery, navigation and robotics technologies have helped reduce surgeons’ exposure to ionizing radiation. Studies have compared radiation exposure during surgery using robotics or navigation to procedures using traditional fluoroscopy, but none have compared robotics and navigation to each other. This study compared the two techniques in terms of fluoroscopy time and radiation dose for minimally invasive transforaminal lumbar interbody fusion (MI-TLIF). The study included 111 patients in the robotics cohort and 133 patients in the navigation cohort. The investigators, led by HSS research fellow Pratyush Shahi, found that for both one- and two-level TLIFs, the fluoroscopy time for surgical procedure, total fluoroscopy time, and total radiation dose were significantly less with robotics compared to navigation. For one-level TLIFs, the overall time of radiation exposure was also lower.  Overall, time in the operating room was similar, with robotic procedures lasting longer but requiring less time for setup and image capture. Based on these findings, the investigators say robotic surgery leads to a significant reduction in radiation exposure both for the surgeon and the patient compared to navigation, but multicenter prospective trials are needed to confirm these findings.

Authors: Pratyush Shahi, Sidhant Singh Dalal (University of Arkansas for Medical Sciences); Junho Song; Daniel Shinn; Robert Kamil; Kasra Araghi; Sheeraz Qureshi, MD, MBA (HSS)